Multiple myeloma

Section editor
	Andrew J. Cowan, MD Seattle, WA LinkedIn

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Guidelines

ASCO

• 2018: Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology Clinical Practice Guideline update PubMed

BSH/UKMF

• 2017: Guidelines for the use of imaging in the management of patients with myeloma PubMed
• 2017: Guidelines for screening and management of late and long-term consequences of myeloma and its treatment PubMed
• 2014: Updates to the guidelines for the diagnosis and management of multiple myeloma PubMed

European Myeloma Network (EMN)

• 2018: From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives

ESMO

• 2017: Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

IMWG

• 2016: Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group
• 2016: International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment PubMed
• 2014: International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation
• 2013: International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease

NCCN

• NCCN Guidelines - Multiple Myeloma

First-line therapy (including transplant ineligible), randomized data

Note: most but not all multiple myeloma first-line regimens specify whether patients are transplant eligible, or not. The top-line inclusion criteria from each prospectively enrolling regimen are reported.

Bortezomib & Dexamethasone

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BD: Bortezomib, Dexamethasone
Bd: Bortezomib, low-dose dexamethasone
Bort-Dex: Bortezomib, Dexamethasone
Vd: Velcade (Bortezomib), low-dose dexamethasone
VD: Velcade (Bortezomib), Dexamethasone

Variant #1

Study	Evidence	Comparator	Efficacy
Niesvizky et al. 2015 (UPFRONT)	Phase III	VMP	Seems not superior
		VTD	Seems not superior

This regimen was meant for transplant ineligible patients.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 5 to 8: 20 mg PO once per day on days 1, 2, 4, 5

21-day cycle for 8 cycles

Treatment followed by bortezomib maintenance.

Variant #2

Study	Evidence	Comparator	Efficacy
Moreau et al. 2011 (IFM 2007-02)	Phase III	vtD	Inferior VGPR rate

This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 2: 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
  • Cycles 3 & 4: 40 mg (route not specified) once per day on days 1 to 4

21-day cycle for 4 cycles

All patients then underwent high dose melphalan, then autologous hematopoietic cell transplant.

Variant #3

Study	Evidence	Comparator	Efficacy
Harousseau et al. 2010 (IFM 2005-01)	Phase III	VAD	Might have superior PFS

This regimen was intended for patients age less than or equal to 65 years with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 h).

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12
  • Cycles 3 & 4: 40 mg PO once per day on days 1 to 4

Supportive medications

• One of the following bisphosphonates recommended:
  • Pamidronate (Aredia) 90 mg IV once every 4 weeks until first transplant
  • Zoledronic acid (Zometa) 4 mg IV once every 4 weeks until first transplant
• "Antibiotics, antifungal agents, and antiviral prophylaxis in accordance with local practice."

21-day cycle for 4 cycles

Patients were then randomized to DCEP consolidation or went directly to autologous hematopoietic cell transplant.

Variant #4, weekly bortezomib

Study	Evidence
Girnius et al. 2014	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.6 mg/m² IV once per week on days 1, 8, 15, 22
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

35-day cycle for up to 6 cycles based on response and tolerance of side effects

References

1. IFM 2005-01: Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010 Oct 20;28(30):4621-9. Epub 2010 Sep 7. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, Marit G, Benboubker L, Voillat L, Mathiot C, Kolb B, Macro M, Campion L, Wetterwald M, Stoppa AM, Hulin C, Facon T, Attal M, Minvielle S, Harousseau JL. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010 Oct 20;28(30):4630-4. Epub 2010 Jul 19. link to original article PubMed
2. Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. link to original article contains verified protocol PubMed
3. Girnius SK, Lee S, Kambhampati S, Rose MG, Mohiuddin A, Houranieh A, Zimelman A, Grady T, Mehta P, Behler C, Hayes TG, Efebera YA, Prabhala RH, Han A, Yellapragada SV, Klein CE, Roodman GD, Lichtenstein A, Munshi NC. A Phase II trial of weekly bortezomib and dexamethasone in veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell transplantation. Br J Haematol. 2015 Apr;169(1):36-43. Epub 2015 Jan 8. Epub 2014 Sep 18. link to original article contains verified protocol PubMed
4. UPFRONT: Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed

CPR

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CPR: Cyclophosphamide, Prednisone, Revlimid (Lenalidomide)

Regimen

Study	Evidence	Comparator	Efficacy
Magarotto et al. 2016 (EMN01)	Phase III	MPR	Might have inferior PFS
		Rd	Seems not superior

This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This is the dosing used after a mid-protocol amendment.

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day on days 1 to 21
• Prednisone (Sterapred) 25 mg PO once every other day
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

Supportive medications

• Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)

28-day cycle for 9 cycles

Patients were then randomized to lenalidomide maintenance versus lenalidomide & prednisone maintenance.

References

1. Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed

CTD

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CTD: Cyclophosphamide, Thalidomide, Dexamethasone
CTDa: Cyclophosphamide, Thalidomide, Dexamethasone, attenuated

Variant #1, CTD

Study	Evidence	Comparator	Efficacy
Morgan et al. 2011 (MRC Myeloma IX)	Phase III	CVAD	Not reported

This is an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference.

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg PO once per week
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21, increasing to 200 mg PO once per day "if tolerated"
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 12 to 15

Supportive medications

• Venous thromboembolism (VTE) prophylaxis was given at physician discretion, but it was suggested that low-risk patients receive Aspirin and high-risk patients receive Warfarin (Coumadin) or low molecular weight heparin according to risk categories as described by Palumbo A et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414–23. link to original article PubMed
• Patients in the study were randomized to one of the following until progression:
  • Sodium clodronate (Bonefos) 1600 mg PO once per day
  • Zoledronic acid (Zometa) 4 mg IV once every 21 to 28 days

21-day cycle for 4 to 6 cycles until maximum response

All responding patients proceeded to high-dose melphalan and autologous hematopoietic cell transplant.

Variant #2, CTDa

Study	Evidence	Comparator	Efficacy
Morgan et al. 2011 (MRC Myeloma IX)	Phase III	MP	Not reported

This is a nonintensive treatment pathway, as determined by performance status, informed discussion, and patient preference.

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg PO once per week
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 28; dose is increased every 4 weeks in 50 mg increments, up to a maximum dose of 200 mg PO once per day
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 15 to 18

Supportive medications

• For the first 12 weeks of treatment, thromboprophylaxis--for example, with Warfarin (Coumadin) or low molecular weight heparin--was recommended
• Patients in the study were randomized to a bisphosphonate and received one of the following until progression:
  • Sodium clodronate (Bonefos) 1600 mg PO once per day
  • Zoledronic acid (Zometa) 4 mg IV once every 21 to 28 days

28-day cycle for 6 to 9 cycles

Patients were then randomized to thalidomide maintenance versus no further treatment.

References

1. Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article contains verified protocol PubMed
   1. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. contains verified protocol link to PMC article PubMed
   2. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed

CVAD

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CVAD: Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Morgan et al. 2011 (MRC Myeloma IX)	Phase III	CTD	Not reported

This is an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference.

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
• Vincristine (Oncovin) 0.4 mg/day IV continuous infusion on days 1 to 4 (total dose per cycle: 1.6 mg)
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion on days 1 to 4 (total dose per cycle: 36 mg/m²)
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 12 to 15

Supportive medications

• Patients in the study were randomized to a bisphosphonate and received one of the following until progression:
  • Sodium clodronate (Bonefos) 1600 mg PO once per day
  • Zoledronic acid (Zometa) 4 mg IV once every 21 to 28 days

21-day cycle for 4 to 6 cycles until maximum response

All responding patients proceeded to high-dose melphalan and autologous hematopoietic cell transplant.

References

1. Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article contains verified protocol PubMed
   1. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. contains protocol link to PMC article PubMed
   2. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed

D-VMP

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D-VMP: Daratumumab, Velcade (Bortezomib), Melphalan, Prednisone

Regimen

Study	Evidence	Comparator	Efficacy
Mateos et al. 2017 (ALCYONE)	Phase III (E)	VMP	Superior PFS

This regimen was intended for patients with newly diagnosed, documented multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older. Note that dexamethasone is substitute for prednisone on day 1.

Chemotherapy

• Daratumumab (Darzalex) as follows:
  • Cycle 1: 16 mg/kg IV once per day on days 1, 8, 15, 22, 29, 36
  • Cycles 2 to 9: 16 mg/kg IV once per day on days 1 & 22
• Bortezomib (Velcade) as follows:
  • Cycle 1: 1.3 mg/m² SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
  • Cycles 2 to 9: 1.3 mg/m² SC once per day on days 1, 8, 22, 29
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 2 to 4

Supportive medications

• Dexamethasone (Decadron) 20 mg PO/IV once prior to each dose of Daratumumab (Darzalex)

42-day cycle for 9 cycles

Subsequent treatment

• Daratumumab maintenance

References

1. ALCYONE: Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. link to original article contains verified protocol PubMed

MPR

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MPR: Melphalan, Prednisone, Revlimid (Lenalidomide)
MPL: Melphalan, Prednisone, Lenalidomide

Variant #1, 0.13/1.5/10

Study	Evidence	Comparator	Efficacy
Magarotto et al. 2016 (EMN01)	Phase III	CPR	Might have superior PFS
		Rd	Might have superior PFS

This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant was intended for patients older than 75.

Chemotherapy

• Melphalan (Alkeran) 0.13 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 1.5 mg/kg PO once per day on days 1 to 4
• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

Supportive medications

• Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)

28-day cycle for 9 cycles

Subsequent treatment

• Lenalidomide versus Lenalidomide & Prednisone maintenance

Variant #2, 0.18/1.5/10

Study	Evidence	Comparator	Efficacy
Magarotto et al. 2016 (EMN01)	Phase III	CPR	Might have superior PFS
		Rd	Might have superior PFS

This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant was intended for patients aged 65 to 75.

Chemotherapy

• Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 1.5 mg/kg PO once per day on days 1 to 4
• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

Supportive medications

• Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)

28-day cycle for 9 cycles

Subsequent treatment

• Lenalidomide versus Lenalidomide & Prednisone maintenance

Variant #3, 0.18/2/10

Study	Evidence	Comparator	Efficacy
Palumbo et al. 2007	Phase II
Palumbo et al. 2012 (MM-015)	Phase III	MP	Superior PFS
		MPR	Superior PFS
Zweegman et al. 2016 (HOVON87/NMSG18)	Phase III	MPT-T	Seems not superior

In Palumbo et al. 2007 this regimen was intended for newly diagnosed multiple myeloma patients greater than or equal to 65 years, or younger if ineligible for high-dose therapy. In MM-015 this regimen was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were not candidates for transplantation (greater than or equal to 65 years of age). In HOVON87/NMSG18 this regimen was intended for patients greater than 65 years of age or patients less than or equal to 65 of age and not eligible for high-dose chemotherapy and peripheral stem cell transplantation with newly diagnosed symptomatic MM.

Chemotherapy

• Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

Supportive medications

• HOVON87/NMSG18:
  • Aspirin 75 or 80 mg PO once per day or Carbasalate calcium (Ascal) 100 mg PO once per day
    • Patients with a history of VTE received LMWH instead
  • Bisphosphonates at physician discretion
  • Prophylactic antibiotics at physician discretion
• MM-015: Aspirin 75 to 100 mg PO once per day as thromboprophylaxis
• Palumbo et al. 2007: Ciprofloxacin (Cipro) 500 mg PO BID and Aspirin 100 mg PO once per day

28-day cycle for 9 cycles

Subsequent treatment

• Lenalidomide maintenance

Variant #4, 5/100/10

Study	Evidence	Comparator	Efficacy
Stewart et al. 2015 (ECOG E1A06)	Phase III	MPT-T	Seems to have non-inferior PFS

This regimen was intended for patients who were greater than or equal to 65 years or were less than 65 years and were not candidates for autologous hematopoietic cell transplantation or had declined transplant.

Chemotherapy

• Melphalan (Alkeran) 5 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 4
• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

Supportive medications

• Aspirin was required (dose not specified)
  • Full anticoagulation was used for patients at "higher risk" for DVT
• Pamidronate (Aredia) 90 mg IV once per month recommended for patients with "active bone disease"

28-day cycle for 12 cycles

Subsequent treatment

• Lenalidomide maintenance

References

1. Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, Crippa C, Ciccone G, Omedè P, Ambrosini MT, Gay F, Bringhen S, Musto P, Foà R, Knight R, Zeldis JB, Boccadoro M, Petrucci MT; GIMEMA--Italian Multiple Myeloma Network. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. J Clin Oncol. 2007 Oct 1;25(28):4459-65. Epub 2007 Sep 4. link to original article contains verified protocol PubMed
2. MM-015: Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. link to original article contains verified protocol PubMed
3. ECOG E1A06: Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article contains verified protocol link to PMC article PubMed
4. EMN01: Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed
5. HOVON87/NMSG18: Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article contains verified protocol PubMed

MPT

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MPT: Melphalan, Prednisone, Thalidomide

Variant #1, "MPT-T"

Study	Evidence	Comparator	Efficacy
Zweegman et al. 2016 (HOVON87/NMSG18)	Phase III	MPR-R	Seems not superior

This regimen was intended for patients greater than 65 years of age or patients less than or equal to 65 of age and not eligible for high-dose chemotherapy and peripheral stem cell transplantation with newly diagnosed symptomatic MM.

Chemotherapy

• Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
• Thalidomide (Thalomid) 200 mg PO once per day

Supportive medications

• Aspirin 75 or 80 mg PO once per day or carbasalate calcium 100 mg PO once per day
  • Patients with a history of VTE received LMWH instead
• Bisphosphonates at physician discretion
• Prophylactic antibiotics at physician discretion

28-day cycle for 9 cycles

Treatment followed by thalidomide maintenance.

Variant #2, "MPT-T"

Study	Evidence	Comparator	Efficacy
Stewart et al. 2015 (ECOG E1A06)	Phase III	mPR-R	Seems to have non-inferior PFS

This regimen was intended for patients who were greater than or equal to 65 years or were less than 65 years and were not candidates for autologous hematopoietic cell transplantation or had declined transplant.

Chemotherapy

• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 4
• Thalidomide (Thalomid) 100 mg PO once per day

Supportive medications

• Aspirin was required (dose not specified)
  • Full anticoagulation was used for patients at "higher risk" for DVT
• Pamidronate (Aredia) 90 mg IV once per month recommended for patients with "active bone disease"

28-day cycle for 12 cycles

Treatment followed by thalidomide maintenance.

Variant #3

Study	Evidence	Comparator	Efficacy
Benboubker et al. 2014 (FIRST)	Phase III	Rd	Inferior OS (*)
		Rd18	Might have inferior OS

This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. Efficacy compared to Rd continuous is based on the 2017 update.

Chemotherapy

• Melphalan (Alkeran) starting dose as follows:
  • Age up to 75 years AND ANC at least 1500/uL AND platelets at least 100 x 10⁹/L: 0.25 mg/kg PO once per day on days 1 to 4
  • Older than 75 years AND ANC at least 1500/uL AND platelets at least 100 x 10⁹/L: 0.2 mg/kg PO once per day on days 1 to 4
  • Age up to 75 years AND ANC less than 1500/uL but greater than or equal to 1000/uL OR platelets less than 100 x 10⁹/L but greater than or equal to 50 x 10⁹/L: 0.125 mg/kg PO once per day on days 1 to 4
  • Older than 75 years AND ANC less than 1500/uL but greater than or equal to 1000/uL OR platelets less than 100 x 10⁹/L but greater than or equal to 50 x 10⁹/L: 0.1 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
• Thalidomide (Thalomid) starting dose as follows:
  • Age up to 75 years: 200 mg PO once per day
  • Older than 75 years: 100 mg PO once per day

42-day cycle for 12 cycles

Variant #4

Study	Evidence	Comparator	Efficacy
Beksac et al. 2010 (TMSG-2005-001)	Phase III	MPT	Seems to have superior ORR

This regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions.

Chemotherapy

• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4
• Thalidomide (Thalomid) 100 mg PO once per day

42-day cycle for 9 cycles

Variant #5

Study	Evidence	Comparator	Efficacy
Waage et al. 2010 (NMSG #12)	Phase III	MPT	Seems not superior

This regimen was intended for patients with previously untreated symptomatic MM, who were not eligible for high-dose treatment with autologous stem cell support.

Chemotherapy

• Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 4
• Thalidomide (Thalomid) as follows:
  • Cycle 1: 200 mg PO once per day for one week, then increased to 400 mg PO once per day
  • Cycle 2 onwards: 400 mg PO once per day

42-day cycles

Treatment was continued until plateau phase, at which point the patients proceeded to maintenance thalidomide.

Variant #6, "MP-T"

Study	Evidence	Comparator	Efficacy
Wijermans et al. 2010 (HOVON 49)	Phase III	MP	Might have superior OS

This regimen was intended for patients with previously untreated MM older than age 65 years.

Chemotherapy

• Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 5
• Prednisone (Sterapred) 1 mg/kg PO once per day on days 1 to 5
• Thalidomide (Thalomid) 200 mg PO once per day

Supportive medications

• Bisphosphonate use recommended with Pamidronate (Aredia) or Clodronate (Bonefos); "a maximum treatment period of 2 years was recommended in patients without active disease."
• During induction therapy, low molecular weight heparin use recommended with Nadroparin (Fraxiparine) 2,850 units anti-Xa (for patients greater than 90 kg, dose of 5,700 units anti-Xa)

28-day cycle for 8 cycles

Thalidomide continues at 200 mg PO once per day for 28 days, followed by maintenance thalidomide.

Variant #7

Study	Evidence	Comparator	Efficacy
Hulin et al. 2009 (IFM 01/01)	Phase III	MP	Seems to have superior OS

This regimen was intended for patients who had stage II or III newly diagnosed multiple myeloma according to the Durie-Salmon criteria and were at least 75 years of age. Certain stage I patients were allowed; see text for details.

Chemotherapy

• Melphalan (Alkeran) 0.2 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
• Thalidomide (Thalomid) 100 mg PO once per day

42-day cycle for 12 cycles

Variant #8

Study	Evidence	Comparator	Efficacy
Facon et al. 2007 (IFM 99-06)	Phase III	MP	Superior OS
		MEL100	Seems to have superior OS

This regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 75 years.

Chemotherapy

• Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
• Thalidomide (Thalomid) 200 mg PO once per day, increased as tolerated after 4 weeks on therapy to maximum dose of 400 mg once per day

42-day cycle for 12 cycles

Variant #9

Study	Evidence	Comparator	Efficacy
Palumbo et al. 2006	Phase III	MP	Seems to have superior PFS

This regimen was intended for patients with newly diagnosed multiple myeloma aged 60 to 85 years.

Chemotherapy

• Melphalan (Alkeran) 4 mg/m² PO once per day on days 1 to 7
• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 7
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 28

Supportive medications

• Enoxaparin (Lovenox) 40 mg SC once per day on days 1 to 28 of cycles 1 to 4

28-day cycle for 6 cycles

Patients then proceeded to maintenance thalidomide.

References

1. Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network (GIMEMA). Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31. link to original article contains protocol PubMed
   1. Update: Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14. Epub 2008 May 27. link to original article contains protocol PubMed
2. IFM 99-06: Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, Doyen C, Kolb B, Anglaret B, Grosbois B, Yakoub-Agha I, Mathiot C, Avet-Loiseau H; Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007 Oct 6;370(9594):1209-18. link to original article contains verified protocol PubMed content property of HemOnc.org
3. IFM 01/01: Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C, Dib M, Guillerm G, Salles B, Eschard JP, Lenain P, Casassus P, Azaïs I, Decaux O, Garderet L, Mathiot C, Fontan J, Lafon I, Virion JM, Moreau P. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009 Aug 1;27(22):3664-70. Epub 2009 May 18. link to original article contains verified protocol PubMed
4. Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, Carlson K, Dahl IM, Forsberg K, Gulbrandsen N, Haukås E, Hjertner O, Hjorth M, Karlsson T, Knudsen LM, Nielsen JL, Linder O, Mellqvist UH, Nesthus I, Rolke J, Strandberg M, Sørbø JH, Wisløff F, Juliusson G, Turesson I; Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010 Sep 2;116(9):1405-12. Epub 2010 May 6. link to original article contains verified protocol PubMed
5. HOVON 49: Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010 Jul 1;28(19):3160-6. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
6. Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N, Sucak G, Kaygusuz I, Karakus S, Kaya E, Ali R, Gulbas Z, Ozet G, Goker H, Undar L. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011 Jan;86(1):16-22. Epub 2010 Nov 22. link to original article contains protocol PubMed
7. Meta-analysis: Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksaç M, Bringhen S, Mary JY, Gimsing P, Termorshuizen F, Haznedar R, Caravita T, Moreau P, Turesson I, Musto P, Benboubker L, Schaafsma M, Sonneveld P, Facon T; Nordic Myeloma Study Group; Italian Multiple Myeloma Network; Turkish Myeloma Study Group; Hemato-Oncologie voor Volwassenen Nederland; Intergroupe Francophone du Myélome; European Myeloma Network. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011 Aug 4;118(5):1239-47. Epub 2011 Jun 13. link to original article PubMed
8. FIRST: Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. link to original article link to supplemental appendix contains verified protocol PubMed
   1. Update: Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, phase III FIRST trial. J Clin Oncol. 2016 Oct;34(30):3609-17. Epub 2016 Jun 20. link to original article PubMed
   2. Update: Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis NJ, Banos A, Tiab M, Delforge M, Cavenagh JD, Geraldes C, Lee JJ, Chen C, Oriol A, De La Rubia J, White D, Binder D, Lu J, Anderson KC, Moreau P, Attal M, Perrot A, Arnulf B, Qiu L, Roussel M, Boyle E, Manier S, Mohty M, Avet-Loiseau H, Leleu X, Ervin-Haynes A, Chen G, Houck V, Benboubker L, Hulin C. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018 Jan 18;131(3):301-310. Epub 2017 Nov 17. link to original article PubMed
9. ECOG E1A06: Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article contains verified protocol link to PMC article PubMed
10. Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article contains verified protocol PubMed

PAD

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PAD: PS-341 (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone
PAd: PS-341 (Bortezomib), Adriamycin (Doxorubicin), low-dose dexamethasone
Note that this regimen is sometimes called VAD but this can create a lot of confusion with the "original" VAD which uses Vincristine.
VAD: Velcade (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone

Variant #1, SC bortezomib, low-dose dex ("PAd")

Study	Evidence	Comparator	Efficacy
Mai et al. 2015 (GMMG-MM5)	Phase III	VCD	Non-inferior VGPR or better rate

This regimen was intended for patients 18 to 70 years of age with newly diagnosed MM who required systemic chemotherapy based on the CRAB criteria. Note that the bortezomib route was changed from IV to SC with a mid-protocol amendment.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 4, 8, 11
• Doxorubicin (Adriamycin) 9 mg/m² IV once per day on days 1 to 4
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20

Supportive medications

• Cotrimoxazole (dose not specified)
• Acyclovir (Zovirax) (dose not specified)
• Bisphosphonate IV every 4 weeks

28-day cycle for 3 cycles

Treatment followed by high-dose melphalan & autologous hematopoietic cell transplant.

Variant #2, IV bortezomib, limited duration (3 cycles)

Study	Evidence	Comparator	Efficacy
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)	Phase III	VAD	Superior PFS (*)

This regimen was intended for patients 18 to 65 years of age with newly diagnosed MM, Durie-Salmon stage II to III, WHO performance status 0 to 2, or WHO 3 when caused by MM. Note that in the initial publication, this arm seemed to have an overall survival advantage; this was no longer present in the updated report of 2017; PFS was the primary endpoint.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Doxorubicin (Adriamycin) 9 mg/m² IV once per day on days 1 to 4
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20

Supportive medications

(described in the appendix of Sonneveld et al. 2012):

• One of the following bisphosphonates recommended:
  • Pamidronate (Aredia) 90 mg IV once every 4 to 6 weeks x at least 2 years
  • Zoledronic acid (Zometa) 4 mg IV once every 4 to 6 weeks x at least 2 years
  • Ibandronate (Boniva) 6 mg IV once every 4 to 6 weeks x at least 2 years
• "Prophylactic antibiotics" (no further specifics) during induction therapy
• Erythropoietin and pain medications at physician discretion
• One of the following for Herpes zoster prophylaxis throughout bortezomib induction:
  • Acyclovir (Zovirax) 800 mg PO per day (did not specify whether taken once per day or as a divided twice per day dose)
  • Valacyclovir (Valtrex) 1000 mg PO per day (did not specify whether taken once per day or as a divided twice per day dose)

28-day cycle for 3 cycles

Stem cells collected 4 to 6 weeks after induction therapy; patients proceed to receive single autologous hematopoietic cell transplant (HOVON-65) or tandem autologous hematopoietic cell transplant (GMMG-HD4).

Variant #3, IV bortezomib, limited duration (4 cycles)

Study	Evidence
Oakervee et al. 2005	Phase II, <20 pts (*)

Note that while this is reported as a phase II, it was also a dose-finding study; only 14 patients were treated at the dose here.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11
• Doxorubicin (Adriamycin) 9 mg/m² IV once per day on days 1 to 4
• Dexamethasone (Decadron) as follows:
  • Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
  • Cycles 2 to 4: 40 mg PO once per day on days 1 to 4

21-day cycle for 4 cycles

Patients proceed to undergo cyclophosphamide mobilization followed by high-dose melphalan & autologous hematopoietic cell transplant.

References

1. Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005 Jun;129(6):755-62. link to original article contains verified protocol PubMed
2. HOVON-65/GMMG-HD4: Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. link to original article PubMed
   2. Update: Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. link to original article PubMed
3. Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article contains verified protocol PubMed

Rd

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Rd: Revlimid (Lenalidomide) & low-dose dexamethasone
RevDex: Revlimid (Lenalidomide) & Dexamethasone
Ld: Lenalidomide & low-dose dexamethasone
Len-Dex: Lenalidomide & Dexamethasone

Variant #1, limited duration (4 cycles)

Study	Evidence	Comparator	Efficacy
Rajkumar et al. 2009 (ECOG E4A03)	Phase III	RD	Superior OS
Gay et al. 2010	Retrospective
Palumbo et al. 2014 (GIMEMA RV-MM-PI-209)	Non-randomized portion of RCT
Gay et al. 2015 (EMN-441)	Non-randomized portion of RCT

In ECOG E4A03 this is the low-dose dexamethasone arm, and was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h. GIMEMA RV-209 was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were 65 years of age or younger. EMN-441 was intended for transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22

Supportive medications

(as described in Rajkumar et al. 2009):

• One of the following bisphosphonates:
  • Pamidronate (Aredia) 90 mg IV over 2 to 4 hours once every 4 weeks
  • Zoledronic acid (Zometa) 4 mg IV over 15 minutes once every 4 weeks
• Thromboprophylaxis mandatory (added mid-protocol after excess rates of DVT)

28-day cycle for 4 cycles (see below)

Responding patients in ECOG E4A03 could choose after 4 cycles to proceed to high-dose melphalan with autologous hematopoietic cell transplant or to continue Rd until progression of disease or intolerable toxicity; nonresponders were transitioned to #Thal-Dex_3Thal-Dex (details not described). Patients in GIMEMA RV-MM-PI-209 were randomized after 4 cycles to tandem high-dose melphalan with autologous hematopoietic cell transplant versus MPR consolidation. Patients in EMN-441 were randomized after 4 cycles to tandem high-dose melphalan with autologous hematopoietic cell transplant versus CRD consolidation.

Variant #2, limited duration (6 cycles)

Study	Evidence	Comparator	Efficacy
Durie et al. 2016 (SWOG S0777)	Phase III	VRd	Seems to have inferior OS

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22

28-day cycle for 6 cycles

Post-induction therapy was not described in the abstract of SWOG S0777.

Variant #3, limited duration (9 cycles)

Study	Evidence	Comparator	Efficacy
Magarotto et al. 2016 (EMN01)	Phase III	CPR	Seems not superior
		MPR	Might have inferior PFS

This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Age 65 to 75 years: 40 mg PO once per day on days 1, 8, 15, 22
  • Age greater than 75 years: 20 mg PO once per day on days 1, 8, 15, 22

Supportive medications

• Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)

28-day cycle for 9 cycles

Patients were then randomized to lenalidomide maintenance versus lenalidomide & prednisone maintenance.

Variant #4, limited duration (18 cycles, "Rd18")

Study	Evidence	Comparator	Efficacy
Benboubker et al. 2014 (FIRST)	Phase III	Rd continuous	Seems not superior (*)
		MPT	Superior OS (*)

This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. Efficacy based on the 2017 update.

Chemotherapy

• Lenalidomide (Revlimid) starting dose as follows:
  • Normal renal function: 25 mg PO once per day on days 1 to 21
  • Moderate renal impairment (CrCl 30 to 50 mL/min/1.73m²): 10 mg PO once per day on days 1 to 21
  • Severe renal impairment (CrCl less than 30 mL/min/1.73m²): 15 mg PO once every other day on days 1 to 21
• Dexamethasone (Decadron) starting dose as follows:
  • Age less than or equal to 75: 40 mg PO once per day on days 1, 8, 15, 22
  • Age greater than 75: 20 mg PO once per day on days 1, 8, 15, 22

28-day cycle for 18 cycles

Variant #5, indefinite 28-day cycles

Study	Evidence	Comparator	Efficacy
Benboubker et al. 2014 (FIRST)	Phase III	Rd18	Seems not superior (*)
		MPT	Seems to have superior OS

This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. Efficacy compared to Rd18 based on the 2017 update.

Chemotherapy

• Lenalidomide (Revlimid) starting dose as follows:
  • Normal renal function: 25 mg PO once per day on days 1 to 21
  • Moderate renal impairment (CrCl 30 to 50 mL/min/1.73m²): 10 mg PO once per day on days 1 to 21
  • Severe renal impairment (CrCl less than 30 mL/min/1.73m²): 15 mg PO once every other day on days 1 to 21
• Dexamethasone (Decadron) starting dose as follows:
  • Age up to 75 years: 40 mg PO once per day on days 1, 8, 15, 22
  • Older than 75 years: 20 mg PO once per day on days 1, 8, 15, 22

28-day cycle given until disease progression

Variant #6, indefinite with 35-day induction cycles

Study	Evidence	Comparator	Efficacy
Zonder et al. 2010 (SWOG S0232)	Phase III	Dexamethasone	Superior PFS

This regimen was intended for transplantation-ineligible or -denying patients who had to have symptomatic disease with a measurable M-protein, be at least 18 years old, and have a performance status less than 3 (unless resulting from myeloma). Note that the first 3 cycles, termed "induction" in the protocol, were 35-day cycles.

Chemotherapy

• Lenalidomide (Revlimid) as follows:
  • Cycles 1 to 3: 25 mg PO once per day on days 1 to 28 of a 35-day cycle
  • Cycle 4 onwards: 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 of a 35-day cycle
  • Cycle 4 onwards: 40 mg PO once per day on days 1 to 4

Supportive medications

• Aspirin 325 mg PO once per day unless already on anticoagulation therapy

28-day cycles (*)

Variant #7, indefinite 28-day cycles, first 4 with high-dose dex

Study	Evidence
Rajkumar et al. 2005	Phase II

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycle 5 onwards: 40 mg PO once per day on days 1 to 4

Supportive medications

• Aspirin 80 mg or 325 mg (depending on physician choice) PO once per day for thromboprophylaxis

28-day cycles

References

1. Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005 Dec 15;106(13):4050-3. Epub 2005 Aug 23. link to original article contains protocol link to PMC article PubMed
2. Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010 Jan;11(1):29-37. Epub 2009 Oct 21. Erratum in: Lancet Oncol. 2010 Jan;11(1):14. link to original article contains verified protocol link to PMC article PubMed
3. Retrospective: Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. link to original article contains verified protocol link to PMC article PubMed
4. Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood. 2010 Dec 23;116(26):5838-41. Epub 2010 Sep 27. link to original article link to PMC article contains verified protocol PubMed
5. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article contains verified protocol PubMed
6. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. link to original article link to supplemental appendix contains verified protocol PubMed
   1. Update: Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, phase III FIRST trial. J Clin Oncol. 2016 Oct;34(30):3609-17. Epub 2016 Jun 20. link to original article PubMed
   2. Update: Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis NJ, Banos A, Tiab M, Delforge M, Cavenagh JD, Geraldes C, Lee JJ, Chen C, Oriol A, De La Rubia J, White D, Binder D, Lu J, Anderson KC, Moreau P, Attal M, Perrot A, Arnulf B, Qiu L, Roussel M, Boyle E, Manier S, Mohty M, Avet-Loiseau H, Leleu X, Ervin-Haynes A, Chen G, Houck V, Benboubker L, Hulin C. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018 Jan 18;131(3):301-310. Epub 2017 Nov 17. link to original article PubMed
7. Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article contains protocol PubMed
8. Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed
9. Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. Epub 2016 Dec 22. link to original article contains protocol PubMed

RVD

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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
VRd: Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone

Variant #1

Study	Evidence	Comparator	Efficacy
Durie et al. 2016 (SWOG S0777)	Phase III	Rd	Seems to have superior OS

This regimen is intended for patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 8 cycles

Variant #2

Study	Evidence	Comparator	Efficacy
Kumar et al. 2012 (EVOLUTION)	Randomized Phase II	VDC	Seems not superior
		VDC-mod	Seems not superior
		VDCR	Seems not superior

This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15

21-day cycle for 8 cycles

Treatment followed by bortezomib consolidation.

Variant #3

Study	Evidence
Attal et al. 2017 (IFM 2009)	Non-randomized portion of RCT

This regimen is intended for patients 65 years of age or younger with symptomatic, measurable, newly diagnosed multiple myeloma.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 3 cycles

Patients were subsequently randomized to high-dose melphalan, then auto HSCT versus RVD consolidation.

Variant #4

Study	Evidence
Roussel et al. 2014	Phase II

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15

Supportive medications

• Low–molecular weight heparin (LMWH)
• Antiviral therapy with example valacyclovir given, for herpes zoster prevention
• Antibiotic prophylaxis with example amoxicillin given, for bacterial infections

21-day cycle for 3 cycles

Treatment followed by high-dose melphalan and autologous hematopoietic cell transplant.

Variant #5

Study	Evidence
Richardson et al. 2010	Phase I/II

This is the MTD level "4M" described in the manuscript.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

Supportive medications

• Aspirin 81 mg or 325 mg PO once per day
• Antiviral therapy, such as Acyclovir (Zovirax) 400 mg PO once per day
• Bisphosphonate

21-day cycle for 8 cycles

Patients who responded and tolerated therapy could proceed to maintenance RVD.

References

1. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12. link to original article contains verified protocol link to PMC article PubMed
2. Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. link to original article contains verified protocol PubMed
3. Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
4. Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. Epub 2016 Dec 22. link to original article contains protocol PubMed
5. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. link to original article contains verified protocol PubMed

RVDC

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RVDC: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
VDCR: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide, Revlimid (Lenalidomide)

Regimen

Study	Evidence	Comparator	Efficacy
Kumar et al. 2012 (EVOLUTION)	Randomized Phase II	VDC	Seems not superior
		VDC-mod	Seems not superior
		VDR	Seems not superior

This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days 1 & 8

Supportive medications

• Aspirin 325 mg PO once per day
  • Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used based on physician discretion
• PCP prophylaxis recommended
• Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
• Bisphosphonates could be used "as necessary"

21-day cycle for 8 cycles

Treatment followed by bortezomib consolidation.

References

1. Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. link to original article contains verified protocol PubMed

TAD

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TAD: Thalidomide, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Lokhorst et al. 2009 (HOVON 50/GMMG-HD3)	Phase III	VAD	Superior EFS

Chemotherapy

• Thalidomide (Thalomid) 200 to 400 mg PO once per day
• Doxorubicin (Adriamycin) 9 mg/m² IV once per day on days 1 to 4
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20

28-day cycle for 3 cycles

Treatment followed by CAD for stem-cell mobilization.

References

1. Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article contains verified protocol PubMed

Thal-Dex

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TD: Thalidomide, Dexamethasone
Thal-Dex: Thalidomide, Dexamethasone

Variant #1

Study	Evidence	Comparator	Efficacy
Rosiñol et al. 2012 (PETHEMA GEM05MENOS65)	Phase III	VTD	Seems to have inferior PFS
		VBMCP/VBAD/B	Not reported

This regimen was intended for patients with newly diagnosed and untreated symptomatic MM who were less than or equal to 65 years of age with measurable serum and/or urine M protein.

Chemotherapy

• Thalidomide (Thalomid) as follows:
  • Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
  • Cycle 2 onwards: Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 28
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12

Supportive medications

• Low-molecular weight heparin or Aspirin recommended

28-day cycle for 6 cycles

Variant #2

Study	Evidence	Comparator	Efficacy
Cavo et al. 2010 (GIMEMA MM-BO2005)	Phase III	VTD	Inferior CR/nCR rate

This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma.

Induction therapy

• Thalidomide (Thalomid) as follows:
  • Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to 21
  • Cycles 2 & 3: 200 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12

21-day cycle for 3 cycles, then proceed to first stem cell transplant

First stem cell transplant

• Melphalan (Alkeran) 200 mg/m² (route not specified) once on day -2
• Autologous hematopoietic cell rescue

Wait until count recovery, then proceed to thalidomide & dexamethasone therapy

Thalidomide & dexamethasone therapy

• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

28-day cycles for 3 to 6 months, then proceed to second stem cell transplant

Second stem cell transplant

• Melphalan (Alkeran) 200 mg/m² (route not specified) once on day -2
• Autologous hematopoietic cell rescue

Wait until 3 months after second transplant, then proceed to thalidomide & dexamethasone therapy

Thalidomide & dexamethasone consolidation

• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 20 to 23

Supportive medications

• Acyclovir (Zovirax) prophylaxis recommended

35-day cycle for 2 cycles

Subsequent treatment

• Dexamethasone maintenance

Variant #3

Study	Evidence	Comparator	Efficacy
Rajkumar et al. 2008	Phase III	Dexamethasone	Superior TTP

This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h.

Chemotherapy

• Thalidomide (Thalomid) as follows:
  • Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
  • Cycle 2 onwards: 200 mg PO once per day on days 1 to 28
• Dexamethasone (Decadron) as folows:
  • Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycle 5 onwards: 40 mg PO once per day on days 1 to 4

28-day cycles

Variant #4

Study	Evidence	Comparator	Efficacy	Toxicity
Rajkumar et al. 2002	Phase II
Rajkumar et al. 2006	Phase III	Dexamethasone	Seems to have superior RR	Inferior toxicity

In Rajkumar et al. 2006 his regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h.

Chemotherapy

• Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 28
• Dexamethasone (Decadron) as follows:
  • Odd-numbered cycles: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Even-numbered cycles: 40 mg PO once per day on days 1 to 4

28-day cycles

Variant #5

Study	Evidence
Cavo et al. 2004 (Bologna 2002)	Phase II

Chemotherapy

• Thalidomide (Thalomid) as follows:
  • Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to end of month
  • Cycles 2 to 4: 200 mg PO once per day on days 1 to end of month
• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycles 2 & 4: 40 mg PO once per day on days 1 to 4

Monthly cycle for 4 cycles

Responders proceeded to tandem high-dose melphalan, then autologous hematopoietic cell transplant.

References

1. Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, Fonseca R, Lust JA, Kyle RA, Witzig TE. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002 Nov 1;20(21):4319-23. link to original article contains protocol PubMed
2. Dose escalation study: Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. link to original article PubMed
3. Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, Testoni N, Tonelli M, de Vivo A, Palareti G, Tura S, Baccarani M. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica. 2004 Jul;89(7):826-31. link to original article contains protocol PubMed
   1. Sub-analysis: Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D, de Vivo A, Testoni N, Nicci C, Terragna C, Grafone T, Perrone G, Ceccolini M, Tura S, Baccarani M; Bologna 2002 study. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005 Jul 1;106(1):35-9. Epub 2005 Mar 10. link to original article contains protocol PubMed
4. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern Cooperative Oncology Group. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006 Jan 20;24(3):431-6. Epub 2005 Dec 19. link to original article contains protocol PubMed
5. Rajkumar SV, Rosiñol L, Hussein M, Catalano J, Jedrzejczak W, Lucy L, Olesnyckyj M, Yu Z, Knight R, Zeldis JB, Bladé J. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 2008 May 1;26(13):2171-7. Epub 2008 Mar 24. link to original article contains verified protocol link to PMC article PubMed
6. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. Erratum in: Lancet. 2011 Nov 26;378(9806):1846. link to original article PubMed
   1. Update: Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. link to original article contains verified protocol PubMed
7. Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. link to original article contains verified protocol PubMed

VAD doxil

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DVD: Doxil (Liposomal Doxorubicin), Vincristine, Dexamethasone
DVd: Doxil (Liposomal Doxorubicin), Vincristine, low-dose dexamethasone
VAD doxil: Vincristine, Adriamycin liposomal (Doxil), Dexamethasone

Variant #1, indefinite ("DVd")

Study	Evidence	Comparator	Efficacy
Rifkin et al. 2006	Phase III	VAd	Non-inferior ORR

This regimen was intended for patients greater than or equal to 18 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria.

Chemotherapy

• Pegylated liposomal doxorubicin (Doxil) 40 mg/m² IV over 60 minutes once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose per cycle capped at 2 mg) IV over 5 minutes once on day 1
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

28-day cycles, given until maximal response, progression of disease, or unacceptable toxicity

Variant #2, limited duration (4 cycles)

Study	Evidence	Comparator	Efficacy
Dimopoulos et al. 2003	Phase III	VAD	Seems not superior
Zervas et al. 2007	Phase III	TVAD-Doxil	Seems to have inferior OS

Dimopoulos et al. 2003 was open to all patients with previously untreated multiple myeloma who were considered candidates for systemic treatment. Zervas et al. 2007 was open to patients aged 18 to 75 years old with previously untreated symptomatic MM and a life expectancy of greater than 6 months.

Chemotherapy

• Vincristine (Oncovin) 2 mg IV once on day 1
• Pegylated liposomal doxorubicin (Doxil) 40 mg/m² IV over 60 minutes once on day 1
• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycles 2 & 4: 40 mg PO once per day on days 1 to 4

Supportive medications

• In the cited Segeren et al. 1999 VAD protocol reference:
• Fluconazole (Diflucan) 200 mg PO once per day
• Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO BID for "prophylaxis"

28-day cycle for 4 cycles

Variant #3, limited duration (6 to 8 cycles)

Study	Evidence
Hussein et al. 2002	Phase II

Chemotherapy

• Pegylated liposomal doxorubicin (Doxil) 40 mg/m² IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1
• Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4

Supportive medications

• Vitamin B6 200 mg PO once per day to help reduce risk of palmar-plantar erythrodysesthesia (PPE)

28-day cycle for 6 to 8 cycles

References

1. Hussein MA, Wood L, Hsi E, Srkalovic G, Karam M, Elson P, Bukowski RM. A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients. Cancer. 2002 Nov 15;95(10):2160-8. link to original article contains protocol PubMed
2. Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A, Katodritou I, Kokkini G, Terpos E, Vyniou N, Tzilianos M, Chatzivassili A, Kyrtsonis MC, Panayiotidis P, Maniatis A; Greek Myeloma Study Group. Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol. 2003 Jul;14(7):1039-44. link to original article contains protocol PubMed
3. Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial. Cancer. 2006 Feb 15;106(4):848-58. link to original article contains verified protocol PubMed
4. Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol. 2007 Aug;18(8):1369-75. link to original article contains verified protocol PubMed

VAD-P

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VAD-P: Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Prednisone

Regimen

Study	Evidence	Comparator	Efficacy
Berenson et al. 2002 (SWOG 9210)	Phase III	VAD-P/Q	Seems not superior

Chemotherapy

• Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1.6 mg)
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 36 mg/m²)
  • Poor-risk patients received 6.75 mg/m²/day in cycle 1 (total dose 27 mg/m²), with increase to full dose starting cycle 2 if no undue toxicity
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
• Prednisone (Sterapred) 50 mg PO once per day on days 9, 11, 13, 15, 17, 19

21-day cycles for at least 6 months or until at least 25% regression of disease

Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were randomized to low-dose prednisone versus |high-dose prednisone maintenance.

References

1. Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002 May 1;99(9):3163-8. link to original article contains protocol PubMed

VAD-P/Q

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VAD-P/Q: Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Prednisone, Quinine

Regimen

Study	Evidence	Comparator	Efficacy
Berenson et al. 2002 (SWOG 9210)	Phase III	VAD-P	Seems not superior

Chemotherapy

• Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 4 days on days 2 to 5 (total dose per cycle: 1.6 mg)
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion over 4 days on days 2 to 5 (total dose per cycle: 36 mg/m²)
  • Poor-risk patients received 6.75 mg/m²/day in cycle 1 (total dose 27 mg/m²), with increase to full dose starting cycle 2 if no undue toxicity
• Dexamethasone (Decadron) 40 mg PO once per day on days 2 to 5
• Prednisone (Sterapred) 50 mg PO once per day on days 10, 12, 14, 16, 18, 20
• Quinine (Qualaquin) 400 mg PO TID on days 1 to 6

21-day cycle for at least 6 months or until at least 25% regression of disease

Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were randomized to low-dose prednisone versus |high-dose prednisone maintenance.

References

1. Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002 May 1;99(9):3163-8. link to original article contains protocol PubMed

VDC

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VDC: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
VDC-mod: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide (modified dose)
VCD: Velcade (Bortezomib), Cyclophosphamide, Dexamethasone
CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone

Variant #1

Study	Evidence	Comparator	Efficacy
Moreau et al. 2016 (IFM 2013-04)	Phase III	VTD	Seems to have inferior ORR rate

This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 4, 8, 11
• Cyclophosphamide (Cytoxan) 500 mg/m² PO once per day on days 1, 8, 15
• Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1 to 4, 9 to 12

21-day cycle for 4 cycles

All patients then underwent autologous hematopoietic cell transplant, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center.

Variant #2, "VCD"

Study	Evidence	Comparator	Efficacy
Mai et al. 2015 (GMMG-MM5)	Phase III	PAd	Non-inferior VGPR or better rate

This regimen was intended for patients 18 to 70 years of age with newly diagnosed MM who required systemic chemotherapy based on the CRAB criteria. Note that the bortezomib route was changed from IV to SC with a mid-protocol amendment.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 4, 8, 11
• Cyclophosphamide (Cytoxan) 900 mg/m² IV once on day 1
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

Supportive medications

• Cotrimoxazole (dose not specified)
• Acyclovir (Zovirax) (dose not specified)
• Bisphosphonate IV every 4 weeks

21-day cycle for 3 cycles

Treatment followed by high-dose melphalan & autologous hematopoietic cell transplant.

Variant #3, "VDC"

Study	Evidence	Comparator	Efficacy
Kumar et al. 2012 (EVOLUTION)	Randomized Phase II	VDR	Seems not superior
		VDCR	Seems not superior

This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation. The only difference between this regimen and VDC-mod is the number of cyclophosphamide doses.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days 1 & 8

Supportive medications

• Aspirin 325 mg PO once per day
  • Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used based on physician discretion
• PCP prophylaxis recommended
• Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
• Bisphosphonates could be used "as necessary"

21-day cycle for 8 cycles

Treatment followed by bortezomib consolidation.

Variant #4, "VDC-mod"

Study	Evidence	Comparator	Efficacy
Kumar et al. 2012 (EVOLUTION)	Randomized Phase II, less than 20 in this arm	VDR	Seems not superior
		VDCR	Seems not superior

This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation. This arm only had 17 patients enrolled; other arms of the EVOLUTION trial all had greater than 20 patients enrolled. The only difference between this and regimen #1 is the number of cyclophosphamide doses.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days 1, 8, 15

Supportive medications

• Aspirin 325 mg PO once per day
  • Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used instead, based on physician discretion
• PCP prophylaxis recommended
• Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
• Bisphosphonates could be used "as necessary"

21-day cycle for 8 cycles

Treatment followed by bortezomib consolidation.

Variant #5, "CyBorD", once per week bortezomib

Study	Evidence
Reeder et al. 2010	Phase II

This regimen was described in a letter to the editor of Blood.

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² PO once per day on days 1, 8, 15, 22
• Bortezomib (Velcade) 1.5 mg/m² IV once per day on days 1, 8, 15, 22
• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycles 3 & 4: 40 mg PO once per week

28-day cycle for 4 cycles

Variant #6, "CyBorD"

Study	Evidence
Reeder et al. 2009	Phase II

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² PO once per day on days 1, 8, 15, 22
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20

Supportive medications

• Proton pump inhibitor (PPI)
• Acyclovir (Zovirax)
• Quinolone antibiotic
• Antifungal mouthwash recommended

28-day cycle for 4 to 12 cycles

References

1. Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, Noble B, Pirooz NA, Spong JE, Piza JG, Zepeda VH, Mikhael JR, Leis JF, Bergsagel PL, Fonseca R, Stewart AK. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009 Jul;23(7):1337-41. Epub 2009 Feb 19. link to original article contains verified protocol link to PMC article PubMed
2. Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K, Hentz J, Pirooz NA, Piza JG, Tiedemann R, Mikhael JR, Bergsagel PL, Leis JF, Fonseca R, Stewart AK. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010 Apr 22;115(16):3416-7. link to original letter contains verified protocol PubMed
3. Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. link to original article contains verified protocol PubMed
4. Meta-Analysis: Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. link to original article PubMed
5. Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article contains verified protocol PubMed
6. Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. Epub 2016 Mar 21. link to original article contains verified protocol PubMed

VMP

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VMP: Velcade (Bortezomib), Melphalan, Prednisone
MPV: Melphalan, Prednisone, Velcade (Bortezomib)

Variant #1, 6 cycles, bi-weekly bortezomib

Study	Evidence
Gasparetto et al. 2009	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Melphalan (Alkeran) 6 mg/m² PO once per day on days 1 to 7, given at least 1 hour prior to bortezomib
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 7

Supportive medications

• Bisphosphonates recommended
• Acyclovir (Zovirax) (dose not specified) recommended

28-day cycle for up to 6 cycles; treatment could be given beyond 6 cycles at investigator discretion

Variant #2, 6 cycles, bi-weekly bortezomib x 1, then weekly bortezomib x 5

Study	Evidence	Comparator	Efficacy
Mateos et al. 2010 (GEM2005)	Phase III	VTP	Seems to have superior OS

This regimen was intended for patients with untreated multiple myeloma, 65 years and older.

Chemotherapy

• Bortezomib (Velcade) as follows:
  • Cycle 1: 1.3 mg/m² IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
  • Cycles 2 to 5: 1.3 mg/m² IV once per day on days 1, 8, 15, 22
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

Supportive medications

• Patients with bone disease received bisphosphonates
• Prophylactic aciclovir was recommended.

42-day cycle for 1 cycle, then 35-day cycle for 5 cycles

Subsequent treatment

• Bortezomib & Prednisone versus VT maintenance

Variant #3, 8 cycles

Study	Evidence	Comparator	Efficacy
Niesvizky et al. 2015 (UPFRONT)	Phase III	VD	Seems not superior
		VTD	Seems not superior

This regimen was meant for transplant ineligible patients.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4 every other cycle
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4 every other cycle

21-day cycle for 8 cycles

Subsequent treatment

• Bortezomib maintenance

Variant #4, 9 cycles, bi-weekly bortezomib x 1, then weekly bortezomib x 8

Study	Evidence	Comparator	Efficacy
Mateos et al. 2017 (ALCYONE)	Phase III	VMP & Daratumumab	Inferior PFS

This regimen was intended for patients with newly diagnosed, documented multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older.

Chemotherapy

• Bortezomib (Velcade) as follows:
  • Cycle 1: 1.3 mg/m² SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
  • Cycles 2 to 9: 1.3 mg/m² SC once per day on days 1, 8, 22, 29
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

42-day cycle for 9 cycles

Variant #5, 9 cycles, bi-weekly bortezomib x 4, then weekly bortezomib x 5

Study	Evidence	Comparator	Efficacy
San Miguel et al. 2008 (VISTA)	Phase III	MP	Superior OS
Palumbo et al. 2010	Phase III	VMPT-VT	Seems to have inferior OS
San-Miguel et al. 2014	Randomized Phase II	VMP & Siltuximab	Seems not superior

In Palumbo et al. 2010 and VISTA this regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions.

Chemotherapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 4: 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32
  • Cycles 5 to 9: 1.3 mg/m² IV bolus once per day on days 1, 8, 22, 29
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

Supportive medications

• Bisphosphonates given to patients with myeloma-associated bone disease unless contraindicated (only mentioned in San Miguel et al. 2008)

42-day cycle for 9 cycles

Variant #6, 9 cycles, weekly bortezomib

Study	Evidence	Comparator	Efficacy
Palumbo et al. 2010	Phase III	VMPT-VT	Seems to have inferior OS

This regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions. This dosing is the result of a mid-protocol amendment.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 8, 15, 22
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

35-day cycle for 9 cycles

References

1. Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Díaz-Mediavilla J, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, de Arriba F, Alegre A, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006 Oct 1;108(7):2165-72. Epub 2006 Jun 13. link to original article PubMed
   1. Update: Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Garcia-Sanchez P, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, Alegre A, de Arriba F, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica. 2008 Apr;93(4):560-5. Epub 2008 Mar 5. link to original article PubMed
2. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17. link to original article contains protocol PubMed
   1. Update: Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010 May 1;28(13):2259-66. Epub 2010 Apr 5. link to original article contains protocol PubMed
   2. Update: San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van de Velde H, Richardson PG. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-55. Epub 2012 Dec 10. link to original article PubMed
3. Gasparetto C, Gockerman JP, Diehl LF, de Castro CM, Moore JO, Long GD, Horwitz ME, Keogh G, Chute JP, Sullivan KM, Neuwirth R, Davis PH, Sutton LM, Anderson RD, Chao NJ, Rizzieri D. "Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma. Biol Blood Marrow Transplant. 2010 Jan;16(1):70-7. Epub 2009 Sep 3. link to original article contains verified protocol PubMed
4. Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. link to original article contains verified protocol PubMed
   1. Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article PubMed
   2. Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. link to original article contains verified protocol PubMed
5. Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. link to original article contains verified protocol PubMed
   1. Post-hoc analysis: Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. link to original article contains verified protocol PubMed
   2. Subset analysis: Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. link to original article PubMed
   3. Update: Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: Updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. link to original article contains verified protocol PubMed
6. San-Miguel J, Bladé J, Shpilberg O, Grosicki S, Maloisel F, Min CK, Polo Zarzuela M, Robak T, Prasad SV, Tee Goh Y, Laubach J, Spencer A, Mateos MV, Palumbo A, Puchalski T, Reddy M, Uhlar C, Qin X, van de Velde H, Xie H, Orlowski RZ. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood. 2014 Jun 26;123(26):4136-42. Epub 2014 May 15. Erratum in: Blood. 2014 Aug 14;124(7):1201. link to original article refers to protocol in San Miguel et al. 2008 link to PMC article PubMed
7. UPFRONT: Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed
8. ALCYONE: Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. link to original article contains verified protocol PubMed

VMP, then Rd

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VMP, then Rd: Velcade (Bortezomib), Melphalan, Prednisone, followed by Revlimid (Lenalidomide), low dose dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Mateos et al. 2015 (PETHEMA GEM05)	Phase III	VMP/Rd	Seems not superior

This regimen was intended for patients aged greater than or equal to 65 years with newly diagnosed, untreated, symptomatic, measurable MM.

Chemotherapy, VMP portion, first cycle

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

42-day cycle for 1 cycle, then:

Chemotherapy, VMP portion, remainder

• Bortezomib (Velcade) 1.3 mg/m² IV once per week on days 1, 8, 15, 22
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

28-day cycle for 8 cycles, followed by:

Chemotherapy, Rd portion

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

28-day cycle for 9 cycles

Supportive medications

• During bortezomib therapy:
  • Bisphosphonates
  • Prophylactic antiviral therapy
• During lenalidomide therapy:
  • Mandatory thromboprophylaxis with either Aspirin or low–molecular weight heparin

References

1. PETHEMA GEM05: Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016 Jan 28;127(4):420-5. Epub 2015 Oct 23. link to original article contains verified protocol PubMed

VMP/Rd

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VMP/Rd: Velcade (Bortezomib), Melphalan, Prednisone alternating with Revlimid (Lenalidomide), low dose dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Mateos et al. 2015 (PETHEMA GEM05)	Phase III	VMP, then Rd	Seems not superior

This regimen was intended for patients aged greater than or equal to 65 years with newly diagnosed, untreated, symptomatic, measurable MM.

Chemotherapy, VMP portion, first cycle

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

42-day cycle for 1 cycle, then Rd cycle #1:

Chemotherapy, VMP portion, remaining cycles

• Bortezomib (Velcade) 1.3 mg/m² IV once per week on days 1, 8, 15, 22
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

28-day cycle for 8 cycles, alternating with Rd:

Chemotherapy, Rd portion

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

28-day cycle alternating with VMP x 9 cycles

Supportive medications

• During bortezomib therapy:
  • Bisphosphonates
  • Prophylactic antiviral therapy
• During lenalidomide therapy:
  • Mandatory thromboprophylaxis with either Aspirin or low–molecular weight heparin

References

1. Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016 Jan 28;127(4):420-5. Epub 2015 Oct 23. link to original article contains verified protocol PubMed

VMPT

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VMPT: Velcade (Bortezomib), Melphalan, Prednisone, Thalidomide

Variant #1

Study	Evidence	Comparator	Efficacy
Palumbo et al. 2010	Phase III	VMP	Seems to have superior OS

This regimen was intended for patients with newly diagnosed myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities.

Chemotherapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 4: 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32
  • Cycles 5 to 9: 1.3 mg/m² IV bolus once per day on days 1, 8, 22, 29
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 42

42-day cycle for 9 cycles

Treatment followed by VT maintenance therapy.

Variant #2

Study	Evidence	Comparator	Efficacy
Palumbo et al. 2010	Phase III	VMP	Seems to have superior OS

This regimen was intended for patients with newly diagnosed myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant represents a mid-protocol change (in 2007) where cycle length was decreased from 6 to 5 weeks and bortezomib was changed to weekly dosing.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 8, 15, 22
• Melphalan (Alkeran) 9 mg/m² PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 42

35-day cycle for 9 cycles

Treatment followed by VT maintenance therapy.

References

1. Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. link to original article contains verified protocol PubMed
   1. Post-hoc analysis: Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. link to original article contains verified protocol PubMed
   2. Subset analysis: Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. link to original article PubMed
   3. Update: Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. link to original article contains verified protocol PubMed

VTD

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VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone
vTD: low-dose velcade (Bortezomib), Thalidomide, Dexamethasone

Variant #1

Study	Evidence	Comparator	Efficacy
Moreau et al. 2016 (IFM 2013-04)	Phase III	VCD	Seems to have superior ORR rate

This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1 to 4, 9 to 12

21-day cycle for 4 cycles

All patients then underwent autologous hematopoietic cell transplant, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center.

Variant #2

Study	Evidence	Comparator	Efficacy
Niesvizky et al. 2015 (UPFRONT)	Phase III	VD	Seems not superior
		VMP	Seems not superior

This regimen was intended for patients with newly diagnosed, symptomatic, measurable MM requiring systemic therapy, and who were ineligible for stem-cell transplantation because of age (greater than or equal to 65 years), comorbidities, or personal preference.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 5 to 8: 20 mg PO once per day on days 1, 2, 4, 5

21-day cycle for 8 cycles

Treatment followed by bortezomib maintenance.

Variant #3

Study	Evidence	Comparator	Efficacy
Ludwig et al. 2013	Randomized Phase II	VTDC	Seems not superior

This regimen was intended for patients aged 18 to 70 years with previously untreated, measurable MM requiring systemic therapy, who were candidates for high-dose chemotherapy and autologous hematopoietic cell transplant.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12

21-day cycle for 4 cycles

Patients who remained eligible for transplant underwent high dose melphalan autologous hematopoietic cell transplant. Transplant ineligible patients or patients achieving CR could undergo 4 additional cycles of VTD.

Variant #4

Study	Evidence	Comparator	Efficacy
Rosiñol et al. 2012 (PETHEMA GEM05MENOS65)	Phase III	TD	Seems to have superior PFS
		VBMCP/VBAD/B	Seems to have superior PFS

This regimen was intended for patients with newly diagnosed and untreated symptomatic MM who were 65 years of age or younger with measurable serum and/or urine M protein.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) as follows:
  • Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
  • Cycles 2 to 6: 200 mg PO once per day on days 1 to 28
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12

Supportive medications

• Low molecular weight heparin (LMWH) or Aspirin recommended

28-day cycle for 6 cycles

All patients then underwent high dose melphalan autologous hematopoietic cell transplant.

Variant #5, "vTD"

Study	Evidence	Comparator	Efficacy
Moreau et al. 2011 (IFM 2007-02)	Phase III	VD	Superior VGPR rate
Lok et al. 2014	Non-randomized

IFM 2007-02 was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours). Lok et al. 2014 uses the same dosing except that bortezomib is given SC.

Chemotherapy

• Bortezomib (Velcade) 1 mg/m² IV/SC once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 2: 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
  • Cycles 3 & 4: 40 mg (route not specified) once per day on days 1 to 4

21-day cycle for 4 cycles

All patients then underwent high dose melphalan autologous hematopoietic cell transplant.

Variant #6

Study	Evidence	Comparator	Efficacy
Cavo et al. 2010 (GIMEMA MM-BO2005)	Phase III	TD	Superior CR/nCR rate

This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma.

Induction therapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) as follows:
  • Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to 21
  • Cycles 2 & 3: 200 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 3 cycles, then proceed to first stem cell transplant

First stem cell transplant

• Melphalan (Alkeran) 200 mg/m² once on day -2
• autologous hematopoietic cell rescue

Wait until count recovery, then proceed to thalidomide & dexamethasone therapy

Thalidomide & Dexamethasone therapy

• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

28-day cycle for 3 to 6 months, then proceed to second stem cell transplant

Second stem cell transplant

• Melphalan (Alkeran) 200 mg/m² once on day -2
• autologous hematopoietic cell rescue

Wait until 3 months after second transplant, then proceed to bortezomib, thalidomide, dexamethasone therapy

Bortezomib, thalidomide, dexamethasone therapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22
• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

35-day cycle for 2 cycles

Patients then proceed to dexamethasone maintenance therapy.

Supportive medications

• Acyclovir (Zovirax) prophylaxis recommended

Variant #7

Study	Evidence
Kaufman et al. 2010	Retrospective

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12

Supportive medications

• Aspirin prophylaxis to decrease risk of DVTs
• Prophylactic "treatment with antiviral and antibiotic medications"

21-day cycle for 3 to 4 cycles

References

1. Retrospective: Kaufman JL, Nooka A, Vrana M, Gleason C, Heffner LT, Lonial S. Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma: a retrospective study. Cancer. 2010 Jul 1;116(13):3143-51. link to original article contains protocol PubMed
2. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. link to original article contains protocol PubMed
   1. Update: # Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. link to original article contains verified protocol PubMed
3. Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. link to original article contains verified protocol PubMed
4. Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. link to original article contains verified protocol PubMed
5. Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Ricci D, Cakana A, Enny C, Feng H, van de Velde H, Harousseau JL. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol. 2013 Jan 10;31(2):247-55. Epub 2012 Oct 22. link to original article contains verified protocol PubMed
   1. Update: Ludwig H, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Chaturvedi S, Ataman O, Enny C, Feng H, van de Velde H, Viterbo L. Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up. Br J Haematol. 2015 Nov;171(3):344-54. Epub 2015 Jul 7. link to original article link to PMC article PubMed
6. Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous Bortezomib incorporated into the Bortezomib-Thalidomide-Dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. link to original article contains verified protocol link to PMC article PubMed
7. Meta-Analysis: Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. link to original article PubMed
8. UPFRONT: Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed
9. IFM2013-04: Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. Epub 2016 Mar 21. link to original article contains verified protocol PubMed

VTP

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VTP: Velcade (Bortezomib), Thalidomide, Prednisone

Regimen

Study	Evidence	Comparator	Efficacy
Mateos et al. 2010 (GEM2005)	Phase III	VMP	Seems to have inferior OS

This regimen was intended for patients with untreated multiple myeloma, 65 years and older.

First cycle

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 15, then 100 mg PO once per day on days 16 to 42
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

Supportive medications

• Patients with bone disease received bisphosphonates
• Prophylactic aciclovir was recommended.
• Thromboprophylaxis with either Aspirin or low-molecular-weight heparin

42-day cycle for 1 cycle, then

Remainder of induction

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22
• Thalidomide (Thalomid) 100 mg PO once per day
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

Supportive medications

• Patients with bone disease received bisphosphonates
• Prophylactic aciclovir was recommended.
• Thromboprophylaxis with either Aspirin or low-molecular-weight heparin

35-day cycle for 5 cycles

Treatment followed by bortezomib & prednisone maintenance versus VT maintenance.

References

1. Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. link to original article contains verified protocol PubMed
   1. Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article PubMed
   2. Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. link to original article contains verified protocol PubMed

First-line therapy (including transplant ineligible), non-randomized or retrospective data

Note: most but not all multiple myeloma first-line regimens specify whether patients are transplant eligible, or not. We will begin to break this section in those respective subsections.

BBD

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BBD: Bendamustine, Bortezomib, Dexamethasone

Regimen

Study	Evidence
Berdeja et al. 2017	Phase II

Chemotherapy

• Bendamustine 80 mg/m² IV once per day on days 1 & 2
• Bortezomib (Velcade) 1.3 mg/m² (route not specified) once per day on days 1, 8, 15
• Dexamethasone (Decadron) 20 mg (route not specified) once per day on days 1, 2, 8, 9, 15, 16

28-day cycle for up to 8 cycles

Treatment followed by maintenance bortezomib.

References

1. Berdeja JG, Bauer T, Arrowsmith E, Essell J, Murphy P, Reeves JA Jr, Boccia RV, Donnellan W, Flinn I. Phase II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of patients with multiple myeloma who are not candidates for high dose chemotherapy. Br J Haematol. 2017 Apr;177(2):254-262. Epub 2017 Feb 7. link to original article contains verified protocol PubMed

BDD

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BDD: Bortezomib, Doxorubicin, Dexamethasone

Regimen

Study	Evidence
Ludwig et al. 2010	Phase II

This is not specifically a first-line regimen but most patients enrolled on the phase II trial were untreated (50 out of 68)

Chemotherapy

• Bortezomib (Velcade) 1 mg/m² (route not specified) once per day on days 1, 4, 8, 11
  • Patients without grade 3 or 4 toxicity during the first two cycles could have bortezomib dose increased to 1.3 mg/m² (route not specified) once per day on days 1, 4, 8, 11
• Doxorubicin (Adriamycin) 9 mg/m² IV once per day on days 1 & 4
  • Patients without grade 3 or 4 toxicity during the first two cycles could have number of doxorubicin doses increased to 9 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1, 4, 8, 11

21-day cycle for up to 8 cycles

References

1. Ludwig H, Adam Z, Hajek R, Greil R, Tóthová E, Keil F, Autzinger EM, Thaler J, Gisslinger H, Lang A, Egyed M, Womastek I, Zojer N. Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study. J Clin Oncol. 2010 Oct 20;28(30):4635-41. Epub 2010 Sep 7. link to original article contains verified protocol PubMed

BiRD

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BiRD: Biaxin, Revlimid (Lenalidomide), Dexamethasone

Regimen

Study	Evidence
Niesvizky et al. 2007	Phase II

Chemotherapy

• Clarithromycin (Biaxin) as follows:
  • Cycle 1: 500 mg PO BID on days 2 to 28
  • Cycle 2 onwards: 500 mg PO BID on days 1 to 28
• Lenalidomide (Revlimid) as follows:
  • Cycle 1: 25 mg PO once per day on days 3 to 21
  • Cycle 2 onwards: 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycle 1: 40 mg PO once per day on days 1, 2, 3, 8, 15, 22
  • Cycle 2 onwards: 40 mg PO once per day on days 1, 8, 15, 22

Supportive medications

• Aspirin 81 mg PO once per day
• Omeprazole (Prilosec) 20 mg PO once per day
• Trimethoprim/Sulfamethoxazole (Bactrim DS) PO BID, 3 times a week

28-day cycles

References

1. Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S, Jalbrzikowski J, Pearse RN, Zafar F, Pekle K, Larow A, Lent R, Mark T, Cho HJ, Shore T, Tepler J, Harpel J, Schuster MW, Mathew S, Leonard JP, Mazumdar M, Chen-Kiang S, Coleman M. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008 Feb 1;111(3):1101-9. Epub 2007 Nov 7. link to original article contains protocol PubMed
   1. Update: Rossi A, Mark T, Jayabalan D, Christos P, Zafar F, Pekle K, Pearse R, Chen-Kiang S, Coleman M, Niesvizky R. BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma. Blood. 2013 Mar 14;121(11):1982-1985. Epub 2013 Jan 8. link to original article contains protocol link to PMC article PubMed
2. Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. link to original article contains protocol link to PMC article PubMed

CAD

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CAD: Cyclophosphamide, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence
Lokhorst et al. 2009 (HOVON 50/GMMG-HD3)	Non-randomized portion of RCT

This is reported as a stem cell mobilization regimen but presumably has anti-myeloma activity.

Preceding treatment

• TAD induction versus VAD induction

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 15 mg/m² IV once per day on days 1 to 4
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
• Filgrastim (Neupogen) 5 mcg/kg SC BID until collection completed

One cycle

Treatment followed by high-dose melphalan, then autologous hematopoietic cell transplant or tandem high-dose melphalan, then autologous hematopoietic cell transplant; this was not a randomization but was pre-determined by the treating center.

References

1. Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article PubMed

CCyd

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CCyd: Carfilzomib, Cyclophosphamide, dexamethasone
KCyd: Kyprolis (Carfilzomib), Cyclophosphamide, dexamethasone

Regimen

Study	Evidence
Bringhen et al. 2014	Phase II

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1 & 2 then 36 mg/m² IV once per day on days 8, 9, 15, 16
  • Cycles 2 to 9: 36 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
• Cyclophosphamide (Cytoxan) 300 mg/m² PO once per day on days 1, 8, 15
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22

28-day cycle for 9 cycles

Subsequent treatment

• Carfilzomib maintenance

References

1. Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. Epub 2014 May 22. link to original article contains verified protocol PubMed
2. Bringhen S, D'Agostino M, De Paoli L, Montefusco V, Liberati AM, Galieni P, Grammatico S, Muccio VE, Esma F, De Angelis C, Musto P, Ballanti S, Offidani M, Petrucci MT, Gaidano G, Corradini P, Palumbo A, Sonneveld P, Boccadoro M. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2018 Apr;32(4):979-985. Epub 2017 Nov 16. link to original article PubMed

CMP

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CMP: Carfilzomib, Melphalan, Prednisone

Regimen

Study	Evidence
Moreau et al. 2015	Phase I/II

This trial was open to patients older than 65 years of age. Although not explicitly stated, this is considered to be a transplant ineligible population in France. The carfilzomib dose of 36 mg/m² was considered to be the MTD in this trial.

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1 & 2, then 36 mg/m² IV once per day on days 8, 9, 22, 23, 29, 30
  • Cycles 2 to 9: 36 mg/m² IV once per day on days 1, 2, 8, 9, 22, 23, 29, 30
• Melphalan (Alkeran) 9 mg/m²/day PO on days 1 to 4
• Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 4

42-day cycle for 9 cycles

References

1. Moreau P, Kolb B, Attal M, Caillot D, Benboubker L, Tiab M, Touzeau C, Leleu X, Roussel M, Chaleteix C, Planche L, Chiffoleau A, Fortin J, Avet-Loiseau H, Mary JY, Hulin C, Facon T. Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. Blood. 2015 May 14;125(20):3100-4. Epub 2015 Mar 17. link to original article contains verified protocol PubMed

CRd

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CRd: Carfilzomib, Revlimid (Lenalidomide), low-dose dexamethasone
KRd: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), low-dose dexamethasone

Variant #1

Study	Evidence
Korde et al. 2016	Phase II

The minimal difference between this and variant #2 below is the steroid dosing.

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1, 2, then 36 mg/m² IV once per day on days 8, 9, 15, 16
  • Cycles 2 to 8: 36 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycle 1: 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
  • Cycles 2 to 4: 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
  • Cycles 5 to 8: 10 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycle for 8 cycles

Transplant eligible patients underwent stem cell collection after the 4th cycle but were not obligated to proceed to transplant. If transplant was not undertaken, patients proceeded to lenalidomide extension after the 8th cycle.

Variant #2

Study	Evidence
Jakubowiak et al. 2012	Phase I/II

This is the MTD dosing in this phase I/II trial.

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1, 2, then 36 mg/m² IV once per day on days 8, 9, 15, 16
  • Cycles 2 to 8: 36 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 40 mg (route not specified) once per week on days 1, 8, 15, 22
  • Cycles 1 & 2 at clinician's discretion: 4 mg IV/PO once per day on days 2, 9, 16 (in addition to above)
  • Cycles 5 to 8: 20 mg (route not specified) once per week on days 1, 8, 15, 22

28-day cycle for 8 cycles

Transplant eligible patients underwent stem cell collection after the 4th cycle but were not obligated to proceed to transplant. If transplant was not undertaken, patients proceeded to CRd maintenance after the 8th cycle.

References

1. Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. link to original article contains verified protocol link to PMC article PubMed
2. Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. link to original article contains verified protocol PubMed

CRd (Cyclophosphamide)

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CRd: Cyclophosphamide, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Evidence
Kumar et al. 2011	Phase II

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² PO once per day on days 1, 8, 15
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

Supportive medications

• Aspirin 325 mg PO once per day
• LMWH or Warfarin (Coumadin) for patients with history of thrombotic events or at "higher" risk

28-day cycle for 4 to 12 cycles

At physician discretion, patient could proceed to lenalidomide maintenance +/- dexamethasone, after the 12th cycle, until progression.

References

1. Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J, Laumann K, Greipp PR, Lust JA, Gertz MA, Zeldenrust SR, Bergsagel PL, Reeder CB, Witzig TE, Fonseca R, Russell SJ, Mikhael JR, Dingli D, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol. 2011 Aug;86(8):640-5. contains verified protocol link to PMC article PubMed

CYKLONE

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CYKLONE: Cyclophosphamide, Kyprolis (Carfilzomib), ThaLlidomide, DexamethasONE

Regimen

Study	Evidence
Mikhael et al. 2015	Phase II

The carfilzomib dose here is the MTD dose, tested in N=29 patients.

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² PO on days 1, 8, 15
• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
  • Cycle 2 onwards: 36 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 28
• Dexamethasone (Decadron) 40 mg PO on days 1, 8, 15, 22

Supportive medications

• Aspirin or LMWH for patients intolerant of aspirin
• Acyclovir (Zovirax) 400 mg PO BID
• Antibacterials (not further specified)
• 250 to 500 ml of IVF prior to cycle 1 doses of Carfilzomib (Kyprolis) and then only for patients "at risk for tumor lysis syndrome" in subsequent cycles

28-day cycle for 4 to 12 cycles

The authors state that patients could proceed to autologous hematopoietic cell transplant after four cycles but do not provide criteria to undergo transplant as opposed to continuing CYKLONE.

References

1. Mikhael JR, Reeder CB, Libby EN, Costa LJ, Bergsagel PL, Buadi F, Mayo A, Nagi Reddy SK, Gano K, Dueck AC, Stewart AK. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015 Apr;169(2):219-27. Epub 2015 Feb 13. link to original article contains verified protocol link to PMC article PubMed

Ixazomib, Lenalidomide, Dexamethasone

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Regimen

Study	Evidence
Kumar et al. 2014	Phase I/II

This is the MTD dose of this phase I/II trial.

Chemotherapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

28-day cycle for up to 12 cycles

Transplant-eligible patients could proceed to autologous hematopoietic cell transplant after 6 cycles. Patients who did not undergo transplant proceeded to ixazomib maintenance after the 12th cycle.

References

1. Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. link to original article PubMed

KTd

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KTd: Kyprolis (Carfilzomib), Thalidomide, dexamethasone

Regimen

Study	Evidence
Sonneveld et al. 2014	Phase II

Three cohorts are reported; optimal dose of carfilzomib is not described.

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1 & 2, and:
  • Cohort 1: 27 mg/m² IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles
  • Cohort 2: 36 mg/m² IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles
  • Cohort 3: 45 mg/m² IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles
• Thalidomide (Thalomid) 200 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

28-day cycle for 4 cycles

Treatment followed by high-dose melphalan with stem cell rescue.

References

1. Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. link to original article contains verified protocol link to PMC article PubMed

Lenalidomide & Prednisone

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RP: Revlimid (Lenalidomide) & Prednisone

Regimen

Study	Evidence
Falco et al. 2012	Phase II

Note: this is a component of the sequential "RP-MPR-RP" protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Prednisone (Sterapred) 50 mg PO three times per week

Supportive medications

• Aspirin 100 mg PO once per day as thromboprophylaxis during Lenalidomide (Revlimid) treatment. Unclear from protocol if this also means off weeks.
• Antiviral prophylaxis if history of VZV.

28-day cycle for 4 cycles

Subsequent treatment

• MPR consolidation

References

1. Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. link to original article contains verified protocol PubMed

PAD doxil

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PAD doxil: PS-341 (Bortezomib), liposomal Adriamycin (Doxorubicin), Dexamethasone
DVD: Doxil (Liposomal doxorubicin), Velcade (Bortezomib), Dexamethasone
VDD: Velcade (Bortezomib), Doxil (Liposomal doxorubicin), Dexamethasone

Variant #1

Study	Evidence
Berenson et al. 2011	Phase II

Chemotherapy

• Pegylated liposomal doxorubicin (Doxil) 5 mg/m² IV once per day on days 1, 4, 8, 11
• Bortezomib (Velcade) 1 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg IV once per day on days 1, 4, 8, 11

28-day cycle for up to 8 cycles

Variant #2

Study	Evidence
Palumbo et al. 2010	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Pegylated liposomal doxorubicin (Doxil) 30 mg/m² IV once on day 4
• Dexamethasone (Decadron) as follows:
  • Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
  • Cycles 2 to 4: 40 mg PO once per day on days 1 to 4

Supportive medications

• Acyclovir (Zovirax) recommended during Bortezomib (Velcade) therapy

21-day cycle for 4 cycles

Treatment followed by tandem MEL-100, then auto HSCT.

Variant #3

Study	Evidence
Jakubowiak et al. 2009	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Pegylated liposomal doxorubicin (Doxil) 30 mg/m² IV once on day 4
• Dexamethasone (Decadron) as follows:
  • Cycle 1: 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

Supportive medications

• Low-molecular weight heparin 40 mg SC once per day or Aspirin 81 mg PO once per day for DVT prophylaxis
• Acyclovir (Zovirax) 400 mg PO BID for Herpes zoster prophylaxis

21-day cycle for 6 cycles

References

1. Jakubowiak AJ, Kendall T, Al-Zoubi A, Khaled Y, Mineishi S, Ahmed A, Campagnaro E, Brozo C, Braun T, Talpaz M, Kaminski MS. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol. 2009 Oct 20;27(30):5015-22. Epub 2009 Sep 8. link to original article contains verified protocol PubMed
   1. Update: Dytfeld D, Griffith KA, Friedman J, Lebovic D, Harvey C, Kaminski MS, Jakubowiak AJ. Superior overall survival of patients with myeloma achieving very good partial response or better to initial treatment with bortezomib, pegylated liposomal doxorubicin, and dexamethasone, predicted after two cycles by a free light chain- and M-protein-based model: extended follow-up of a phase II trial. Leuk Lymphoma. 2011 Jul;52(7):1271-80. link to original article contains verified protocol PubMed
2. Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. link to original article contains verified protocol PubMed
   1. Update: Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. link to original article contains protocol PubMed
3. Berenson JR, Yellin O, Chen CS, Patel R, Bessudo A, Boccia RV, Yang HH, Vescio R, Yung E, Mapes R, Eades B, Hilger JD, Wirtschafter E, Hilger J, Nassir Y, Swift RA. A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients. Br J Haematol. 2011 Dec;155(5):580-7. Epub 2011 Sep 26. link to original article contains verified protocol PubMed

Total Therapy

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Regimen

Study	Evidence
Barlogie et al. 2007 (Total Therapy 3)	Prospective

Total Therapy is a very complicated regimen, you are highly recommended to refer to the original protocols for further details. Total Therapy 3 is replicated here; the references for Total Therapy 2 are provided below but there are no plans to add this regimen here, for now.

Induction therapy, VTD-PACE

VTD-PACE: Velcade (Bortezomib), Thalidomide, Dexamethasone, Platinum (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide

• Bortezomib (Velcade) 1 mg/m² SC once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 200 mg PO once per day on days 4 to 7
• Dexamethasone (Decadron) 40 mg PO once per day on days 4 to 7
• Cisplatin (Platinol) 10 mg/m²/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m²)
• Doxorubicin (Adriamycin) 10 mg/m²/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m²)
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 160 mg/m²)
• Peripheral blood stem cells (PBSC) are usually collected during cycle 1--cycle 2 PBSC collection is done if needed--with a median CD34 count of 29 x 10⁶/kg. 87% of collections yielded at least 20 x 10⁶/kg.

Duration of each cycle not specified; 2 cycles total are given, no more than 8 weeks apart

During the interim period between cycle 1 and cycle 2, as well as after cycle 2 and prior to transplant, this is given once platelets have recovered to at least 50 x 10⁹/L:

• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 21

21-day cycles, given between induction cycles and transplant

In other words, the initial therapy consists of: Induction therapy cycle 1, dexamethasone & thalidomide, induction therapy cycle 2, dexamethasone & thalidomide, then transplant.

Supportive medications

• As described in Barlogie et al. 2006, which Barlogie et al. 2007 refers to. Note: Barlogie et al. 2007 lists an incorrect title for the reference. See below for the the correct full reference.
• Filgrastim (Neupogen) "was administered to support induction and consolidation chemotherapy regimens"
• "Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed
• Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide

Autologous hematopoietic cell transplant

Full details were not provided in Barlogie et al. 2007. Tandem autologous transplants were done between 2 to 6 months apart.

• Melphalan (Alkeran) 200 mg/m2

During the interim period after transplant 1 and transplant 2, patients receive:

• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 21

21-day cycles, given in the time between and after each transplant; if platelets less than 50 x 10⁹/L, proceed to year 1 of maintenance therapy. Otherwise, if platelets are at least 50 x 10⁹/L, proceed to consolidation therapy.

Consolidation therapy, VTD-PACE

VTD-PACE: Velcade (Bortezomib), Thalidomide, Dexamethasone, Platinum (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide

Cycle 1 of consolidation starts 1.5 to 4 months after the last transplant. Cycle 2 of consolidation starts 2 to 4 months after cycle 1 of consolidation.

• Bortezomib (Velcade) 1 mg/m² SC once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 4
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
• Cisplatin (Platinol) 7.5 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 30 mg/m²)
• Doxorubicin (Adriamycin) 7.5 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 30 mg/m²)
• Cyclophosphamide (Cytoxan) 300 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1200 mg/m²)
• Etoposide (Vepesid) 30 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 120 mg/m²)

2 cycles total are given according to the interval specified above, with the interim therapy below used

During the interim period between cycle 1 and cycle 2, as well as after cycle 2 and prior to maintenance therapy, this is given once platelets have recovered to at least 50 x 10⁹/L:

• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21

21-day cycles, given between consolidation cycles and maintenance

In other words, consolidation therapy consists of: Consolidation therapy cycle 1, dexamethasone & thalidomide, consolidation therapy cycle 2, dexamethasone & thalidomide, then maintenance therapy.

Supportive medications

• As described in Barlogie et al. 2006, which Barlogie et al. 2007 refers to. Note: Barlogie et al. 2007 lists an incorrect title for the reference. See below for the the correct full reference.
• Filgrastim (Neupogen) "was administered to support induction and consolidation chemotherapy regimens"
• "Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed
• Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide

Maintenance therapy, year 1 - VTD

VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

Year 1 of maintenance therapy starts 1 to 4 months after consolidation cycle 2.

• Bortezomib (Velcade) 1 mg/m² SC once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 28
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 8 to 11

28-day cycle for 1 year, then proceed to maintenance therapy years 2 to 3

Maintenance therapy, years 2 & 3 - TD

TD: Thalidomide, Dexamethasone

• Thalidomide (Thalomid) 100 mg PO once every other day
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4

28-day cycle for 2 years

References

1. Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93. link to original article PubMed
   1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
2. Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, Fassas A, Zangari M, Hollmig K, Pineda-Roman M, Lee C, Talamo G, Thertulien R, Kiwan E, Krishna S, Fox M, Crowley J. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006 Mar 9;354(10):1021-30. link to original article supportive medication details PubMed
   1. Update: Zangari M, van Rhee F, Anaissie E, Pineda-Roman M, Haessler J, Crowley J, Barlogie B. Eight-year median survival in multiple myeloma after total therapy 2: roles of thalidomide and consolidation chemotherapy in the context of total therapy 1. Br J Haematol. 2008 May;141(4):433-44. Epub 2008 Mar 26. link to original article link to PMC article PubMed
   2. Subgroup analysis: Barlogie B, Pineda-Roman M, van Rhee F, Haessler J, Anaissie E, Hollmig K, Alsayed Y, Waheed S, Petty N, Epstein J, Shaughnessy JD Jr, Tricot G, Zangari M, Zeldis J, Barer S, Crowley J. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008 Oct 15;112(8):3115-21. Epub 2008 May 20. link to original article link to PMC article PubMed
   3. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
3. Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007 Jul;138(2):176-85. link to original article contains verified protocol PubMed
   1. Update: Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van Rhee F, Crowley J, Shaughnessy JD Jr, Barlogie B. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol. 2008 Mar;140(6):625-34. link to original article link to PMC article PubMed
   2. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
4. Nair B, van Rhee F, Shaughnessy JD Jr, Anaissie E, Szymonifka J, Hoering A, Alsayed Y, Waheed S, Crowley J, Barlogie B. Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood. 2010 May 27;115(21):4168-73. Epub 2010 Feb 2. link to original article link to PMC article PubMed

VP

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VP: Velcade (Bortezomib) & Prednisone

Regimen

Study	Evidence
Larocca et al. 2016	Phase II

Note: doses and schedules were not specified in the abstract.

Chemotherapy

• Bortezomib (Velcade) SC
• Prednisone (Sterapred)

Treatment followed by bortezomib maintenance.

References

1. Larocca A, Bringhen S, Petrucci MT, Oliva S, Falcone AP, Caravita T, Villani O, Benevolo G, Liberati AM, Morabito F, Montefusco V, Passera R, De Rosa L, Omedé P, Vincelli ID, Spada S, Carella AM, Ponticelli E, Derudas D, Genuardi M, Guglielmelli T, Nozzoli C, Aghemo E, De Paoli L, Conticello C, Musolino C, Offidani M, Boccadoro M, Sonneveld P, Palumbo A. A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma. Leukemia. 2016 Jun;30(6):1320-6. link to original article PubMed

VTD-PACE

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VTD-PACE: Velcade (Bortezomib), Thalidomide, Dexamethasone, Platinum (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide

Regimen

Study	Evidence
Barlogie et al. 2007 (Total Therapy 3)	Prospective

Note: this is the induction therapy used in Total Therapy 3. We are not aware of other sources prospectively describing VTD-PACE.

Chemotherapy

• Bortezomib (Velcade) 1 mg/m² SC once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 200 mg PO once per day on days 4 to 7
• Dexamethasone (Decadron) 40 mg PO once per day on days 4 to 7
• Cisplatin (Platinol) 10 mg/m²/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m²)
• Doxorubicin (Adriamycin) 10 mg/m²/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m²)
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 160 mg/m²)

Duration of each cycle not specified; 2 cycles total are given, no more than 8 weeks apart

References

1. Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007 Jul;138(2):176-85. link to original article contains verified protocol PubMed
2. Retrospective: Abstract: Preet Paul Singh, Wilson I. Gonsalves, Vinay Gupta, Francis Buadi, Martha Lacy, Angela Dispenzieri, Morie Gertz, Suzanne R. Hayman, David Dingli, Stephen J. Russell, John Anthony Lust, Steven R. Zeldenrust, Prashant Kapoor, Arleigh Robertson McCurdy, S. Vincent Rajkumar, Shaji Kumar. Clinical outcomes after intensive VDT-PACE therapy for relapsed multiple myeloma. J Clin Oncol 31, 2013 (suppl; abstr 8600) link to abstract

Consolidation after first-line therapy

Note that there is no crisp distinction between consolidation and maintenance. Generally regimens that are intended for a long or indefinite duration would be considered maintenance, whereas regimens with a short intended course would be considered consolidation.

DCEP

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DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol (Cisplatin)

Regimen

Study	Evidence	Comparator	Efficacy
Harousseau et al. 2010 (IFM 2005-01)	Phase III	autologous hematopoietic cell transplant	Seems not superior

Preceding treatment

• VD x 4 versus VAD x 4

Chemotherapy

• Dexamethasone (Decadron) 40 mg once per day on days 1 to 4
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m²)
• Cisplatin (Platinol) 15 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 60 mg/m²)

28-day cycle for 2 cycles

All patients then proceeded to receive autologous hematopoietic cell transplant.

References

1. IFM 2005-01: Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010 Oct 20;28(30):4621-9. Epub 2010 Sep 7. link to original article contains verified protocol PubMed

KTd

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KTd: Kyprolis (Carfilzomib), Thalidomide, dexamethasone

Regimen

Study	Evidence
Sonneveld et al. 2014	Phase II

Preceding treatment

• high-dose melphalan with stem cell rescue.

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cohort 1: 27 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
  • Cohort 2: 36 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
• Thalidomide (Thalomid) 50 mg PO once per day
• Dexamethasone (Decadron) 20 mg PO once per week on days 1, 8, 15, 22

28-day cycle for 4 cycles

References

1. Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. link to original article contains verified protocol link to PMC article PubMed

Lenalidomide & Prednisone

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Regimen

Study	Evidence
Palumbo et al. 2010	Phase II

Preceding treatment

• Tandem MEL-100, then auto HSCT

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Prednisone (Sterapred) 50 mg PO once every other day

Supportive medications

• Aspirin 100 mg PO once per day during Lenalidomide (Revlimid) treatment

28-day cycle for 4 cycles

Treatment followed by lenalidomide maintenance.

References

1. Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. link to original article contains verified protocol PubMed
   1. Update: Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. link to original article contains protocol PubMed

Melphalan, then auto HSCT

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Regimen, "MEL200"

Study	Evidence	Comparator	Efficacy
Moreau et al. 2002 (IFM 9502)	Phase III	Melphalan & TBI, then auto HSCT	Might have superior OS
Bladé et al. 2005 (PETHEMA)	Phase III	VBMCP/VBAD	Seems not superior
Cavo et al. 2007 (Bologna 96)	Phase III	Melphalan, then auto HSCT, then Melphalan & Busulfan, then auto HSCT	Inferior EFS
Lokhorst et al. 2009 (HOVON 50/GMMG-HD3)	Non-randomized portion of RCT
Björkstrand et al. 2011	Non-randomized
Moreau et al. 2011 (IFM 2007-02)	Non-randomized
Morgan et al. 2011 (MRC Myeloma IX)	Non-randomized portion of RCT
Rosiñol et al. 2012 (PETHEMA/GEM GEM05MENOS65)	Non-randomized portion of RCT
Sonneveld et al. 2012 (HOVON-65)	Non-randomized portion of RCT
Lok et al. 2014	Non-randomized
Roussel et al. 2014	Phase II
Sonneveld et al. 2014	Phase II
Mai et al. 2015 (GMMG-MM5)	Non-randomized portion of RCT
Mai et al. 2016 (GMMG-HD2)	Phase III	Tandem melphalan, then auto HSCT	Non-inferior EFS
Attal et al. 2017 (IFM 2009)	Phase III	RVD consolidation	Superior PFS

Treatment preceded by varying induction regimens:

Trial	Induction regimen	# of cycles
IFM 9502	VAD	3
Bladé et al. 2005	VBMCP/VBAD	4
Bologna 96	VAD	4
HOVON 50/GMMG-HD3	TAD	3
	VAD	3
IFM2007-02	vtD	4
	VD	4
MRC Myeloma IX	CTD	4 to 6
	CVAD	4 to 6
PETHEMA/GEM GEM05MENOS65	TD	6
	VBMCP/VBAD/B	6
	VTD	6
HOVON-65	PAD	3
	VAD	3
Lok et al. 2014	vtD	4
Roussel et al. 2014	RVD	3
Sonneveld et al. 2014	KTd	4
GMMG-MM5	VCD	3
	PAd	3
IFM 2009	RVD	3

Chemotherapy

• Melphalan (Alkeran) 200 mg/m² IV once on day -2

Stem cells re-infused on day 0

Treatment followed by varying consolidation and/or maintenance regimens:

Trial	Subsequent regimen	Type of regimen	Duration
IFM 9502	Interferon alfa	Maintenance	1 year
Bladé et al. 2005	IFN & Dexamethasone	Maintenance	Indefinite
Bologna 96	Interferon alfa	Maintenance	Indefinite
HOVON 50/GMMG-HD3	Interferon alfa (if induced with VAD)	Maintenance	Indefinite
	Thalidomide (if induced with TAD)	Maintenance	Indefinite
IFM2007-02	Unspecified	Unspecified	Unspecified
MRC Myeloma IX	Thalidomide	Maintenance	Indefinite
	No further treatment	N/A	N/A
PETHEMA/GEM GEM05MENOS65	Interferon alfa-2b	Maintenance	3 years
	Thalidomide	Maintenance	3 years
	TV	Maintenance	3 years
HOVON-65	Bortezomib (if induced with PAD)	Maintenance	2 years
	Thalidomide (if induced with VAD)	Maintenance	2 years
Lok et al. 2014	vtD	Consolidation	2 cycles
Roussel et al. 2014	RVD	Consolidation	2 cycles
Sonneveld et al. 2014	KTd	Consolidation	4 cycles
GMMG-MM5	MEL200, then auto HSCT (if at least nCR not achieved)	Consolidation	1 cycle
	Lenalidomide	Consolidation	Not specified in abstract
IFM 2009	RVD	Consolidation	2 cycles

References

1. Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, Doyen C, Jaubert J, Fuzibet JG, François S, Benboubker L, Monconduit M, Voillat L, Macro M, Berthou C, Dorvaux V, Pignon B, Rio B, Matthes T, Casassus P, Caillot D, Najman N, Grosbois B, Bataille R, Harousseau JL; Intergroupe Francophone du Myélome. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood. 2002 Feb 1;99(3):731-5. link to original article PubMed
2. Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, García-Laraña J, Mateos MV, Palomera L, Fernández-Calvo J, Martí JM, Giraldo P, Carbonell F, Callís M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA). High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005 Dec 1;106(12):3755-9. Epub 2005 Aug 16. link to original article contains verified protocol PubMed
3. Bologna 96: Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. link to original article contains verified protocol PubMed
4. Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article contains verified protocol PubMed
5. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
6. Björkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Musto P, Beksac M, Bosi A, Milone G, Corradini P, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Gahrton G. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol. 2011 Aug 1;29(22):3016-22. Epub 2011 Jul 5. Erratum in: J Clin Oncol. 2011 Sep 20;29(27):3721. link to original article contains verified protocol PubMed
7. Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. link to original article contains verified protocol PubMed
8. Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article contains verified protocol PubMed
   1. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. contains verified protocol link to PMC article PubMed
   2. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed
9. Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. link to original article contains verified protocol PubMed
10. HOVON-65/GMMG-HD4: Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
    1. Update: Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. link to original article PubMed
11. Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous Bortezomib incorporated into the Bortezomib-Thalidomide-Dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. link to original article contains verified protocol link to PMC article PubMed
12. Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
13. Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. link to original article contains verified protocol link to PMC article PubMed
14. Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article contains verified protocol PubMed
15. GMMG-HD2: Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, Naumann R, Neben K, Egerer G, Ho AD, Hillengass J, Raab MS, Neubauer A, Peyn A, Ko YD, Peter N, Scheid C, Goldschmidt H. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol. 2016 Jun;173(5):731-41. Epub 2016 Mar 17. link to original article PubMed
16. IFM 2009: Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. link to original article contains verified protocol PubMed

MPR

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MPR: Melphalan, Prednisone, Revlimid (Lenalidomide)

Variant #1, 0.18/2/10

Study	Evidence	Comparator	Efficacy
Palumbo et al. 2014 (GIMEMA RV-209)	Phase III	Tandem Melphalan, then auto HSCT	Seems to have inferior OS

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Rd induction x 4

Chemotherapy

• Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

28-day cycle for 6 cycles

Subsequent treatment

• Lnalidomide maintenance versus no further treatment

Variant #2

Study	Evidence
Falco et al. 2012	Phase II

Note: this is a component of the sequential "RP-MPR-RP" protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• RP induction x 4

Chemotherapy

• Melphalan (Alkeran) 2 mg PO three times per week
• Prednisone (Sterapred) 50 mg PO three times per week
• Lenalidomide (Revlimid) 10 or 15 mg PO once per day on days 1 to 21

Supportive medications

• Aspirin 100 mg PO once per day as thromboprophylaxis during Lenalidomide (Revlimid) treatment. Unclear from protocol if this also means off weeks.
• Antiviral prophylaxis if history of VZV.

28-day cycle for 6 cycles

Subsequent treatment

• RP maintenance

References

1. Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. link to original article contains verified protocol PubMed
2. GIMEMA RV-209: Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article contains verified protocol PubMed

RVD

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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
VRd: Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone

Variant #1, 2 cycles post-transplant with lower-dose dex

Study	Evidence
Attal et al. 2017 (IFM 2009)	Non-randomized portion of RCT

Preceding treatment

• High-dose melphalan & autologous hematopoietic stem cell transplant

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 2 cycles

Subsequent treatment

• Lenalidomide maintenance

Variant #2, 2 cycles post-transplant with higher-dose dex

Study	Evidence
Roussel et al. 2014	Phase II

Two months after hematologic recovery, patients without progressive disease began treatment.

Preceding treatment

• High-dose melphalan & autologous hematopoietic stem cell transplant

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15

Supportive medications

• Low–molecular weight heparin (LMWH) for DVT prophylaxis
• Antiviral therapy with example valacyclovir given, for herpes zoster prevention
• Antibiotic prophylaxis with example amoxicillin given, for bacterial infections

21-day cycle for 2 cycles

Subsequent treatment

• Lenalidomide maintenance

Variant #3, 5 cycles, no transplant

Study	Evidence	Comparator	Efficacy
Attal et al. 2017 (IFM 2009)	Phase III	Melphalan, then auto HSCT	Inferior PFS

Preceding treatment

• RVD induction x 3

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 5 cycles

Subsequent treatment

• Lenalidomide maintenance

Variant #4, 8 cycles, no transplant

Study	Evidence	Comparator	Efficacy
Jacobus et al. 2016 (E1A05)	Phase III	Rd	Not reported

Note: this trial closed early due to poor accrual so only descriptive results are available.

Preceding treatment

• Dexamethasone-based induction for 1 to 6 cycles

Chemotherapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15

21-day cycle for 8 cycles

References

1. Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014 Mar;28(3):690-3. Epub 2013 Nov 13. link to original article PubMed
2. Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
3. E1A05: Jacobus SJ, Rajkumar SV, Weiss M, Stewart AK, Stadtmauer EA, Callander NS, Dreosti LM, Lacy MQ, Fonseca R. Randomized phase III trial of consolidation therapy with bortezomib-lenalidomide-Dexamethasone (VRd) vs bortezomib-dexamethasone (Vd) for patients with multiple myeloma who have completed a dexamethasone based induction regimen. Blood Cancer J. 2016 Jul 29;6(7):e448. link to original article link to PMC article contains verified protocol PubMed
4. IFM 2009: Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. link to original article contains verified protocol PubMed

Tandem melphalan, then auto HSCT

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Variant #1, MEL200, then MEL200

Study	Evidence	Comparator	Efficacy
Lokhorst et al. 2009 (HOVON 50/GMMG-HD3)	Non-randomized portion of RCT
Krishnan et al. 2011 (BMT CTN 0102)	Phase III	MEL200, then auto HSCT, then RIC allo HSCT	Seems not superior
Sonneveld et al. 2012 (GMMG-HD4)	Non-randomized portion of RCT
Palumbo et al. 2014 (RV-MM-PI-209)	Phase III	MPR consolidation	Seems to have superior OS
Gay et al. 2015 (EMN-441)	Phase III	CRD consolidation	Superior PFS
Mai et al. 2016 (GMMG-HD2)	Phase III	Melphalan, then auto HSCT	Non-inferior EFS

Preceding treatment

Trial	Induction regimen	# of cycles
HOVON 50/GMMG-HD3	TAD	3
	VAD	3
BMT CTN 0102	Not specified	N/A
GMMG-HD4	PAD	3
	VAD	3
RV-MM-PI-209	Rd	4
EMN-441	Rd	4

Chemotherapy, first transplant

• Melphalan (Alkeran) 200 mg/m² IV once on day -2

Stem cells re-infused on day 0

Chemotherapy, second transplant

• Melphalan (Alkeran) 200 mg/m² IV once on day -2

Stem cells re-infused on day 0

Treatment followed by varying consolidation and/or maintenance regimens:

Trial	Subsequent regimen	Type of regimen	Duration
HOVON 50/GMMG-HD3	Interferon alfa (if induced with VAD)	Maintenance	Indefinite
	Thalidomide (if induced with TAD)	Maintenance	Indefinite
BMT CTN 0102	No further treatment	N/A	N/A
	Thal-Dex	Maintenance	1 year
HOVON-65	Bortezomib (if induced with PAD)	Maintenance	2 years
	Thalidomide (if induced with VAD)	Maintenance	2 years
RV-MM-PI-209	Lenalidomide	Maintenance	Indefinite
	No further treatment	N/A	N/A
EMN-441	Lenalidomide	Maintenance	Indefinite
	Lenalidomide & Prednisone	Maintenance	Indefinite

Variant #2, MEL200, then MEL200 (split doses)

Study	Evidence	Efficacy
Barlogie et al. 1999 (Total Therapy)	Non-randomized	83%

Preceding treatment

• EDAP x 1

Chemotherapy, first transplant

• Melphalan (Alkeran) 100 mg/m² IV once per day on days -3 & -2

Stem cells re-infused on day 0

Chemotherapy, second transplant

• Melphalan (Alkeran) 100 mg/m² IV once per day on days -3 & -2

Stem cells re-infused on day 0

Treatment followed by interferon alfa maintenance.

Variant #3, MEL100, then MEL100

Study	Evidence	Efficacy
Palumbo et al. 2010	Phase II	VGPR or better: 82%

Preceding treatment

• PAD doxil induction x 4. ORR as reported is VGPR or better.

Chemotherapy, first transplant

• Melphalan (Alkeran) 100 mg/m² IV once (day not specified)

Stem cells re-infused on day 0

Chemotherapy, second transplant

• Melphalan (Alkeran) 100 mg/m² IV once (day not specified)

Treatment followed by lenalidomide & prednisone maintenance.

References

1. Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. link to original article contains verified protocol PubMed
2. Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, Giaccone L, Sorasio R, Omedè P, Baldi I, Bringhen S, Massaia M, Aglietta M, Levis A, Gallamini A, Fanin R, Palumbo A, Storb R, Ciccone G, Boccadoro M. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007 Mar 15;356(11):1110-20. link to original article does not contain protocol PubMed
3. Rosiñol L, Pérez-Simón JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ, González JD, Díaz-Mediavilla J, Hernández B, García-Frade J, Carrera D, León A, Hernández M, Abellán PF, Bergua JM, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas y Grupo Español de Mieloma (PETHEMA/GEM). A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood. 2008 Nov 1;112(9):3591-3. Epub 2008 Jul 8. link to original article does not contain protocol PubMed
4. Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article contains verified protocol PubMed
5. Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. link to original article contains verified protocol PubMed
   1. Update: Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. link to original article contains protocol PubMed
6. Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG; Blood Marrow Transplant Clinical Trials Network (BMT CTN). Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203. Epub 2011 Sep 29. link to PMC article contains verified protocol PubMed
7. HOVON-65/GMMG-HD4: Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
   1. Update: Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. link to original article PubMed
8. Meta-analysis: Armeson KE, Hill EG, Costa LJ. Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant. 2013 Apr;48(4):562-7. Epub 2012 Sep 10. Review. link to original article PubMed
9. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article contains verified protocol PubMed
10. Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article contains protocol PubMed
11. Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, Naumann R, Neben K, Egerer G, Ho AD, Hillengass J, Raab MS, Neubauer A, Peyn A, Ko YD, Peter N, Scheid C, Goldschmidt H. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol. 2016 Jun;173(5):731-41. Epub 2016 Mar 17. link to original article PubMed

VTD

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VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

Variant #1, "vTD"

Study	Evidence
Lok et al. 2014	Non-randomized

Preceding treatment

• Melphalan with autologous hematopoietic stem cell transplantation

Chemotherapy

• Bortezomib (Velcade) 1 mg/m² SC once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1 to 4

21-day cycle for 2 cycles

Variant #2

Study	Evidence
Cavo et al. 2010 (GIMEMA MM-BO2005)	Non-randomized

VTD consolidation is to begin 3 months after the second transplant.

Preceding treatment

• VTD induction and high-dose melphalam with tandem autologous hematopoietic stem cell transplant

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 35
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

Supportive medications

• Acyclovir (Zovirax) prophylaxis recommended

35-day cycle for 2 cycles

Subsequent treatment

• Dexamethasone maintenance

Variant #3

Study	Evidence
Ladetto et al. 2010 (GIMEMA VEL-03-096)	Phase II

Preceding treatment

• Melphalan, then HSCT, with at least a very good partial response (VGPR)

Chemotherapy

• Bortezomib (Velcade) 1.6 mg/m² IV once per day on days 1, 8, 15, 22
• Thalidomide (Thalomid) 50 mg PO once per day, increased by 50 mg each week, up to a maximum of 200 mg PO once per day
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18

35-day cycle for 4 cycles

References

1. GIMEMA VEL-03-096: Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L, Crippa C, De Rosa L, Pregno P, Grasso M, Liberati AM, Caravita T, Pisani F, Guglielmelli T, Callea V, Musto P, Cangialosi C, Passera R, Boccadoro M, Palumbo A. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010 Apr 20;28(12):2077-84. Epub 2010 Mar 22. link to original article contains verified protocol PubMed
   1. Update: Ferrero S, Ladetto M, Drandi D, Cavallo F, Genuardi E, Urbano M, Caltagirone S, Grasso M, Rossini F, Guglielmelli T, Cangialosi C, Liberati AM, Callea V, Carovita T, Crippa C, De Rosa L, Pisani F, Falcone AP, Pregno P, Oliva S, Terragna C, Musto P, Passera R, Boccadoro M, Palumbo A. Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival. Leukemia. 2015 Mar;29(3):689-95. Epub 2014 Jul 16. link to original article PubMed
2. GIMEMA MM-BO2005: Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. link to original article contains protocol PubMed
   1. Update: Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. link to original article contains verified protocol PubMed
3. Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous bortezomib incorporated into the bortezomib-thalidomide-dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. link to original article contains verified protocol link to PMC article PubMed

Maintenance after first-line therapy

Note that there is no crisp distinction between consolidation and maintenance. Generally regimens that are intended for a long or indefinite duration would be considered maintenance, whereas regimens with a short intended course would be considered consolidation.

Bortezomib monotherapy

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Variant #1

Study	Evidence	Comparator	Efficacy
Mellqvist et al. 2013 (NMSG 15/05)	Phase III	Observation	Might have superior PFS

This trial only included bortezomib-naive patients; induction regimen was not specified but the majority received Cy-Dex. All patients underwent autologous hematopoietic cell transplant at least 3 months prior to starting maintenance.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11

21-day cycle for 2 cycles, then:

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22

Supportive medications

• Bisphosphonates were administered "according to national guidelines."

28-day cycle for 4 cycles

Variant #2, every other week for 2 years

Study	Evidence	Comparator	Efficacy
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)	Phase III	Thalidomide	Superior PFS (*)

Note that in the initial publication, this arm seemed to have an overall survival advantage; this was no longer present in the updated report of 2017; PFS was the primary endpoint.

Preceding treatment

• HOVON-65: High-dose melphalan with single autologous hematopoietic stem cell transplant
• GMMG-HD4: High-dose melphalan with tandem autologous hematopoietic stem cell transplants

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once on day 1

14-day cycle for 2 years

Variant #3, every other week indefinitely

Study	Evidence	Efficacy
Berdeja et al. 2017	Phase II	91%

Preceding treatment

• BBD x 8

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² (route not specified) once on day 1

14-day cycles

Variant #4, 4 out of 5 weeks for 6 months

Study	Evidence
Niesvizky et al. 2015 (UPFRONT)	Non-randomized portion of RCT

Preceding treatment

• VD x 8 versus VMP x 8 versus VTD x 8

Chemotherapy

• Bortezomib (Velcade) 1.6 mg/m² IV once per day on days 1, 8, 15, 22

35-day cycle for 5 cycles

Variant #5, 4 out of 6 weeks for 6 months

Study	Evidence
Kumar et al. 2012 (EVOLUTION)	Non-randomized portion of RCT

Preceding treatment

• VDC versus VDC-mod versus VDR versus VDCR

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22

Supportive medications

• Aspirin 325 mg PO once per day
  • Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used based on physician discretion
• PCP prophylaxis recommended
• Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
• Bisphosphonates could be used "as necessary"

42-day cycle for 4 cycles

References

1. Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. link to original article contains verified protocol PubMed
2. HOVON-65/GMMG-HD4: Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. link to original article PubMed
   2. Update: Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. link to original article PubMed
3. Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, Steingrimsdottir H, Abildgaard N, Ahlberg L, Blimark C, Dahl IM, Forsberg K, Gedde-Dahl T, Gregersen H, Gruber A, Guldbrandsen N, Haukås E, Carlson K, Kvam AK, Nahi H, Lindås R, Andersen NF, Turesson I, Waage A, Westin J; Nordic Myeloma Study Group. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013 Jun 6;121(23):4647-54. Epub 2013 Apr 24. link to original article contains verified protocol link to PMC article PubMed
4. UPFRONT: Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed
5. Berdeja JG, Bauer T, Arrowsmith E, Essell J, Murphy P, Reeves JA Jr, Boccia RV, Donnellan W, Flinn I. Phase II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of patients with multiple myeloma who are not candidates for high dose chemotherapy. Br J Haematol. 2017 Apr;177(2):254-262. Epub 2017 Feb 7. link to original article contains verified protocol PubMed

Bortezomib & Prednisone

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Regimen

Study	Evidence	Comparator	Efficacy
Mateos et al. 2010 (GEM2005)	Phase III	VT	Seems not superior

Preceding treatment

• VMP x 6 versus VTP x 6

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Prednisone (Sterapred) 50 mg PO once every other day

Supportive medications

• Patients with bone disease received bisphosphonates
• Prophylactic aciclovir was recommended.

3-month cycle for up to 3 years

References

1. Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. link to original article contains verified protocol PubMed
   1. Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article PubMed
   2. Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. link to original article contains verified protocol PubMed

Carfilzomib monotherapy

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Regimen

Study	Evidence
Bringhen et al. 2014	Phase II

Preceding treatment

• CCyd x 9

Chemotherapy

• Carfilzomib (Kyprolis) 36 mg/m² IV once per day on days 1, 2, 15, 16

28-day cycles

References

1. Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. Epub 2014 May 22. link to original article contains verified protocol PubMed

CRd

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CRd: Carfilzomib, Revlimid (Lenalidomide), low-dose dexamethasone
KRd: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Evidence
Jakubowiak et al. 2012	Phase II

This is the MTD dosing in this phase I/II trial.

Preceding treatment

• CRd x 8

Chemotherapy

• Carfilzomib (Kyprolis) 36 mg/m² IV once per day on days 1, 2, 15, 16
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 20 mg (route not specified) once per week on days 1, 8, 15, 22

28-day cycle for 16 cycles

After a total of 24 cycles (including induction), it was recommended that patients proceed to lenalidomide maintenance.

References

1. Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. link to original article contains verified protocol link to PMC article PubMed

Daratumumab monotherapy

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Regimen

Study	Evidence
Mateos et al. 2017 (ALCYONE)	Non-randomized portion of RCT

Preceding treatment

• VMP & Daratumumab x 9

Chemotherapy

• Daratumumab (Darzalex) 16 mg/kg IV once on day 1

Supportive medications

• Dexamethasone (Decadron) 20 mg PO/IV once prior to Daratumumab (Darzalex)

28-day cycles

References

1. ALCYONE: Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. link to original article contains verified protocol PubMed

Ixazomib monotherapy

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Regimen

Study	Evidence
Kumar et al. 2014	Phase I/II

Preceding treatment

• Ixazomib, Lenalidomide, Dexamethasone x 12

Chemotherapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15

28-day cycles until progression

References

1. Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. link to original article PubMed

Lenalidomide monotherapy

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Variant #1, indefinite 10 mg 21/28

Study	Evidence	Comparator	Efficacy
Palumbo et al. 2007	Phase II
Palumbo et al. 2010	Phase II
Palumbo et al. 2012 (MM-015)	Phase III	Placebo	Superior PFS
Palumbo et al. 2014 (RV-MM-PI-209)	Phase III	Observation	Superior PFS
Stewart et al. 2015 (ECOG E1A06)	Non-randomized portion of RCT
Gay et al. 2015 (EMN-441)	Phase III	Lenalidomide & Prednisone	Seems not superior
Magarotto et al. 2016 (EMN01)	Phase III	Lenalidomide & Prednisone	Not reported
Zweegman et al. 2016 (HOVON87/NMSG18)	Phase III	Thalidomide	Seems not superior

Preceding treatment

• Palumbo et al. 2007 and MM-015: MPR induction x 9
• Palumbo et al. 2010: Lenalidomide & Prednisone consolidation.
• RV-MM-PI-209: Tandem high-dose melphalan with autologous hematopoietic stem cell transplants versus MPR consolidation
• ECOG E1A06: mPR induction x 12
• EMN-441: Tandem high-dose melphalan with autologous hematopoietic cell transplants versus CRD consolidation
• EMN01: CPR versus MPR versus Rd induction x 9
• HOVON87/NMSG18: MPR induction x 9

Chemotherapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

Supportive medications

• Varies depending on reference:
• MM-015: Aspirin 75 to 100 mg PO once per day
• Palumbo et al. 2007 and Palumbo et al. 2010: Aspirin 100 mg PO once per day
• ECOG E1A06: Aspirin was required (dose not specified)
  • Full anticoagulation was used for patients at "higher risk" for DVT
• EMN01: Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)
• ECOG E1A06: Pamidronate (Aredia) 90 mg IV once per month recommended for patients with "active bone disease"
• Palumbo et al. 2007: Ciprofloxacin (Cipro) 500 mg PO BID

28-day cycles, given until progression or intolerable toxicity

Variant #2, indefinite 15 mg per day

Study	Evidence	Comparator	Efficacy
Attal et al. 2012 (IFM 2005-02)	Phase III	Placebo	Superior PFS

Consolidation

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycle for 2 cycles, then

Maintenance

• Lenalidomide (Revlimid) 10 mg PO once per day x 3 months, then increased to 15 mg PO once per day if tolerated

Supportive medications

• "Thromboprophylaxis was not used"

Given until progression of disease or unacceptable toxicity, or patient choice

Variant #3, indefinite 30 mg per day

Study	Evidence	Comparator	Efficacy
McCarthy et al. 2012 (CALGB 100104)	Phase III	Placebo	Seems to have superior OS

Patients started therapy 100 to 120 days after autologous hematopoietic cell transplant (AHCT).

Chemotherapy

• Lenalidomide (Revlimid) 20 mg PO once per day; after 3 months, dose may be increased to 30 mg PO once per day if the patient's ANC remains at least 1000/uL and platelet count is at least 75 x 10⁹/L
  • Dose adjustments can be found in the paper's supplementary appendix

Supportive medications

• Patients at high risk of deep venous thrombosis (DVT) or pulmonary embolism (PE) received Aspirin, low molecular weight heparin, or Warfarin (Coumadin) unless contraindicated. High risk patients were defined as people with: history of diabetes, coronary artery disease, "DVT/PE, significant family history, performance status = 2, smoking history, use of oral contraceptives, and[/or] concurrent use of epoetin."

Given until progression of disease or unacceptable toxicity

Variant #4, 2 years of 25 mg 21/28

Study	Evidence
Korde et al. 2016	Phase II

Preceding treatment

• CRd x 8

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycle for up to 24 cycles

Variant #5, 1 year of 10 to 15 mg per day

Study	Evidence
Roussel et al. 2014	Phase II
Attal et al. 2017 (IFM 2009)	Non-randomized portion of RCT

Preceding treatment

• RVD consolidation

Chemotherapy

• Lenalidomide (Revlimid) 10 mg PO once per day, escalated to 15 mg PO once per day after 3 months, if tolerated.

12-month course

Variant #6, indefinite 25 mg 21/28

Study	Evidence
Jakubowiak et al. 2012	Phase II

Preceding treatment

• CRd x 24

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycles until progression

References

1. Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, Crippa C, Ciccone G, Omedè P, Ambrosini MT, Gay F, Bringhen S, Musto P, Foà R, Knight R, Zeldis JB, Boccadoro M, Petrucci MT; GIMEMA--Italian Multiple Myeloma Network. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. J Clin Oncol. 2007 Oct 1;25(28):4459-65. Epub 2007 Sep 4. link to original article contains verified protocol PubMed
2. Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. link to original article contains verified protocol PubMed
   1. Update: Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. link to original article contains protocol PubMed
3. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Seiler M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1770-81. link to original article link to supplementary appendix contains verified protocol link to PMC article PubMed
   1. Update: Holstein SA, Jung SH, Richardson PG, Hofmeister CC, Hurd DD, Hassoun H, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, van Besien K, Gentile TG, Isola L, Maziarz RT, Bashey A, Landau H, Martin T, Qazilbash MH, Rodriguez C, McClune B, Schlossman RL, Smith SE, Hars V, Owzar K, Jiang C, Boyd M, Schultz C, Wilson M, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Linker C, Anderson KC, McCarthy PL. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol. 2017 Sep;4(9):e431-e442. Epub 2017 Aug 17. link to original article PubMed
4. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, Stoppa AM, Hulin C, Benboubker L, Garderet L, Decaux O, Leyvraz S, Vekemans MC, Voillat L, Michallet M, Pegourie B, Dumontet C, Roussel M, Leleu X, Mathiot C, Payen C, Avet-Loiseau H, Harousseau JL; IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1782-91. link to original article contains verified protocol PubMed
   1. Abstract: Update: Michel Attal, MD, Valerie Cances Lauwers, Gerald Marit, Denis Caillot, Thierry Facon, MD, Cyrille Hulin, Philippe Moreau, MD, Claire Mathiot, Murielle Roussel, Catherine Payen, H. Avet-Loiseau and Jean Luc Harousseau. Maintenance Treatment with Lenalidomide After Transplantation for MYELOMA : Final Analysis of the IFM 2005-02. ASH 2010 Abstract 310. link to abstract
5. Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. link to original article contains verified protocol link to PMC article PubMed
6. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. link to original article contains verified protocol PubMed
7. Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
8. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article contains verified protocol PubMed
9. Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article PubMed
10. Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article contains verified protocol link to PMC article PubMed
11. Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article contains protocol PubMed
12. Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed
13. Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article contains verified protocol PubMed
14. Abstract: Meta-analysis: Michel Attal, Antonio Palumbo, Sarah A. Holstein, Valerie Lauwers-Cances, Maria Teresa Petrucci, Paul G. Richardson, Cyrille Hulin, Patrizia Tosi, Kenneth Carl Anderson, Denis Caillot, Valeria Magarotto, Philippe Moreau, Gerald Marit, Zhinuan Yu, Philip L. McCarthy. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): A meta-analysis (MA) of overall survival (OS). J Clin Oncol 34, 2016 (suppl; abstr 8001) link to abstract
15. Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. link to original article contains verified protocol PubMed
16. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. link to original article contains verified protocol PubMed

Lenalidomide & Prednisone

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Variant #1, prednisone 25 mg every other day

Study	Evidence	Comparator	Efficacy
Magarotto et al. 2016 (EMN01)	Phase III	Lenalidomide	Not reported

Preceding treatment

• CPR x 9 versus MPR x 9 versus Rd x 9

Chemotherapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
• Prednisone (Sterapred) 25 mg PO once every other day

Supportive medications

• Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)

28-day cycles

Variant #2, prednisone 25 mg TIW

Study	Evidence
Falco et al. 2012	Phase II

Preceding treatment

• MPR consolidation x 6

Chemotherapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
• Prednisone (Sterapred) 25 mg PO three times per week

Supportive medications

• Aspirin 100 mg PO once per day as thromboprophylaxis during Lenalidomide (Revlimid) treatment. Unclear from protocol if this also means off weeks.
• Antiviral prophylaxis if history of VZV.

28-day cycles

Variant #3, prednisone 50 mg every other day

Study	Evidence	Comparator	Efficacy
Gay et al. 2015 (EMN-441)	Phase III	Lenalidomide	Seems not superior

Preceding treatment

• Tandem high-dose melphalan with autologous hematopoietic stem cell transplants versus CRD consolidation

Chemotherapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
• Prednisone (Sterapred) 50 mg PO once every other day

28-day cycles

References

1. Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. link to original article contains verified protocol PubMed
2. EMN-441: Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article contains protocol PubMed
3. EMN01: Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed

RVD

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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
VRd: Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Evidence
Richardson et al. 2010	Phase II

Preceding treatment

• RVD x 4 to 8 cycles

Chemotherapy

• Lenalidomide (Revlimid) 25 mg (or previously tolerated dose) PO once per day on days 1 to 14
• Bortezomib (Velcade) 1.3 mg/m² (or previously tolerated dose) IV once per day on days 1 & 8
• Dexamethasone (Decadron) 20 mg (or previously tolerated dose) PO once per day on days 1, 2, 8, 9

Supportive medications

• Aspirin 81 mg or 325 mg PO once per day
• Antiviral therapy, such as Acyclovir (Zovirax) 400 mg PO once per day
• Bisphosphonate

21-day cycles until progression or intolerance

References

1. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12. link to original article contains protocol link to PMC article PubMed
2. Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014 Mar;28(3):690-3. Epub 2013 Nov 13. link to original article PubMed

Thalidomide monotherapy

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Variant #1, 3 years of 100 mg/d

Study	Evidence	Comparator	Efficacy
Rosiñol et al. 2017 (PETHEMA/GEM GEM05MENOS65)	Phase III	Interferon alfa-2b	Not reported
		TV	Seems to have inferior PFS

Preceding treatment

• High-dose melphalan & autologous HSCT

Chemotherapy

• Thalidomide (Thalomid) 100 mg PO once per day

Up to 3 years

Variant #2, indefinite 100 mg/d

Study	Evidence	Comparator	Efficacy
Palumbo et al. 2006	Non-randomized portion of RCT
Stewart et al. 2015 (ECOG E1A06)	Non-randomized portion of RCT
Zweegman et al. 2016 (HOVON87/NMSG18)	Phase III	Lenalidomide	Seems not superior

Preceding treatment

• Palumbo et al. 2006: MPT x 6
• ECOG E1A06: MPT x 12
• HOVON87/NMSG18: MPT x 9

Chemotherapy

• Thalidomide (Thalomid) 100 mg PO once per day

Supportive medications

• Per ECOG E1A06, Aspirin was required (dose not specified)
  • Per ECOG E1A06, full anticoagulation was used for patients at "higher risk" for DVT
• Per ECOG E1A06, Pamidronate (Aredia) 90 mg IV once per month recommended for patients with "active bone disease"

Continued until evidence of relapse or refractory disease

Variant #3, 2 years of 50 mg/d

Study	Evidence	Comparator	Efficacy
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)	Phase III	Bortezomib	Inferior PFS (*)

Note that in the initial publication, this arm seemed to have an overall survival disadvantage; this was no longer present in the updated report of 2017; PFS was the primary endpoint. Observed efficacy is for induction PAD, then transplant, then maintenance bortezomib compared with induction VAD, then transplant, then maintenance thalidomide. Treatment starts 4 weeks after the final autologous hematopoietic stem cell transplant.

Preceding treatment

• HOVON-65: High-dose melphalan with autologous hematopoietic stem cell transplant
• GMMG-HD4: High-dose melphalan with tandem autologous hematopoietic stem cell transplants

Chemotherapy

• Thalidomide (Thalomid) 50 mg PO once per day

2-year course

Variant #4, indefinite with lead-in

Study	Evidence	Comparator	Efficacy
Morgan et al. 2012 (MRC Myeloma IX)	Phase III	Observation	Superior PFS

Preceding treatment

• Intensive treatment pathway: High-dose melphalan & autologous hematopoietic stem cell transplant
• Non-intensive treatment pathway: CTDa versus MP

Chemotherapy

• Thalidomide (Thalomid) as follows:
  • Weeks 1 to 4: 50 mg PO once per day
  • Week 5 onwards: 100 mg PO once per day

Continued until progression

Variant #5, indefinite 400 mg/d

Study	Evidence	Comparator	Efficacy
Attal et al. 2006 (IFM 99-02)	Phase III	Observation	Superior OS

Preceding treatment

• VAD x 3 to 4 and high-dose melphalan with tandem autologous hematopoietic stem cell transplant

Chemotherapy

• Thalidomide (Thalomid) 400 mg PO once per day
  • Dose reductions to a minimum of 50 mg PO once per day were allowed

Continued until progression

Variant #6, indefinite 50 mg/d

Study	Evidence
Wijermans et al. 2010 (HOVON 49)	Non-randomized portion of RCT
Lokhorst et al. 2009 (HOVON 50/GMMG-HD3)	Non-randomized portion of RCT

Preceding treatment

• HOVON 49: MPT x 8
• HOVON 50/GMMG-HD3: High-dose melphalan with autologous hematopoietic stem cell transplant or high-dose melphalan with tandem autologous hematopoietic stem cell transplants; this was not a randomization but was pre-determined by the treating center

Chemotherapy

• Thalidomide (Thalomid) 50 mg PO once per day

Supportive medications

• HOVON 49: Bisphosphonate use recommended with Pamidronate (Aredia) or Clodronate (Bonefos); "a maximum treatment period of 2 years was recommended in patients without active disease."
• HOVON 49: During maintenance therapy, "low-dose Aspirin was advised"

Continued until progression

Variant #7, 18 months of 400 mg/d

Study	Evidence
Sahebi et al. 2006	Phase II

Preceding treatment

• High-dose melphalan & autologous hematopoietic stem cell transplant

Chemotherapy

• Thalidomide (Thalomid) 50 mg PO once per day, escalated by 50 mg once per week to a target dose of 400 mg PO once per day

Supportive medications

• Bisphosphonate once per month
• Vitamin B6

18 months of treatment or 6 months past CR, whichever comes first

References

1. Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network (GIMEMA). Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31. link to original article contains protocol PubMed
   1. Update: Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14. Epub 2008 May 27. link to original article contains protocol PubMed
2. Sahebi F, Spielberger R, Kogut NM, Fung H, Falk PM, Parker P, Krishnan A, Rodriguez R, Nakamura R, Nademanee A, Popplewell L, Frankel P, Ruel C, Tin R, Ilieva P, Forman SJ, Somlo G. Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma. Bone Marrow Transplant. 2006 May;37(9):825-9. link to original article contains verified protocol PubMed
3. Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. link to original article contains verified protocol PubMed
   1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
4. **RETRACTED** Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB, Omri HE, Elloumi M, Belaaj H, Jeddi R, Aissaouï L, Ksouri H, Hassen AB, Msadek F, Saad A, Hsaïri M, Boukef K, Amouri A, Louzir H, Dellagi K, Abdeladhim AB; Tunisian Multiple Myeloma Study Group. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood. 2008 Feb 15;111(4):1805-10. Epub 2007 Sep 17. link to original article contains verified protocol PubMed **RETRACTED**
5. Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article contains verified protocol PubMed
6. HOVON 49: Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010 Jul 1;28(19):3160-6. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
7. Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article contains verified protocol PubMed
8. HOVON-65/GMMG-HD4: Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
   1. Update: Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. link to original article PubMed
9. Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article contains verified protocol link to PMC article PubMed
10. Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article contains verified protocol PubMed
11. Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. link to original article contains verified protocol PubMed

Thal-Dex

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TD: Thalidomide, Dexamethasone
Thal-Dex: Thalidomide, Dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Maiolino et al. 2012	Phase III	Dexamethasone	Superior PFS

Preceding treatment

• High-dose melphalan & autologous hematopoietic stem cell transplant

Chemotherapy

• Thalidomide (Thalomid) 200 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

28-day cycle for 12 months or until disease progression

References

1. Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG; Blood Marrow Transplant Clinical Trials Network (BMT CTN). Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203. Epub 2011 Sep 29. link to PMC article contains verified protocol PubMed
2. Maiolino A, Hungria VT, Garnica M, Oliveira-Duarte G, Oliveira LC, Mercante DR, Miranda EC, Quero AA, Peres AL, Barros JC, Tanaka P, Magalhães RP, Rego EM, Lorand-Metze I, Lima CS, Renault IZ, Braggio E, Chiattone C, Nucci M, de Souza CA; Brazilian Multiple Myeloma Study Group (BMMSG/GEMOH). Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012 Oct;87(10):948-52. Epub 2012 Jun 23. link to original article contains verified protocol PubMed

Thalidomide & Prednisolone

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Regimen

Study	Evidence	Comparator	Efficacy
Spencer et al. 2009	Phase III	Prednisolone	Superior OS

Preceding treatment

• High-dose melphalan & auto HSCT

Chemotherapy

• Thalidomide (Thalomid) 100 mg PO once per day, increased to 200 mg PO once per day after 14 days (if tolerated)
• Prednisolone (Millipred) 50 mg PO once every other day

Thalidomide stopped after 12 months; prednisolone given until disease progression

References

1. Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009 Apr 10;27(11):1788-93. Epub 2009 Mar 9. link to original article contains verified protocol PubMed

Thalidomide & Prednisone

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Stewart et al. 2013 (NCICCTG Myeloma 10 Trial)	Phase III	Observation	Improved PFS	Decreased QOL

Preceding treatment

• High-dose melphalan with autologous hematopoietic stem cell transplant

Chemotherapy

• Thalidomide (Thalomid) 200 mg PO once per day
• Prednisone (Sterapred) 50 mg PO once every other day

Supportive medications

• "Bisphosphonates, histamine-2 blockers, and laxatives were recommended"
• "Anticoagulant and antiplatelet medications were not mandated"

Four years or until disease progression

References

1. Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, Reiman T, Roy J, Shustik C, Kovacs MJ, Rubinger M, Cantin G, Song K, Tompkins KA, Marcellus DC, Lacy MQ, Sussman J, Reece D, Brundage M, Harnett EL, Shepherd L, Chapman JA, Meyer RM. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013 Feb 28;121(9):1517-23. Epub 2013 Jan 7. link to original article contains verified protocol link to PMC article PubMed

VT

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VT: Velcade (Bortezomib) & Thalidomide TV: Thalidomide & Velcade (Bortezomib)

Variant #1

Study	Evidence	Comparator	Efficacy
Rosiñol et al. 2017 (PETHEMA/GEM GEM05MENOS65)	Phase III	Interferon alfa-2b Thalidomide	Seems to have superior PFS

Preceding treatment

• High-dose melphalan & autologous HCT

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 100 mg PO once per day

3-month cycle for up to 3 years

Variant #2

Study	Evidence	Comparator	Efficacy
Mateos et al. 2010 (GEM2005)	Phase III	Bortezomib & Prednisone	Seems not superior

Preceding treatment

• VMP x 6 versus VTP x 6

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Thalidomide (Thalomid) 50 mg PO once per day

Supportive medications

• Patients with bone disease received bisphosphonates
• Prophylactic aciclovir was recommended.
• Thromboprophylaxis with either aspirin or low molecular weight heparin

3-month cycle for up to 3 years

Variant #3

Study	Evidence
Palumbo et al. 2010	Non-randomized portion of RCT

Preceding treatment

• VMPT x 9

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once on day 1
• Thalidomide (Thalomid) 50 mg PO once per day

14-day cycle for 2 years or until disease progression or relapse

References

1. Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. link to original article contains verified protocol PubMed
   1. Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article PubMed
   2. Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. link to original article contains verified protocol PubMed
2. Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. link to original article contains verified protocol PubMed
   1. Post-hoc analysis: Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. link to original article contains verified protocol PubMed
   2. Subset analysis: Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. link to original article PubMed
   3. Update: Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. link to original article contains verified protocol PubMed
3. Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. link to original article contains verified protocol PubMed

Relapsed or refractory, randomized data

Bortezomib monotherapy

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Variant #1, indefinite 35-day cycles with lead-in

Study	Evidence	Comparator	Efficacy
Orlowski et al. 2015	Randomized Phase II	Bortezomib & Siltuximab	Seems not superior

Chemotherapy, part 1

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32

42-day cycle for up to 4 cycles, followed by:

Chemotherapy, part 2

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22

35-day cycles until progression

Variant #2, IV 21-day cycles (8 total)

Study	Evidence	Comparator	Efficacy
Jagannath et al. 2004 (CREST)	Randomized Phase II	Low-dose Bortezomib +/- Dexamethasone	Seems not superior
Moreau et al. 2011 (MMY-3021)	Phase III	Subcutaneous Bortezomib +/- Dexamethasone	Non-inferior ORR

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11

21-day cycle for 8 cycles (see note)

In CREST, patients with PD after 2 cycles or SD after 4 cycles could escalate to bortezomib & dexamethasone. In MMY-3021, patients with suboptimal response after 4 cycles could escalate to bortezomib & dexamethasone; patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles.

Variant #3, 11 cycles with lead-in

Study	Evidence	Comparator	Efficacy
Richardson et al. 2005 (APEX)	Phase III	High-dose dexamethasone	Seems to have superior OS (*)

Note: efficacy is reported based on the 2007 update.

Chemotherapy, part 1

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11

21-day cycle for 8 cycles, followed by:

Chemotherapy, part 2

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22

35-day cycle for 3 cycles

Supportive medications

• Bisphosphonate IV therapy once every 3 to 4 weeks unless contraindicated

Variant #4, SC 21-day cycles (8 total)

Study	Evidence	Comparator	Efficacy
Moreau et al. 2011 (MMY-3021)	Phase III	Intravenous Bortezomib +/- Dexamethasone	Non-inferior ORR

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 4, 8, 11
  • Subcutaneous injections are 2.5 mg/mL (3.5 mg bortezomib reconstituted in 1.4 mL NS)
  • SC injections are in the thighs or abdomen, with injection sites rotated between proximal/distal right/left thigh and upper/lower right/left abdominal quadrants

Supportive medications

• Bisphosphonates "according to established guidelines"

21-day cycle for 8 cycles (see note)

Patients with suboptimal response after 4 cycles could escalate to bortezomib & dexamethasone; patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles.

Variant #5, indefinite 21-day cycles

Study	Evidence	Comparator	Efficacy
Richardson et al. 2003 (SUMMIT)	Phase II
Orlowski et al. 2007	Phase III	Bortezomib & Doxorubicin liposomal	Inferior TTP
Mikhael et al. 2008	Phase IIIb
Dimopoulos et al. 2013 (VANTAGE 088)	Phase III	Bortezomib & Vorinostat	Seems to have inferior PFS

Note: SUMMIT and Mikhael et al. 2008 specified a total of 8 cycles, but those who were deriving clinical benefit could continue beyond this.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11

21-day cycles until progression or intolerance

In SUMMIT and Mikhael et al. 2008, patients with PD after 2 cycles or SD after 4 cycles could escalate to bortezomib & dexamethasone.

Variant #6

Study	Evidence	Comparator	Efficacy
Jagannath et al. 2004 (CREST)	Randomized Phase II	Bortezomib +/- Dexamethasone	Seems not superior

Chemotherapy

• Bortezomib (Velcade) 1 mg/m² IV bolus once per day on days 1, 4, 8, 11

21-day cycle for 8 cycles

Patients with PD after 2 cycles or SD after 4 cycles could escalate to bortezomib & dexamethasone.

Variant #7, 35-day cycles (10 total)

Study	Evidence
Hainsworth et al. 2008	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.6 mg/m² IV bolus once per day on days 1, 8, 15, 22

35-day cycle for up to 10 cycles

References

1. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. link to original article contains verified protocol PubMed
   1. Subgroup Analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains protocol PubMed
2. Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004 Oct;127(2):165-72. link to original article contains verified protocol PubMed
   1. Subgroup Analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains protocol PubMed
   2. Update: Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Esseltine DL, Anderson KC. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol. 2008 Nov;143(4):537-40. Epub 2008 Sep 6. link to original article PubMed
3. APEX: Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. link to original article contains verified protocol PubMed
   1. Update: Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Miguel JS, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007 Nov 15;110(10):3557-60. Epub 2007 Aug 9. link to original article contains verified protocol PubMed
4. Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. link to original article contains verified protocol PubMed
   1. Update: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. link to original article PubMed
5. Hainsworth JD, Spigel DR, Barton J, Farley C, Schreeder M, Hon J, Greco FA. Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network. Cancer. 2008 Aug 15;113(4):765-71. link to original article contains verified protocol PubMed
6. Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009 Jan;144(2):169-75. Epub 2008 Nov 19. link to original article contains verified protocol PubMed
7. MMY-3021: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. Epub 2011 Apr 18. link to original article contains verified protocol PubMed
   1. Update: Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, Feng H, Cakana A, Deraedt W, Moreau P. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec;97(12):1925-8. Epub 2012 Jun 11. link to original article link to PMC article PubMed
   2. Subgroup analysis: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Rekhtman G, Masliak Z, Robak P, Esseltine DL, Feng H, Deraedt W, van de Velde H, Arnulf B. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica. 2015 May;100(5):e207-10. Epub 2015 Jan 16. link to original article link to PMC article PubMed
8. Petrucci MT, Giraldo P, Corradini P, Teixeira A, Dimopoulos MA, Blau IW, Drach J, Angermund R, Allietta N, Broer E, Mitchell V, Bladé J. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol. 2013 Mar;160(5):649-59. Epub 2013 Jan 7. link to original article PubMed
9. VANTAGE 088: Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, Rosinol L, Williams C, Blacklock H, Goldschmidt H, Hungria V, Spencer A, Palumbo A, Graef T, Eid JE, Houp J, Sun L, Vuocolo S, Anderson KC. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013 Oct;14(11):1129-1140. Epub 2013 Sep 19. link to original article contains verified protocol PubMed
10. Orlowski RZ, Gercheva L, Williams C, Sutherland H, Robak T, Masszi T, Goranova-Marinova V, Dimopoulos MA, Cavenagh JD, Špička I, Maiolino A, Suvorov A, Bladé J, Samoylova O, Puchalski TA, Reddy M, Bandekar R, van de Velde H, Xie H, Rossi JF. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol. 2015 Jan;90(1):42-9. contains verified protocol link to PMC article PubMed

Bortezomib & Dexamethasone

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BD: Bortezomib, Dexamethasone
Bd: Bortezomib, low-dose dexamethasone
Bort-Dex: Bortezomib, Dexamethasone
Vd: Velcade (Bortezomib), low-dose dexamethasone
VD: Velcade (Bortezomib), Dexamethasone

Variant #1, indefinite 21-day then 28-day cycles

Study	Evidence	Comparator	Efficacy
Jakubowiak et al. 2016 (CA204-009)	Randomized Phase II	EBd	Might have inferior PFS

Chemotherapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² SC/IV once per day on days 1, 4, 8, 11
  • Cycle 9 onwards: 1.3 mg/m² SC/IV once per day on days 1, 8, 15
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycle 9 onwards: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16

21-day cycle for 8 cycles, then 28-day cycles

Variant #2, SC 21-day cycles (8 total)

Study	Evidence	Comparator	Efficacy
Moreau et al. 2011 (MMY-3021)	Phase III	IV Bort-Dex	Non-inferior ORR
Palumbo et al. 2016 (CASTOR)	Phase III	DVd	Inferior PFS

Preceding treatment

• MMY-3021: Bortezomib x 4

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 8 cycles (see note)

In MMY-3021, patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles.

Variant #3, 21-day followed by 42-day cycles (12 total)

Study	Evidence	Comparator	Efficacy
San-Miguel et al. 2014 (PANORAMA 1)	Phase III	Bortezomib, Dexamethasone, Panobinostat	Inferior PFS

Chemotherapy, Phase 1

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 8 cycles

Patients who had clinical benefit per the modified European Group for Blood and Marrow Transplantation [EBMT] criteria on day 1 of cycle 8 proceeded to phase 2 treatment:

Chemotherapy, Phase 2

• Bortezomib (Velcade) 1.3 mg/m² IV once per week days 1, 8, 22, 29
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 22, 23, 29, 30

42-day cycle for 4 cycles

Variant #4, 21-day cycles, response-adapted

Study	Evidence	Comparator	Efficacy
Hjorth et al. 2012 (NMSG 17/07)	Phase III	Thal-Dex	Seems not superior
Dimopoulos et al. 2013 (CR013165)	Phase II	Not evaluable

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

Supportive medications

• "Antithrombotic prophylaxis and acyclovir prophylaxis were not mandatory according to the study protocol but used routinely in an increasing proportion of participating centers during the study period."

21-day cycles, to be continued until progression or best response, which would then be followed by 1 to 2 additional cycles

Variant #5, IV 21-day cycles (8 total)

Study	Evidence	Comparator	Efficacy
Jagannath et al. 2004 (CREST)	Randomized Phase II	Low-dose Bort-Dex	Seems not superior
Moreau et al. 2011 (MMY-3021)	Phase III	SC Bort-Dex	Non-inferior ORR
Kropff et al. 2017 (CR015247)	Phase III	VCD	Seems not superior

Preceding treatment

• CREST: Bortezomib x 2 to 4 cycles
• MMY-3021: bortezomib x 4

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 8 cycles (see note)

In MMY-3021, patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles.

Variant #6, low-dose IV 21-day cycles (8 total)

Study	Evidence	Comparator	Efficacy
Jagannath et al. 2004 (CREST)	Randomized Phase II	Standard-dose Bort-Dex	Seems not superior

Preceding treatment

• Bortezomib x 2 to 4 cycles

Chemotherapy

• Bortezomib (Velcade) 1 mg/m² IV bolus once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 8 cycles

Variant #7, indefinite 21-day cycles

Study	Evidence	Efficacy
Richardson et al. 2003 (SUMMIT)	Phase II	RR: 35%
Mikhael et al. 2008 (MMY-3001)	Phase IIIb	ORR: 67%

Note: these trials specified a total of 8 cycles, but those who were deriving clinical benefit could continue beyond this.

Preceding treatment

• Bortezomib x 2 to 4 cycles

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycles

Variant #8, indefinite 35-day cycles

Study	Evidence	Efficacy
Fukushima et al. 2011	Phase II	ORR: 77%

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22
• Dexamethasone (Decadron) 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23

35-day cycles, to be continued until complete response, progression of disease, or severe adverse events

References

1. SUMMIT: Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. link to original article contains verified protocol PubMed
2. CREST: Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004 Oct;127(2):165-72. link to original article contains verified protocol PubMed
   1. Subgroup Analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains protocol PubMed
   2. Update: Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Esseltine DL, Anderson KC. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol. 2008 Nov;143(4):537-40. Epub 2008 Sep 6. link to original article PubMed
3. MMY-3001: Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009 Jan;144(2):169-75. Epub 2008 Nov 19. link to original article contains verified protocol PubMed
4. MMY-3021: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. Epub 2011 Apr 18. link to original article contains verified protocol PubMed
   1. Update: Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, Feng H, Cakana A, Deraedt W, Moreau P. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec;97(12):1925-8. Epub 2012 Jun 11. link to original article link to PMC article PubMed
   2. Subgroup analysis: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Rekhtman G, Masliak Z, Robak P, Esseltine DL, Feng H, Deraedt W, van de Velde H, Arnulf B. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica. 2015 May;100(5):e207-10. Epub 2015 Jan 16. link to original article link to PMC article PubMed
5. Fukushima T, Nakamura T, Iwao H, Nakajima A, Miki M, Sato T, Sakai T, Sawaki T, Fujita Y, Tanaka M, Masaki Y, Nakajima H, Motoo Y, Umehara H. Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events. Anticancer Res. 2011 Jun;31(6):2297-302. link to original article contains verified protocol PubMed
6. NMSG 17/07: Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group (NMSG). Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. Epub 2012 Mar 30. link to original article contains verified protocol link to PMC article PubMed
7. CR013165: Dimopoulos MA, Beksac M, Benboubker L, Roddie H, Allietta N, Broer E, Couturier C, Mazier MA, Angermund R, Facon T. Phase 2 study of bortezomib-dexamethasone alone or with added cyclophosphamide or lenalidomide for sub-optimal response as second-line treatment for patients with multiple myeloma. Haematologica. 2013 Aug;98(8):1264-72. Epub 2013 May 28. link to original article contains verified protocol link to PMC article PubMed
8. PANORAMA 1: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. Epub 2014 Sep 18. Erratum in: Lancet Oncol. 2015 Jan;16(1):e6. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. link to original article link to PMC article PubMed
   2. Update: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Nov;3(11):e506-e515. Epub 2016 Oct 14. link to original article PubMed
9. ENDEAVOR: Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. Epub 2015 Dec 5. link to original article PubMed
   1. Subgroup analysis: Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017 Jun;31(6):1368-1374. Epub 2016 Dec 27. link to original article link to PMC article PubMed
   2. Update: Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1327-1337. Epub 2017 Aug 23. link to original article PubMed
10. CA204-009: Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016 Jun 9;127(23):2833-40. Epub 2016 Apr 18. link to original article contains verified protocol in supplement link to PMC article PubMed
11. CASTOR: Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed
12. CR015247: Kropff M, Vogel M, Bisping G, Schlag R, Weide R, Knauf W, Fiechtner H, Kojouharoff G, Kremers S, Berdel WE. Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. Ann Hematol. 2017 Nov;96(11):1857-1866. Epub 2017 Sep 14. link to original article PubMed

Bortezomib, Dexamethasone, Panobinostat

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Regimen

Study	Evidence	Comparator	Efficacy
Richardson et al. 2013 (PANORAMA 2)	Phase II
San-Miguel et al. 2014 (PANORAMA 1)	Phase III	Bortezomib & Dexamethasone	Superior PFS

Phase 1

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 8, 10, 12

21-day cycle for 8 cycles

Patients who had clinical benefit per the modified European Group for Blood and Marrow Transplantation [EBMT] criteria on day 1 of cycle 8 proceeded to phase 2 treatment:

Phase 2

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 22, 29
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 22, 23, 29, 30
• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 8, 10, 12, 22, 24, 26, 29, 31, 33

42-day cycles

Patients in PANORAMA 1 received 4 cycles; PANORAMA 2 continued treatment until progression of disease, unacceptable toxicity, or death.

References

1. Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, Mukhopadhyay S, Ondovik MS, Khan M, Paley CS, Lonial S. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013 Oct 3;122(14):2331-7. link to original article contains verified protocol PubMed
2. PANORAMA 1: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. Epub 2014 Sep 18. Erratum in: Lancet Oncol. 2015 Jan;16(1):e6. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. link to original article link to PMC article PubMed
   2. Update: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Nov;3(11):e506-e515. Epub 2016 Oct 14. link to original article PubMed

Bortezomib & Doxorubicin liposomal

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Regimen

Study	Evidence	Comparator	Efficacy
Orlowski et al. 2007	Phase III	Bortezomib	Superior TTP

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11
• Pegylated liposomal doxorubicin (Doxil) 30 mg/m² IV over at least 1 hour once on day 4, given after Bortezomib (Velcade)

Supportive medications

• Bisphosphonates were used according to established guidelines

21-day cycle for up to 8 cycles

Treatment given until progression of disease, or unacceptable toxicity; treatment could be continued beyond 8 cycles if it was tolerated.

References

1. Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. link to original article contains verified protocol PubMed
   1. Update: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. link to original article PubMed

Bortezomib & Vorinostat

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Regimen

Study	Evidence	Comparator	Efficacy
Dimopoulos et al. 2013 (VANTAGE 088)	Phase III	Bortezomib	Seems to have superior PFS

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11
• Vorinostat (Zolinza) 400 mg PO once per day on days 1 to 14

21-day cycles

References

1. VANTAGE 088: Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, Rosinol L, Williams C, Blacklock H, Goldschmidt H, Hungria V, Spencer A, Palumbo A, Graef T, Eid JE, Houp J, Sun L, Vuocolo S, Anderson KC. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013 Oct;14(11):1129-1140. Epub 2013 Sep 19. link to original article contains verified protocol PubMed

Carfilzomib monotherapy

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Variant #1, 20/27 dosing, variant #1

Study	Evidence	Comparator	Efficacy
Hájek et al. 2016 (FOCUS)	Phase III	Cyclophosphamide & Dexamethasone Cyclophosphamide & Prednisone	Seems not superior

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 10 minutes once per day on days 1 & 2, then 27 mg/m² IV over 10 minutes once per day on days 8, 9, 15, 16
  • Cycles 2 to 9: 27 mg/m² IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycle 10 onwards: 27 mg/m² IV over 10 minutes once per day on days 1, 2, 15, 16

Supportive medications

• IV and PO hydration required for cycle 1
• Dexamethasone (Decadron) 4 mg PO/IV prior to each cycle 1 dose
• Ciprofloxacin (Cipro) 500 mg PO once per day during cycle 1

28-day cycles

Variant #2, 20/27 dosing, variant #2

Study	Evidence
Watanabe et al. 2016	Phase I/II

This is the maximum predetermined dose, there was no MTD.

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1 & 2, then 27 mg/m² IV once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 27 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16

Supportive medications

• IV and PO hydration required for cycle 1, then as needed
• Dexamethasone (Decadron) 4 mg PO/IV prior to each cycle 1 dose, then as needed
• Prophylactic antibiotics (not specified) in cycle 1
• Acyclovir (Zovirax) for patients with history of herpes infection, in cycle 1

28-day cycles until progression or excess toxicity

Variant #3, 20/56 dosing

Study	Evidence
Lendvai et al. 2014	Phase II

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once per day on days 1 & 2, then 56 mg/m² IV over 30 minutes once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 56 mg/m² IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16

Supportive medications

• Normal saline pre- and post-hydration, tapered over subsequent cycles (see text for details)
• Dexamethasone (Decadron) 8 mg (route not specified) mandated with each cycle 1 dose, then optional
• Palonosetron (Aloxi) 250 mcg (route not specified) mandated with each cycle 1 dose, then optional
• Acyclovir (Zovirax) 400 mg PO once per day

Variant #4, 20/27 dosing, with BSA cap

Study	Evidence
Vij et al. 2012 (PX-171-004)	Phase II
Siegel et al. 2012 (PX-171-003-A1)	Phase II

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² (body surface area capped at 2.2 m²) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycle 2 onwards: 27 mg/m² (body surface area capped at 2.2 m²) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Note: Neither Vij et al. 2012 nor Siegel et al. 2012 specify that carfilzomib is capped at a body surface area of 2.2 m2, but the Carfilzomib (Kyprolis) package insert specifies that: "The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m² should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%."

Supportive medications

• Dexamethasone (Decadron) 4 mg PO/IV before all doses in cycle 1 (Vij et al. 2012 also administered one dose of dexamethasone 4 mg before the first increased dose of carfilzomib 27 mg/m²). Restart dexamethasone premedication if patients experience infusion reactions: "fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina."
• "All patients were to receive oral and intravenous fluids before dosing to assure adequate hydration."

Dose modifications

• "Carfilzomib was withheld for grade 3 or 4 hematologic or nonhematologic toxicities and resumed at reduced doses of 15 mg/m² in cycle 1 or 20 mg/m² in cycle 2 and above on resolution."

28-day cycle for up to 12 cycles

Variant #5, 20/20 dosing

Study	Evidence
Vij et al. 2012 (PX-171-004)
Jagannath et al. 2012 (PX-171-003-A0)	Phase II

Chemotherapy

• Carfilzomib (Kyprolis) 20 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16

28-day cycle for up to 12 cycles (see note)

Patients enrolled in PX-171-004 could continue therapy beyond 12 cycles on PX-171-010; results of this extension study have not been published, to our knowledge.

Variant #6, 15/20/27 dosing, for renal impairment

Study	Evidence
Badros et al. 2013 (PX-171-005)	Phase II

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 15 mg/m² IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycle 2: 20 mg/m² IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycle 3 onwards: 27 mg/m² IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16

Supportive medications

• Dexamethasone (Decadron) 4 mg (route not specified) before all doses in cycle 1. Continue dexamethasone premedication if patients experience "treatment-related fever, chills, and/or dyspnea."
• "All patients were "required to be well hydrated."

28-day cycle for 12 cycles or longer if deriving clinical benefit

Patients with less than PR after 2 cycles or less than CR after 4 cycles were allowed to escalate to carfilzomib & dexamethasone.

References

1. Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012 Jun 14;119(24):5661-70. Epub 2012 May 3. link to original article contains verified protocol link to PMC article PubMed
2. Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, Bahlis N, Belch A, Kunkel LA, Wear S, Wong AF, Wang M. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012 Sep;158(6):739-48. Epub 2012 Jul 30. link to original article PubMed
3. Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T, Somlo G, Bahlis N, Lonial S, Kunkel LA, Wong A, Orlowski RZ, Siegel DS. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8. link to original article contains protocol PubMed
4. Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012 Oct 4;120(14):2817-25. Epub 2012 Jul 25. link to original article contains verified protocol link to PMC article PubMed Pivotal trial for accelerated FDA approval
   1. Subset analysis: Jakubowiak AJ, Siegel DS, Martin T, Wang M, Vij R, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Harrison BL, Wong AF, Orlowski RZ, Jagannath S. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leukemia. 2013 Dec;27(12):2351-6. Epub 2013 May 14. link to original article link to PMC article PubMed
5. Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, Lee S, Wong AF, Niesvizky R. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013 Aug;27(8):1707-14. Epub 2013 Jan 31. contains verified protocol link to PMC article PubMed
6. Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, Tsakos I, Redling K, Koehne G, Chung DJ, Schaffer WL, Giralt SA. A phase 2 single-center study of carfilzomib 56 mg/m² with or without low-dose dexamethasone in relapsed multiple myeloma. Blood. 2014 Aug 7;124(6):899-906. Epub 2014 Jun 24. link to original article contains verified protocol link to PMC article PubMed
7. Watanabe T, Tobinai K, Matsumoto M, Suzuki K, Sunami K, Ishida T, Ando K, Chou T, Ozaki S, Taniwaki M, Uike N, Shibayama H, Hatake K, Izutsu K, Ishikawa T, Shumiya Y, Kashihara T, Iida S. A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma. Br J Haematol. 2016 Mar;172(5):745-56. Epub 2016 Jan 5. link to original article contains verified protocol link to PMC article PubMed
8. Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. link to original article link to PMC article contains verified protocol PubMed

Carfilzomib & Dexamethasone

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Kd: Kyprolis (Carfilzomib) & low-dose dexamethasone

Variant #1, 20/56 dosing

Study	Evidence	Comparator	Efficacy
Dimopoulos et al. 2015 (ENDEAVOR)	Phase III	Vd	Superior OS (*)

Note: efficacy based on the 2017 update.

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once per day on days 1 & 2, then 56 mg/m² IV over 30 minutes once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 56 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
• Dexamethasone (Decadron) 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycles

Variant #2, 20/70 dosing

Study	Evidence
Berenson et al. 2016 (CHAMPION-1)	Phase I/II

The carfilzomib dose is the MTD in this phase I/II trial.

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once on day 1, then 70 mg/m² IV over 30 minutes once per day on days 8 & 15
  • Cycle 2 onwards: 70 mg/m² IV once per day on days 1, 8, 15
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 40 mg PO/IV once per day on days 1, 8, 15, 22
  • Cycle 9 onwards: 40 mg PO/IV once per day on days 1, 8, 15

28-day cycles until progression or intolerance

Variant #3, 27 dosing

Study	Evidence
Badros et al. 2013 (PX-171-005)	Phase II

Preceding treatment

• Carfilzomib x 2 to 4 cycles (carfilzomib dose escalation attained during this period)

Chemotherapy

• Carfilzomib (Kyprolis) 27 mg/m² IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
• Dexamethasone (Decadron) 20 mg (route not specified) once per day on days 1, 2, 8, 9, 15, 16, given first

28-day cycle for 12 cycles or longer if deriving clinical benefit

References

1. Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, Lee S, Wong AF, Niesvizky R. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013 Aug;27(8):1707-14. Epub 2013 Jan 31. contains verified protocol link to PMC article PubMed
2. ENDEAVOR: Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. Epub 2015 Dec 5. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017 Jun;31(6):1368-1374. Epub 2016 Dec 27. link to original article link to PMC article PubMed
   2. Update: Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1327-1337. Epub 2017 Aug 23. link to original article PubMed
3. Berenson JR, Cartmell A, Bessudo A, Lyons RM, Harb W, Tzachanis D, Agajanian R, Boccia R, Coleman M, Moss RA, Rifkin RM, Patel P, Dixon S, Ou Y, Anderl J, Aggarwal S, Berdeja JG. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016 Jun 30;127(26):3360-8. Epub 2016 May 12. link to original article contains verified protocol link to PMC article PubMed

CP

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CP: Cyclophosphamide & Prednisone
CyPred: Cyclophosphamide & Prednisone

Variant #1

Study	Evidence	Comparator	Efficacy
Hájek et al. 2016 (FOCUS)	Phase III	Carfilzomib	Seems not superior

Note: cyclophosphamide was described as optional for the control arm but 95% of patients received it.

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day
• Prednisone (Sterapred) 30 mg PO once every other day

Continued until progression

Variant #2

Study	Evidence
de Weerdt et al. 2001	Non-randomized

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg PO once per day
• Prednisone (Sterapred) 10 to 20 mg PO once per day

Continued until progression or intolerance

References

1. de Weerdt O, van de Donk NW, Veth G, Bloem AC, Hagenbeek A, Lokhorst HM. Continuous low-dose cyclophosphamide-prednisone is effective and well tolerated in patients with advanced multiple myeloma. Neth J Med. 2001 Aug;59(2):50-6. contains protocol PubMed
2. Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. link to original article link to PMC article contains verified protocol PubMed

CRd

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CRd: Carfilzomib, Revlimid (Lenalidomide), low-dose dexamethasone
KRd: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), low-dose dexamethasone

Variant #1

Study	Evidence	Comparator	Efficacy	Toxicity
Stewart et al. 2014 (ASPIRE)	Phase III	Rd	Superior OS (*)	Superior GHS/QoL

Efficacy based on the 2018 update.

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 10 minutes once per day on days 1 & 2, then 27 mg/m² IV over 10 minutes once per day on days 8, 9, 15, 16
  • Cycles 2 to 12: 27 mg/m² IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycles 13 to 18: 27 mg/m² IV over 10 minutes once per day on days 1, 2, 15, 16
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

Supportive medications

• Valacyclovir (Valtrex) (dose not specified) or equivalent antiviral while taking Lenalidomide (Revlimid)
• Aspirin (dose not specified) or other anticoagulant or antiplatelet medication such as Clopidogrel (Plavix), low-molecular-weight heparin or Warfarin (Coumadin) while taking Lenalidomide (Revlimid)
• Bisphosphonates while taking Dexamethasone (Decadron)
• Lansoprazole (Prevacid) (dose not specified) or other proton pump inhibitor while taking Dexamethasone (Decadron)
• A prophylactic antibiotic (Ciprofloxacin (Cipro), Amoxicillin, Trimethoprim/Sulfamethoxazole (Bactrim DS) are given as examples)

28-day cycles until progression or intolerable side effects (Carfilzomib stopped after 18 cycles)

Variant #2

Study	Evidence
Wang et al. 2013	Phase II

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1 & 2, then 27 mg/m² IV once per day on days 8, 9, 15, 16
  • Cycles 2 to 12: 27 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
  • Cycles 13 to 18: 27 mg/m² IV once per day on days 1, 2, 15, 16
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

28-day cycle for up to 18 cycles, longer duration allowed at discretion of investigator

Patients with at least SD after 4 cycles received up to 12 cycles; patients with at least SD after 12 cycles received up to 18 cycles.

References

1. Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E, Huang M, Orlowski RZ, Niesvizky R. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013 Oct 31;122(18):3122-8. Epub 2013 Sep 6. link to original article contains verified protocol link to PMC article PubMed
2. ASPIRE: Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. link to original article link to PMC article PubMed
   2. HRQoL analysis: Stewart AK, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Buchanan J, Cocks K, Yang X, Xing B, Zojwalla N, Tonda M, Moreau P, Palumbo A. Health-related quality-of-life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol. 2016 Nov 10;34(32):3921-3930. link to original article PubMed
   3. Update: Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, San-Miguel J, Obreja M, Blaedel J, Stewart AK. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 10;36(8):728-734. Epub 2018 Jan 17. link to original article PubMed

Cyclophosphamide & Dexamethasone

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Regimen

Study	Evidence	Comparator	Efficacy
Hájek et al. 2016 (FOCUS)	Phase III	Carfilzomib	Seems not superior

Note: cyclophosphamide was described as optional for the control arm but 95% of patients received it.

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day
• Dexamethasone (Decadron) 6 mg PO once every other day

Continued until progression

References

1. Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. link to original article link to PMC article contains verified protocol PubMed

DRd

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DRd: Daratumumab, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Plesner et al. 2016	Phase I/II
Dimopoulos et al. 2016 (POLLUX)	Phase III	Rd	Superior PFS

Chemotherapy

• Daratumumab (Darzalex) as follows:
  • Cycles 1 & 2: 16 mg/kg IV once per week
  • Cycles 3 to 6: 16 mg/kg IV once every two weeks
  • Cycle 7 onwards: 16 mg/kg IV once per cycle
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
  • POLLUX: Patients with CrCl of 30 to 60 mL/min/1.73m² received 10 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
  • POLLUX: Patients older than 75 years or underweight (BMI less than 18.5) could receive 20 mg PO once per week

28-day cycle for up to 24 months (Plesner et al. 2014) or until progression (POLLUX)

References

1. Plesner T, Arkenau HT, Gimsing P, Krejcik J, Lemech C, Minnema MC, Lassen U, Laubach JP, Palumbo A, Lisby S, Basse L, Wang J, Sasser AK, Guckert ME, de Boer C, Khokhar NZ, Yeh H, Clemens PL, Ahmadi T, Lokhorst HM, Richardson PG. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016 Oct 6;128(14):1821-8. Epub 2016 Aug 16. link to original article contains verified protocol link to PMC article PubMed
2. POLLUX: Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. link to original article link to original protocol contains verified protocol PubMed

DVd

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DVd: Daratumumab, Velcade (Bortezomib), low-dose dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Palumbo et al. 2016 (CASTOR)	Phase III	Vd	Superior PFS

Chemotherapy

• Daratumumab (Darzalex) as follows:
  • Cycles 1 to 3: 16 mg/kg IV once per week
  • Cycles 4 to 8: 16 mg/kg IV once on day 1
• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO/IV once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Can be dose-reduced to 20 mg PO/IV once per week for patients greater than 75 years, with BMI less than 18.5, or with previous side effects

21-day cycle for 8 cycles

Subsequent treatment

• Daratumumab maintenance

References

1. CASTOR: Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed

EBd

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EBd: Elotuzumab, Bortezomib, low-dose dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Jakubowiak et al. 2016	Randomized Phase II	Bd	Might have superior PFS

Chemotherapy

• Elotuzumab (Empliciti) as follows:
  • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15
  • Cycles 3 to 8: 10 mg/kg IV once per day on days 1 & 11
  • Cycle 9 onwards: 10 mg/kg IV once per day on days 1 & 15
• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² SC/IV once per day on days 1, 4, 8, 11
  • Cycle 9 onwards: 1.3 mg/m² SC/IV once per day on days 1, 8, 15
• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 2:
    • 20 mg PO once per day on days 2, 4, 5, 9, 11, 12
    • 8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to Elotuzumab (Empliciti) on days 1, 8, 15
  • Cycles 3 to 8:
    • 20 mg PO once per day on days 2, 4, 5, 8, 9, 12
    • 8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to Elotuzumab (Empliciti) on days 1 & 11
  • Cycle 9 onwards:
    • 20 mg PO once per day on days 2, 8, 9, 16
    • 8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to Elotuzumab (Empliciti) on days 1 & 15

Supportive medications

• Diphenhydramine (Benadryl) 25 to 50 mg (route not specified) 30 to 90 minutes prior to Elotuzumab (Empliciti)
• Ranitidine (Zantac) 50 mg (route not specified) 30 to 90 minutes prior to Elotuzumab (Empliciti)
• Acetaminophen (Tylenol) 650 to 1000 mg PO 30 to 90 minutes prior to Elotuzumab (Empliciti)

21-day cycle for 8 cycles, then 28-day cycles

References

1. Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016 Jun 9;127(23):2833-40. Epub 2016 Apr 18. link to original article contains verified protocol in supplement link to PMC article PubMed

ELd

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ELd: Elotuzumab, Lenalidomide, low-dose dexamethasone

Variant #1

Study	Evidence	Comparator	Efficacy
Lonial et al. 2015 (ELOQUENT-2)	Phase III	Ld	Seems to have superior OS (*)
Richardson et al. 2015 (1703 Study)	Randomized Phase Ib/II	Elotuzumab 20 mg, Lenalidomide, Dexamethasone	Seems not superior

Note: the complex dexamethasone instructions for ELOQUENT-2 were not described in the abstract of Richardson et al. 2015. Efficacy reported for ELOQUENT-2 is based on the 2017 update.

Chemotherapy

• Elotuzumab (Empliciti) as follows:
  • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15, 22
  • Cycle 3 onwards: 10 mg/kg IV once per day on days 1 & 15
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on weeks without elotuzumab; 28 mg PO and 8 mg IV on days when Elotuzumab (Empliciti) is administered
  • According to the elotuzumab package insert, the 28 mg PO dose should be given between 3 and 24 hours before elotuzumab; the 8 mg IV dose should be given 45 to 90 minutes before elotuzumab.

Supportive medications

• Mandatory premedications 30 to 90 minutes prior to Elotuzumab (Empliciti):
  • Diphenhydramine (Benadryl) 25 to 50 mg (route not specified) or its equivalent
  • Ranitidine (Zantac) 50 mg (route not specified) or its equivalent
  • Acetaminophen (Tylenol) 650 to 1000 mg (route not specified) or its equivalent
• "Thromboembolic prophylaxis (e.g., aspirin, low-molecular-weight heparin, or vitamin K antagonists) was administered according to institutional guidelines or at the discretion of the investigator."

28-day cycles

Variant #2

Study	Evidence	Comparator	Efficacy
Richardson et al. 2015 (1703 Study)	Randomized Phase Ib/II	Elotuzumab 10 mg, Lenalidomide, Dexamethasone	Seems not superior

Chemotherapy

• Elotuzumab (Empliciti) as follows:
  • Cycles 1 & 2: 20 mg/kg IV once per day on days 1, 8, 15, 22
  • Cycle 3 onwards: 20 mg/kg IV once per day on days 1 & 15
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week

28-day cycles

References

1. Phase I: Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK, Jagannath S. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012 Jun 1;30(16):1953-9. link to original article contains verified protocol PubMed
   1. Abstract: Update: Paul G. Richardson, Sundar Jagannath, MD, Philippe Moreau, MD, Andrzej Jakubowiak, MD, PhD, Marc S Raab, MD, PhD, Thierry Facon, MD, Ravi Vij, MBBS, MD, Darrell White, MD, Donna E. Reece, MD, Lotfi Benboubker, MD, PhD, Jeffrey Zonder, MD, L. Claire Tsao, PhD, Kenneth C. Anderson, MD, Eric Bleickardt, MD, Anil K Singhal, MD and Sagar Lonial, MD. Final Results for the 1703 Phase 1b/2 Study of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. ASH 2014 Abstract 302 link to abstract
2. ELOQUENT-2: Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. link to original article contains verified protocol PubMed
   1. Update: Dimopoulos MA, Lonial S, White D, Moreau P, Palumbo A, San-Miguel J, Shpilberg O, Anderson K, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Bleickardt E, Poulart V, Sheng J, Sy O, Katz J, Singhal A, Richardson P. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017 Sep;178(6):896-905. Epub 2017 Jul 5. link to original article PubMed
3. Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, Vij R, White D, Reece DE, Benboubker L, Zonder J, Tsao LC, Anderson KC, Bleickardt E, Singhal AK, Lonial S; 1703 study investigators. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015 Dec;2(12):e516-27. Epub 2015 Nov 16. link to original article contains protocol PubMed

IRd

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IRd: Ixazomib, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Moreau et al. 2016 (TOURMALINE-MM1)	Phase III	Rd	Superior PFS

Chemotherapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15, taken at least one hour before or at least two hours after food
• Lenalidomide (Revlimid) as follows:
  • Normal renal function: 25 mg PO once per day on days 1 to 21
  • CrCl of less than or equal to 60 mL/min/1.73m² or less than or equal to 50 mL/min/1.73m² (depends on local practice): 10 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22

Supportive medications

• Thromboprophylaxis required

28-day cycles

References

1. TOURMALINE-MM1: Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-1634. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, Ganly P, Palumbo A, Cavo M, Langer C, Pluta A, Nagler A, Kumar S, Ben-Yehuda D, Rajkumar SV, San-Miguel J, Berg D, Lin J, van de Velde H, Esseltine DL, di Bacco A, Moreau P, Richardson PG. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017 Dec 14;130(24):2610-2618. Epub 2017 Oct 20. link to original article PubMed
2. Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, Lu J, Du X, Chen X, Li J, Liu J, Gupta N, Hanley MJ, Li H, Hua Z, Wang B, Zhang X, Wang H, van de Velde H, Richardson PG, Moreau P. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study. J Hematol Oncol. 2017 Jul 6;10(1):137. link to original article link to PMC article PubMed

Ixazomib & Dexamethasone

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Variant #1

Study	Evidence	Comparator	Efficacy
Kumar et al. 2015	Phase II
Kumar et al. 2016	Randomized Phase II	Ixazomib 4 mg & Dexamethasone	Might have superior ORR

Chemotherapy

• Ixazomib (Ninlaro) 5.5 mg PO once per day on days 1, 8, 15
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 15, 16

Supportive medications

• Herpes zoster prophylaxis

28-day cycles until progression

Variant #2

Study	Evidence	Comparator	Efficacy
Kumar et al. 2016	Randomized Phase II	Ixazomib 5.5 mg & Dexamethasone	Might have inferior ORR

Chemotherapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 15, 16

Supportive medications

• Herpes zoster prophylaxis

28-day cycles until progression

References

1. Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338. link to original article contains verified protocol link to PMC article PubMed
2. Kumar SK, LaPlant BR, Reeder CB, Roy V, Halvorson AE, Buadi F, Gertz MA, Bergsagel PL, Dispenzieri A, Thompson MA, Crawley J, Kapoor P, Mikhael J, Stewart K, Hayman SR, Hwa YL, Gonsalves W, Witzig TE, Ailawadhi S, Dingli D, Go RS, Lin Y, Rivera CE, Rajkumar SV, Lacy MQ. Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib. Blood. 2016 Nov 17;128(20):2415-2422. link to original article contains verified protocol link to PMC article PubMed

Lenalidomide monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Richardson et al. 2006	Randomized Phase II	Lenalidomide 15 mg PO BID	Seems not superior
Richardson et al. 2009	Phase II

This regimen is essentially of historical interest, as neither dosing of lenalidomide is in common use now.

Chemotherapy

• Lenalidomide (Revlimid) 30 mg PO once per day on days 1 to 21

28-day cycles

Patients in Richardson et al. 2006 with SD or progression after 2 cycles were escalated to RD.

References

1. Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, Williams SF, Bensinger W, Badros AZ, Vescio R, Kenvin L, Yu Z, Olesnyckyj M, Zeldis J, Knight R, Anderson KC. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009 Jul 23;114(4):772-8. Epub 2009 May 26. link to original article contains verified protocol PubMed
2. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. link to original article contains verified protocol link to PMC article PubMed

Pomalidomide & Dexamethasone

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PD: Pomalidomide, Dexamethasone
PomDex: Pomalidomide, Dexamethasone
Pom + LoDEX: Pomalidomide, Low-dose Dexamethasone

Variant #1, 4 mg 21/28

Study	Evidence	Comparator	Efficacy
San Miguel et al. 2013 (MM-003)	Phase III	Dexamethasone	Superior OS (*)
Leleu et al. 2013 (IFM 2009-02)	Randomized Phase II	Pom-Dex (28/28)	Seems not superior
Richardson et al. 2014	Randomized Phase II	Pomalidomide	Seems to have superior PFS
Leleu et al. 2015 (IFM 2010-02)	Phase II
Baz et al. 2016	Randomized Phase I/II	PomCyDex	Seems to have inferior ORR rate
Dimopoulos et al. 2016 (STRATUS)	Phase IIIb

Note: efficacy reported for MM-003 is based on the 2015 update.

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Age less than or equal to 75: 40 mg PO once per day on days 1, 8, 15, 22
  • Age greater than 75: 20 mg PO once per day on days 1, 8, 15, 22

Supportive medications

• San Miguel et al. 2013: Thromboprohpylaxis required. "Choice of thromboprophylaxis and use of myeloid and erythroid growth factors was left to the physician's discretion."
• Leleu et al. 2013: Thromboprophylaxis "at the physician's discretion"
• Richardson et al. 2014: Aspirin 81 to 100 mg once per day unless contraindicated
• Baz et al. 2016: Aspirin 81 mg once per day unless contraindicated
• STRATUS: Thromboprophylaxis with low-dose Aspirin, |LMWH, or equivalent was required
• Leleu et al. 2013: G-CSF allowed beginning with cycle 2 and on

28-day cycles until disease progression or unacceptable toxicity

Variant #2, 4 mg continuous

Study	Evidence	Comparator	Efficacy
Lacy et al. 2011	Phase II
Leleu et al. 2013 (IFM 2009-02)	Randomized phase II, >20 patients	Pom-Dex (21/28)	Seems not superior

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 28
• Dexamethasone (Decadron) 40 mg PO once per day on day 1, 8, 15, 22

Supportive medications

• Lacy et al. 2011: Aspirin 325 mg PO once per day
  • low molecular weight heparin or Warfarin (Coumadin) could be substituted at physician discretion
• Leleu et al. 2013: Thromboprophylaxis "at the physician's discretion"
• Leleu et al. 2013: G-CSF allowed beginning with cycle 2 and on

28-day cycles until disease progression or unacceptable toxicity

Variant #3, 2 mg continuous

Study	Evidence
Lacy et al. 2009	Phase II
Lacy et al. 2010	Phase II
Lacy et al. 2011	Phase II

Chemotherapy

• Pomalidomide (Pomalyst) 2 mg PO once per day on days 1 to 28
• Dexamethasone (Decadron) 40 mg PO once per day on day 1, 8, 15, 22

Supportive medications

• Aspirin 325 mg PO once per day
  • low molecular weight heparin or Warfarin (Coumadin) could be substituted at physician discretion

28-day cycles given until disease progression or unacceptable toxicity

References

1. Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Kyle RA, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009 Oct 20;27(30):5008-14. Epub 2009 Aug 31. link to original article contains verified protocol PubMed
2. Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV, Buadi F. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010 Nov;24(11):1934-9. Epub 2010 Sep 9. link to original article contains verified protocol link to PMC article PubMed
3. Lacy MQ, Allred JB, Gertz MA, Hayman SR, Short KD, Buadi F, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Stewart AK, Laumann K, Mandrekar SJ, Reeder C, Rajkumar SV, Mikhael JR. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011 Sep 15;118(11):2970-5. Epub 2011 Jun 20. link to original article contains verified protocol link to PMC article PubMed
4. Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, Mathiot C, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B, Stoppa AM, Hennache B, Bréchignac S, Meuleman N, Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L, Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, Fermand JP, Avet-Loiseau H, Facon T. Pomalidomide plus low dose dexamethasone is active and well tolerated in bortezomib and lenalidomide refractory multiple myeloma: IFM 2009-02. 2013 Mar 14;121(11):1968-1975. Epub 2013 Jan 14. link to original article contains verified protocol PubMed
5. MM-003: San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-66. Epub 2013 Sep 3. link to original article contains verified protocol PubMed
   1. Update: Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Spencer A, Knop S, Bahlis NJ, Renner C, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel JF. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015 Oct;100(10):1327-33. Epub 2015 Aug 6. link to original article link to PMC article PubMed
6. Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article contains verified protocol link to PMC article PubMed
7. Leleu X, Karlin L, Macro M, Hulin C, Garderet L, Roussel M, Arnulf B, Pegourie B, Kolb B, Stoppa AM, Brechiniac S, Marit G, Thielemans B, Onraed B, Mathiot C, Banos A, Lacotte L, Tiab M, Dib M, Fuzibet JG, Petillon MO, Rodon P, Wetterwald M, Royer B, Legros L, Benboubker L, Decaux O, Escoffre-Barbe M, Caillot D, Fermand JP, Moreau P, Attal M, Avet-Loiseau H, Facon T; Intergroupe Francophone du Myélome (IFM). Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015 Feb 26;125(9):1411-7. Epub 2015 Jan 9. link to original article contains verified protocol PubMed
8. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. link to original article contains verified protocol PubMed
9. Dimopoulos MA, Palumbo A, Corradini P, Cavo M, Delforge M, Di Raimondo F, Weisel KC, Oriol A, Hansson M, Vacca A, Blanchard MJ, Goldschmidt H, Doyen C, Kaiser M, Petrini M, Anttila P, Cafro AM, Raymakers R, San-Miguel J, de Arriba F, Knop S, Röllig C, Ocio EM, Morgan G, Miller N, Simcock M, Peluso T, Herring J, Sternas L, Zaki MH, Moreau P. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016 Jul 28;128(4):497-503. Epub 2016 May 25. link to original article contains verified protocol link to PMC article PubMed

Pomalidomide monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Richardson et al. 2014	Randomized Phase II	POM+LoDEX (PD)	Seems to have inferior PFS

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Supportive medications

• Aspirin 81 to 100 mg per day unless contraindicated

28-day cycles until disease progression or unacceptable toxicity

References

1. Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article contains verified protocol link to PMC article PubMed

PomCyDex

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PomCyDex: Pomalidomide, Cyclophosphamide, Dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Baz et al. 2016	Randomized Phase I/II	PomDex	Seems to have superior ORR rate

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Cyclophosphamide (Cytoxan) 400 mg PO once per day on days 1, 8, 15
• Dexamethasone (Decadron) 40 mg (20 mg for patients greater than 75 years old) PO once per day on days 1, 8, 15, 22

Supportive medications

• Aspirin 81 mg once per day unless contraindicated

28-day cycles until disease progression or unacceptable toxicity

References

1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. link to original article contains verified protocol PubMed

Rd

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Rd: Revlimid (Lenalidomide) & low-dose dexamethasone
RevDex: Revlimid (Lenalidomide) & Dexamethasone
Ld: Lenalidomide & low-dose dexamethasone
Len-Dex: Lenalidomide & Dexamethasone

Variant #1, Len @ 25 mg 21/28

Study	Evidence	Comparator	Efficacy	Toxicity
Stewart et al. 2014 (ASPIRE)	Phase III	KRd	Inferior OS (*)	Inferior GHS/QoL
Lonial et al. 2015 (ELOQUENT-2)	Phase III	ELd	Seems to have inferior OS (*)
Moreau et al. 2016 (TOURMALINE-MM1)	Phase III	IRd	Inferior PFS
Dimopoulos et al. 2016 (POLLUX)	Phase III	DRd	Inferior PFS

Efficacy reported for ELOQUENT-2 is based on the 2017 update. Efficacy reported for ASPIRE is based on the 2018 update.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
  • POLLUX: Patients with CrCl of 30 to 60 mL/min/1.73m² received 10 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
  • POLLUX: Patients older than 75 years or underweight (BMI less than 18.5) could receive 20 mg PO once per week

Supportive medications

Best described by ASPIRE:

• Valacyclovir (Valtrex) (dose not specified) or equivalent antiviral while taking Lenalidomide (Revlimid)
• Aspirin (dose not specified) or other anticoagulant or antiplatelet medication such as Clopidogrel (Plavix), low-molecular-weight heparin or Warfarin (Coumadin) while taking Lenalidomide (Revlimid)
• Bisphosphonates while taking Dexamethasone (Decadron)
• Lansoprazole (Prevacid) (dose not specified) or other proton pump inhibitor while taking Dexamethasone (Decadron)
• A prophylactic antibiotic (Ciprofloxacin (Cipro), Amoxicillin, Trimethoprim/Sulfamethoxazole (Bactrim DS) are given as examples)

28-day cycles until progression or intolerable side effects

Variant #2, Len @ 25 mg 21/28, with high-dose dex lead-in

Study	Evidence	Comparator	Efficacy
Weber et al. 2007 (MM-009)	Phase III	Dexamethasone	Seems to have superior OS (*)
Dimopoulos et al. 2007 (MM-010)	Phase III	Dexamethasone	Seems to have superior OS

Note: efficacy of MM-009 is based on the 2009 pooled update.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycle 5 onwards: 40 mg PO once per day on days 1 to 4

28-day cycles until progression or intolerable side effects

Variant #3, Len @ 30 mg 21/28

Study	Evidence	Comparator	Efficacy
Richardson et al. 2006	Randomized Phase II	Dexamethasone & twice-daily Lenalidomide	Seems not superior

This regimen is essentially of historical interest.

Preceding treatment

• Lenalidomide x 2 cycles

Chemotherapy

• Lenalidomide (Revlimid) 30 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 15 to 18

28-day cycles until progression

Variant #4, Len @ 15 mg 21/28 ("RevLite")

Study	Evidence
Quach et al. 2017 (RevLite)	Phase II

Chemotherapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycle 5 onwards: 20 mg PO once per day on days 1 to 4

28-day cycles until progression

References

1. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. link to original article contains verified protocol link to PMC article PubMed
2. MM-010: Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32. link to original article contains verified protocol PubMed
   1. Update: Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. link to original article PubMed
3. MM-009: Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007 Nov 22;357(21):2133-42. link to original article contains verified protocol PubMed
   1. Update: Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. link to original article PubMed
4. ASPIRE: Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. link to original article link to PMC article PubMed
   2. HRQoL analysis: Stewart AK, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Buchanan J, Cocks K, Yang X, Xing B, Zojwalla N, Tonda M, Moreau P, Palumbo A. Health-related quality-of-life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol. 2016 Nov 10;34(32):3921-3930. link to original article PubMed
   3. Update: Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, San-Miguel J, Obreja M, Blaedel J, Stewart AK. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 10;36(8):728-734. Epub 2018 Jan 17. link to original article PubMed
5. ELOQUENT-2: Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. link to original article contains verified protocol PubMed
   1. Update: Dimopoulos MA, Lonial S, White D, Moreau P, Palumbo A, San-Miguel J, Shpilberg O, Anderson K, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Bleickardt E, Poulart V, Sheng J, Sy O, Katz J, Singhal A, Richardson P. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017 Sep;178(6):896-905. Epub 2017 Jul 5. link to original article PubMed
6. TOURMALINE-MM1: Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-1634. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, Ganly P, Palumbo A, Cavo M, Langer C, Pluta A, Nagler A, Kumar S, Ben-Yehuda D, Rajkumar SV, San-Miguel J, Berg D, Lin J, van de Velde H, Esseltine DL, di Bacco A, Moreau P, Richardson PG. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017 Dec 14;130(24):2610-2618. Epub 2017 Oct 20. link to original article PubMed
7. POLLUX: Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. link to original article link to original protocol contains verified protocol PubMed
8. RevLite: Quach H, Fernyhough L, Henderson R, Corbett G, Baker B, Browett P, Blacklock H, Forsyth C, Underhill C, Cannell P, Trotman J, Neylon A, Harrison S, Link E, Swern A, Cowan L, Dimopoulos MA, Miles Prince H. Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study. Br J Haematol. 2017 May;177(3):441-448. Epub 2017 Feb 15. link to original articlecontains verified protocol PubMed
9. Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, Lu J, Du X, Chen X, Li J, Liu J, Gupta N, Hanley MJ, Li H, Hua Z, Wang B, Zhang X, Wang H, van de Velde H, Richardson PG, Moreau P. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study. J Hematol Oncol. 2017 Jul 6;10(1):137. link to original article link to PMC article PubMed

Thal-Dex

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TD: Thalidomide, Dexamethasone
Thal-Dex: Thalidomide, Dexamethasone

Variant #1

Study	Evidence	Comparator	Efficacy
Garderet et al. 2012 (MMVAR/IFM 2005-04)	Phase III	VTD	Inferior TTP

Intended for patients who have relapsed after an autologous stem-cell transplant

Chemotherapy

• Thalidomide (Thalomid) 200 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of a 21-day cycle

Supportive medications

• Enoxaparin (Lovenox) 40 mg SC once per day for primary prophylaxis; Warfarin (Coumadin) for secondary prophylaxis

One year of treatment

Variant #2

Study	Evidence	Comparator	Efficacy
Hjorth et al. 2012 (NMSG 17/07)	Phase III	Bort-Dex	Seems not superior

Chemotherapy

• Thalidomide (Thalomid) 50 mg PO once per day, increased by 50 mg every 3 weeks to a maximum of 200 mg PO once per day "unless sufficient response was achieved by a lower dose"
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive medications

• "Antithrombotic prophylaxis and acyclovir prophylaxis were not mandatory according to the study protocol but used routinely in an increasing proportion of participating centers during the study period."

21-day cycles, to be continued until progression or best response, which would then be followed by 1 to 2 additional cycles

References

1. NMSG 17/07: Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group (NMSG). Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. Epub 2012 Mar 30. link to original article contains verified protocol link to PMC article PubMed
2. MMVAR/IFM 2005-04: Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012 Jul 10;30(20):2475-82. Epub 2012 May 14. Erratum in: J Clin Oncol. 2012 Sep 20;30(27):3429. link to original article contains verified protocol PubMed

VDC

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VDC: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
VCD: Velcade (Bortezomib), Cyclophosphamide, Dexamethasone
CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone

Variant #1

Study	Evidence	Comparator	Efficacy
Kropff et al. 2017 (CR015247)	Phase III	VD	Seems not superior

Treatment details are from the NCT record.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
• Cyclophosphamide (Cytoxan) 50 mg PO once per day

21-day cycle for up to 8 cycles

Variant #2

Study	Evidence
de Waal et al. 2015	Phase II

Treatment intended for bortezomib-naive patients.

Chemotherapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 3: 1.3 mg/m² IV/SC once per day on days 1, 4, 8, 11
  • Cycles 4 to 6: 1.6 mg/m² IV/SC once per day on days 1, 8, 15, 22
• Cyclophosphamide (Cytoxan) 50 mg PO once per day (continuous)
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 3: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 4 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

Supportive medications

• Pneumococccal and anti-fungal prophylaxis "according to local protocols"
• Valacyclovir (Valtrex) (dose not specified) for herpes prophylaxis

21-day cycle for 3 cycles then 35-day cycle for 3 cycles

Patients with PR/CR after 6 cycles proceeded to bortezomib & cyclophosphamide maintenance.

Variant #3

Study	Evidence
Kropff et al. 2007	Phase II

Treatment intended for bortezomib-naive patients.

Chemotherapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 3: 1.3 mg/m² IV once per day on days 1, 4, 8, 11
  • Cycles 4 to 6: 1.3 mg/m² IV once per day on days 1, 8, 15, 22
• Cyclophosphamide (Cytoxan) 50 mg PO once per day (continuous)
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 3: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 4 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

21-day cycle for 3 cycles then 35-day cycle for 3 cycles

References

1. Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, Dechow T, Kröger N, Salwender H, Metzner B, Sezer O, Engelhardt M, Wolf HH, Einsele H, Volpert S, Heinecke A, Berdel WE, Kienast J; Deutsche Studiengruppe Multiples Myelom,. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007 Aug;138(3):330-7. link to original article contains verified protocol PubMed
2. de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. link to original article contains verified protocol PubMed
3. CR015247: Kropff M, Vogel M, Bisping G, Schlag R, Weide R, Knauf W, Fiechtner H, Kojouharoff G, Kremers S, Berdel WE. Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. Ann Hematol. 2017 Nov;96(11):1857-1866. Epub 2017 Sep 14. link to original article PubMed

VTD

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VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Garderet et al. 2012 (MMVAR/IFM 2005-04)	Phase III	TD	Superior TTP

Intended for patients who have relapsed after an autologous stem-cell transplant

Chemotherapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11 of a 21-day cycle
  • Cycles 9 to 12: 1.3 mg/m² IV bolus once per week on days 1, 8, 15, 22 of a 42-day cycle
• Thalidomide (Thalomid) 200 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of a 21-day cycle

Supportive medications

• Enoxaparin (Lovenox) 40 mg SC once per day for primary prophylaxis; Warfarin (Coumadin) for secondary prophylaxis
• Herpes zoster prophylaxis highly recommended

One year of treatment

References

1. MMVAR/IFM 2005-04: Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012 Jul 10;30(20):2475-82. Epub 2012 May 14. Erratum in: J Clin Oncol. 2012 Sep 20;30(27):3429. link to original article contains verified protocol PubMed

Relapsed or refractory, non-randomized or retrospective data

BBD

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BBD: Bendamustine, Bortezomib, Dexamethasone

Regimen

Study	Evidence
Ludwig et al. 2013	Phase II

Chemotherapy

• Bendamustine 70 mg/m² IV once per day on days 1 & 4
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg (route not specified) once per day on days 1, 4, 8, 11

28-day cycle for up to 8 cycles

References

1. Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, Greil R, Seebacher A, Pour L, Weißmann A, Adam Z. Bendamustine-bortezomib-dexamethasone is an active and well tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood. 2014 Feb 13;123(7):985-91. Epub 2013 Nov 13. link to original article contains verified protocol link to PMC article PubMed

BLD

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BLD: Bendamustine, Lenalidomide, Dexamethasone

Regimen

Study	Evidence
Lentzsch et al. 2012	Phase I/II

Dosages listed are the determined maximally tolerated doses (MTD) of this phase I/II trial.

Chemotherapy

• Bendamustine 75 mg/m² IV once per day on days 1 & 2
• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg (no route specified) once per week

Supportive medications

• Aspirin 325 mg PO once per day
• "Gastroprotectant" (H2-blocker or PPI)

28-day cycle for up to 8 cycles

References

1. Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, Burt S, Boyiadzis M, Roodman GD, Mapara MY, Agha M, Waas J, Shuai Y, Normolle D, Zonder JA. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012 May 17;119(20):4608-13. Epub 2012 Mar 26. link to original article contains verified protocol link to PMC article PubMed

Bortezomib-HyperCAD

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Bortezomib-HyperCAD: Bortezomib, Hyperfractionated Cyclophosphamide, Adriamycin (Doxorubicin), Dexamethasone

Regimen

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Study	Evidence
Saraceni et al. 2018	Retrospective

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² subcutaneous on days 1 and 4
• Cyclophosphamide (Cytoxan) 300 mg/m² IV every 12 hours for 8 doses on days 1 to 4 (total dose per cycle: 1200 mg/m²)
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 36 mg/m²)
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks

Supportive Medications

• Pegfilgrastim (Neulasta) 6 mg subcutaneous once on day 5 or 6
• Mesna (Mesnex) 350 mg/m²/d continuous I.V. infusion every 24 hours on days 1 to 4
• Antiviral prophylaxis with acyclovir daily
• "Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"

References

1. Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, Medvedova E. Modified HyperCVAD Versus Bortezomib-HyperCAD in Patients With Relapsed/Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e77-e84. link to original article PubMed

Bortezomib, Thalidomide, Dexamethasone, Panobinostat

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Regimen

Study	Evidence
Popat et al. 2016 (MUK-six)	Phase I/II

Note: this is the dose used in the phase II portion of the trial.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1 & 8
• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9
• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 8, 10, 12

21-day cycle for 16 cycles

References

1. Popat R, Brown SR, Flanagan L, Hall A, Gregory W, Kishore B, Streetly M, Oakervee H, Yong K, Cook G, Low E, Cavenagh J; Myeloma UK Early Phase Clinical Trial Network.. Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial. Lancet Haematol. 2016 Dec;3(12):e572-e580. link to original article contains protocol PubMed

BTD

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BTD: Bendamustine, Thalidomide, Dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Schey et al. 2015 (MUKone)	Randomized Phase II	BTD with higher-dose benadmustine	See below

This study involved two doses of bendamustine but the higher dose was too toxic, leading to premature closure. Note that while this study was randomized, it was "not powered to directly compare the two arms for statistically significant superiority." Dosage listed is the lower dose.

Chemotherapy

• Bendamustine 60 mg/m² IV once per day on days 1 & 8
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21 (**Note: abstract says days 1 to 21 but body of paper says days 1 to 28**)
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15, 22

Supportive medications

• Thromboprophylaxis (not specified)
• Anti-infective prophylaxis (not specified)

28-day cycle for 6 to 9 cycles (2 cycles past best response)

References

1. Schey S, Brown SR, Tillotson AL, Yong K, Williams C, Davies F, Morgan G, Cavenagh J, Cook G, Cook M, Orti G, Morris C, Sherratt D, Flanagan L, Gregory W, Cavet J; Myeloma UK Early Phase Clinical Trial Network. Bendamustine, thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial. Br J Haematol. 2015 Aug;170(3):336-48. Epub 2015 Apr 20. link to original article contains verified protocol PubMed

Carfilzomib & Panobinostat

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Regimen

Study	Evidence
Berdeja et al. 2015	Phase II

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once on days 1 & 2, then 45 mg/m² IV over 30 minutes once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 45 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
• Panobinostat (Farydak) 30 mg PO once per day on days 1, 3, 5, 15, 17, 19

28-day cycles until progression or intolerance

References

1. Berdeja JG, Hart LL, Mace JR, Arrowsmith ER, Essell JH, Owera RS, Hainsworth JD, Flinn IW. Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma. Haematologica. 2015 May;100(5):670-6. Epub 2015 Feb 20. link to original article contains verified protocol link to PMC article PubMed

CPD

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CPD: Carfilzomib, Pomalidomide, Dexamethasone
KPD: Kyprolis (Carfilzomib), Pomalidomide, Dexamethasone

Regimen

Study	Evidence
Shah et al. 2015	Phase I (*)

Note, although this is described as a Phase I trial, an additional 20 patients were enrolled at the MTD, which is the dose reported here.

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once per day on days 1 & 2, then 27 mg/m² IV over 30 minutes once per day on days 8, 9, 15, 16
  • Cycles 2 to 6: 27 mg/m² IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16
• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 40 mg PO/IV once per week on days 1, 8, 15, 22
  • Cycles 5 to 6: 20 mg PO/IV once per week on days 1, 8, 15, 22

Supportive medications

• "Anti-viral therapy"
• Aspirin 81 mg PO once per day
  • Low molecular weight heparin was used in patients intolerant of aspirin

28-day cycle for 6 cycles or until disease progression, or unacceptable toxicity

Treatment followed by maintenance CPD.

References

1. Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. Epub 2015 Sep 17. link to original article contains verified protocol link to PMC article PubMed

CPR

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CPR: Cyclophosphamide, Prednisone, Revlimid (Lenalidomide)
REP: Revlimid (Lenalidomide), Endoxan (Cyclophosphamide), Prednisone

Variant #1, "REP"

Study	Evidence
Nijhof et al. 2016 (REPEAT)	Phase I/II

Details are for the MTD/phase II portion of the published phase I/II trial.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Cyclophosphamide (Cytoxan) 50 mg PO once per day
• Prednisone (Sterapred) 20 mg PO once per day

28-day cycles

Variant #2, "CPR"

Study	Evidence
Reece et al. 2014	Phase I/II

Details are for the phase II portion of the published phase I/II trial.

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² PO on days 1, 8, 15
• Prednisone (Sterapred) 100 mg PO once every other day
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycles

References

1. Reece DE, Masih-Khan E, Atenafu EG, Jimenez-Zepeda VH, Anglin P, Chen C, Kukreti V, Mikhael JR, Trudel S. Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma. Br J Haematol. 2015 Jan;168(1):46-54. Epub 2014 Aug 22. link to original article contains protocol PubMed
2. Nijhof IS, Franssen LE, Levin MD, Bos GM, Broijl A, Klein SK, Koene HR, Bloem AC, Beeker A, Faber LM, van der Spek E, Ypma PF, Raymakers R, van Spronsen DJ, Westerweel PE, Oostvogels R, van Velzen J, van Kessel B, Mutis T, Sonneveld P, Zweegman S, Lokhorst HM, van de Donk NW. Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma. Blood. 2016 Nov;128(19), 2297-2306. Epub 2016 Sep 19. link to original article contains verified protocol PubMed

CRD (Cyclophosphamide)

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CRD: Cyclophosphamide, Revlimid (Lenalidomide), Dexamethasone

Regimen

Study	Evidence
Schey et al. 2010	Phase I/II

This is the MTD of this phase I/II trial.

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg PO once per day on days 1 & 8
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 8 to 11

Supportive medications

• Aspirin 75 mg PO once per day

28-day cycles

References

1. Schey SA, Morgan GJ, Ramasamy K, Hazel B, Ladon D, Corderoy S, Jenner M, Phekoo K, Boyd K, Davies FE. The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study. Br J Haematol. 2010 Aug;150(3):326-33. link to original article contains verified protocol PubMed

CTD

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CTD: Cyclophosphamide, Thalidomide, Dexamethasone

Regimen

Study	Evidence
Dimopoulos et al. 2004	Phase II

Chemotherapy

• Cyclophosphamide (Cytoxan) 150 mg/m² PO every 12 hours (before meals) on days 1 to 5
• Thalidomide (Thalomid) as follows:
  • Cycles 1 to 3: 400 mg PO every evening on days 1 to 5 and 14 to 18
  • Cycle 4 onwards: 400 mg PO every evening on days 1 to 5
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 3: 20 mg PO every morning after breakfast on days 1 to 5 and 14 to 18
  • Cycle 4 onwards: 20 mg PO every morning after breakfast on days 1 to 5

28-day cycles

References

1. Dimopoulos MA, Hamilos G, Zomas A, Gika D, Efstathiou E, Grigoraki V, Poziopoulos C, Xilouri I, Zorzou MP, Anagnostopoulos N, Anagnostopoulos A. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J. 2004;5(2):112-7. PubMed

Daratumumab monotherapy

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Regimen

Study	Evidence
Lokhorst et al. 2015 (GEN501 part 2)	Phase I/II
Lonial et al. 2016 (SIRIUS)	Phase II

Note: although SIRIUS was a randomized phase II trial, the randomization was to choose the dose for further assessment in an expansion cohort; the dose chosen (16 mg/kg from the start) is the one reported here:

Chemotherapy

• Daratumumab (Darzalex) as follows:
  • Weeks 1 to 8: 16 mg/kg IV once per week
  • Weeks 9 to 24: 16 mg/kg IV once every 2 weeks
  • Weeks 25 and on: 16 mg/kg IV once every 4 weeks
  • Per the package insert, daratumumab infusion should complete within 15 hours. In Lokhorst et al. 2015, daratumumab was given over 8 hours.

Supportive medications

This is a combination of what is listed in the daratumumab package insert and Lokhorst et al. 2015. There were protocol amendments in Lokhorst et al. 2015; listed medications are what was eventually used.

• Prior to all daratumumab infusions:
  • Methylprednisolone (Solumedrol) 100 mg IV prior to every dose of daratumumab. Per the package insert, after the second dose of daratumumab, dose may be reduced to 60 mg IV. Per Lokhorst et al. 2015, after the fourth dose of daratumumab, dose "could be reduced to 50 mg."
  • Acetaminophen (Tylenol) (paracetamol) 1000 mg (package insert: 650 to 1000 mg) PO 1 to 2 hours prior to daratumumab
  • Antihistamine: Clemastine (Tavist) 1 mg IV, Cetirizine (Zyrtec) 10 mg PO, Diphenhydramine (Benadryl) 25 to 50 mg PO/IV, or equivalent 1 to 2 hours prior to daratumumab
• Post-treatment medications:
  • Methylprednisolone (Solumedrol) 20 to 25 mg (package insert: 20 mg) PO or equivalent one and two days after every daratumumab infusion
  • Package insert: "For patients with a history of obstructive pulmonary disorder, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids."
• Package insert: "Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting DARZALEX and continue for 3 months following treatment"

Given until progression of disease or unacceptable toxicity

References

1. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. link to original article contains verified protocol link to supplementary appendix link to study protocol PubMed
2. SIRIUS: Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Bladé J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. Epub 2016 Jan 7. link to original article contains protocol PubMed
3. Pooled update: Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, Lokhorst HM, Voorhees PM, Richardson PG, Chari A, Sasser AK, Axel A, Feng H, Uhlar CM, Wang J, Khan I, Ahmadi T, Nahi H. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. Epub 2016 May 23. link to original article link to PMC article PubMed

DCEP

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DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol (Cisplatin)

Variant #1

Study	Evidence
Lazzarino et al. 2001	Phase II

Note: this protocol is reported as a mobilization regimen prior to high dose autologous transplant; all patients had received prior therapy.

Chemotherapy

• Dexamethasone (Decadron) 40 mg once per day on days 1 to 4
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m²)
• Cisplatin (Platinol) 10 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 40 mg/m²)

Supportive medications

• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 48 hours after chemotherapy and continuing through stem cell collection

One course

Variant #2

Study	Evidence
Dadacaridou et al. 2007	Phase II, <20 patients reported

These limited details are based on the abstract's description only. Full article was not available for review.

Chemotherapy

• Dexamethasone (Decadron) 40 mg IV bolus once per day on days 1 to 4
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m²)
• Cisplatin (Platinol) 15 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 60 mg/m²)

Supportive medications

• G-CSF SC once per day, starting on day 5, to continue until neutrophil recovery

28-day cycles

References

1. Lazzarino M, Corso A, Barbarano L, Alessandrino EP, Cairoli R, Pinotti G, Ucci G, Uziel L, Rodeghiero F, Fava S, Ferrari D, Fiumanò M, Frigerio G, Isa L, Luraschi A, Montanara S, Morandi S, Perego D, Santagostino A, Savarè M, Vismara A, Morra E. DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) is an effective regimen for peripheral blood stem cell collection in multiple myeloma. Bone Marrow Transplant. 2001 Nov;28(9):835-9. link to original article contains verified protocol PubMed
2. Dadacaridou M, Papanicolaou X, Maltesas D, Megalakaki C, Patos P, Panteli K, Repousis P, Mitsouli-Mentzikof C. Dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) for relapsed or refractory multiple myeloma patients. J BUON. 2007 Jan-Mar;12(1):41 to 4. PubMed

DTPACE

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DTPACE: Dexamethasone, Thalidomide, Platinol (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide

Regimen

Study	Evidence
Lee et al. 2003	Prospective

To be completed

Chemotherapy

• Dexamethasone (Decadron)
• Thalidomide (Thalomid)
• Cisplatin (Platinol)
• Doxorubicin (Adriamycin)
• Cyclophosphamide (Cytoxan)
• Etoposide (Vepesid)

References

1. Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, van Rhee F, Cottler-Fox M, Muwalla F, Tricot G. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol. 2003 Jul 15;21(14):2732-9. Erratum in: J Clin Oncol. 2008 Apr 20;26(12): 2066. link to original article PubMed

FRD

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FRD: Farydak (Panobinostat), Revlimid (Lenalidomide), Dexamethasone

Regimen

Study	Evidence
Chari et al. 2017	Phase II

Chemotherapy

• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 15, 17, 19
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15

28-day cycles

References

1. Ajai Chari, Hearn J. Cho, Amishi Dhadwal, Gillian Morgan, Lisa La, Katarzyna Zarychta, Donna Catamero, Erika Florendo, Nadege Stevens, Daniel Verina, Elaine Chan, Violetta Leshchenko, Alessandro Laganà, Deepak Perumal, Anna Huo-Chang Mei, Kaity Tung, Jami Fukui, Sundar Jagannath and Samir Parekh. A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. Blood Advances 2017 1:1575-1583. link to original article contains verified protocol

Hyper-CVAD

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Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Variant 1

Study	Evidence
Dimopoulos et al. 1996	Phase II

To be completed

Variant 2

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Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence
Saraceni et al. 2018	Retrospective

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² IV every 12 hours for 8 doses on days 1 to 4 (total dose per cycle: 1200 mg/m²)
• Vincristine (Oncovin) 0.4 mg/d IV continuous infusion every 24 hours on days 1 to 4 (total dose per cycle: 1.6 mg)
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 36 mg/m²)
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks

Supportive Medications

• Pegfilgrastim (Neulasta) 6 mg subcutaneous once on day 5 or 6
• Mesna (Mesnex) 350 mg/m²/d continuous I.V. infusion every 24 hours on days 1 to 4
• Antiviral prophylaxis with acyclovir daily
• "Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"

References

1. Dimopoulos MA, Weber D, Kantarjian H, Delasalle KB, Alexanian R. HyperCVAD for VAD-resistant multiple myeloma. Am J Hematol. 1996 Jun;52(2):77-81. link to original article PubMed
2. Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, Medvedova E. Modified HyperCVAD Versus Bortezomib-HyperCAD in Patients With Relapsed/Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e77-e84. link to original article PubMed

Ixazomib monotherapy

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Regimen

Study	Evidence
Kumar et al. 2015	Phase II

Chemotherapy

• Ixazomib (Ninlaro) 5.5 mg PO once per day on days 1, 8, 15

28-day cycles until progression

Patients with no minor response by end of cycle 2, no PR by end of cycle 4, or progression proceeded to receive ixazomib & dexamethasone.

References

1. Phase 1: Kumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, Hui AM, Gupta N, Di Bacco A, Yu J, Shou Y, Niesvizky R. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014 Aug 14;124(7):1047-55. Epub 2014 Jun 5. link to original article link to PMC article PubMed
2. Phase 1: Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, Talpaz M, Berg D, Liu G, Yu J, Gupta N, Di Bacco A, Hui AM, Lonial S. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 Aug 14;124(7):1038-46. Epub 2014 Jun 11. link to original article link to PMC article PubMed
3. Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338. link to original article contains verified protocol link to PMC article PubMed

PAD

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PAD: PS-341 (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone
Note that this regimen is sometimes called VAD but this can create a lot of confusion with the "original" VAD which uses Vincristine.
VAD: Velcade (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence
Cook et al. 2016 (BSBMT/UKMF Myeloma X)	Non-randomized portion of RCT

Note: length of cycle is not reported in the manuscript, but presumably is 28 days, similar to other PAD regimens.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Doxorubicin (Adriamycin) 9 mg/m² IV once per day on days 1 to 4
  • Could be given as a 4-day continuous infusion or as bolus injections
• Dexamethasone (Decadron) as follows:
  • Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
  • Cycles 2 to 4: 40 mg PO once per day on days 1 to 4

2 to 4 cycles

Patients were then randomized to high-dose melphalan & autologous hematopoietic cell transplant versus weekly oral cyclophosphamide.

References

1. Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. Epub 2014 Jun 16. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Dosage error in article text. link to original article PubMed
   1. Update: Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. link to original article contains protocol PubMed

PCP

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PCP: Pomalidomide, Cyclophosphamide, Prednisone

Regimen

Study	Evidence
Larocca et al. 2013	Phase I/II

Details are for the phase II portion of the published phase I/II trial.

Chemotherapy

• Pomalidomide (Pomalyst) 2.5 mg PO once per day
• Cyclophosphamide (Cytoxan) 50 mg PO once every other day
• Prednisone (Sterapred) 50 mg PO once every other day

Supportive medications

• Aspirin 100 mg PO once per day or low-molecular-weight heparin "according to patient risk"

28-day cycle for 6 cycles

Treatment followed by pomalidomide & prednisone maintenance.

References

1. Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A. Pomalidomide, cyclophosphamide and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013 Oct 17;122(16):2799-806. Epub 2013 Aug 16. link to original article contains verified protocol PubMed

Pomalidomide, Dexamethasone, Daratumumab

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Regimen

FDA-recommended dose

Study	Evidence	Efficacy
Chari et al. 2017 (EQUULEUS)	Phase Ib	ORR: 59% (95% CI, 49-69)

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week
  • Patients older than 75 years or BMI less than 18.5: 20 mg PO once per week
• Daratumumab (Darzalex) as follows:
  • Cycles 1 & 2: 16 mg/kg IV once per week
  • Cycles 3 to 6: 16 mg/kg IV once every 2 weeks
  • Cycle 7 onwards: 16 mg/kg IV once every 4 weeks

Supportive medications

• Dexamethasone (Decadron) 20 mg prior to Daratumumab (Darzalex) infusions
  • For patients receiving the 40 mg/wk dose, the remainder is given after the infusion on day of infusion
• Acetaminophen (Tylenol) prior to Daratumumab (Darzalex)
• An antihistamine prior to Daratumumab (Darzalex)

28-day cycles

References

1. EQUULEUS: Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, Weiss BM, Krishnan A, Lentzsch S, Comenzo R, Wang J, Nottage K, Chiu C, Khokhar NZ, Ahmadi T, Lonial S. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017 Aug 24;130(8):974-981. Epub 2017 Jun 21. link to original article contains verified protocol PubMed

PVD

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PVD: Pomalidomide, Velcade (Bortezomib), Dexamethasone

Regimen

Study	Evidence	Efficacy
Paludo et al. 2017 (MC1082)	Phase I/II	ORR: 86%

This is the MTD used in the phase II portion of the trial.

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Bortezomib (Velcade) 1.3 mg/m² IV/SC once per day on days 1, 8, 15, 22
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22

Supportive medications

• Aspirin 325 mg PO once per day
  • Full dose anticoagulation with LMWH or Warfarin (Coumadin) could be substituted at physician discretion
• Acyclovir (Zovirax) or equivalent for VZV prophylaxis

28-day cycle for 8 cycles

Subsequent treatment

• Optionally, pomalidomide maintenance

References

1. MC1082: Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1198-1204. Epub 2017 Jul 6. link to original article contains verified protocol link to PMC article PubMed

RVD

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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
VRd: Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Evidence	ORR
Richardson et al. 2014	Phase II	64%

Chemotherapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

Supportive medications

• Aspirin 81 mg or 325 mg PO once per day
• Antiviral therapy for VZV prophylaxis

21-day cycle for 8 cycles

Patients who had at least stable disease and tolerated therapy could proceed to maintenance RVD at previously tolerated dose.

References

1. Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial IM, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9. Epub 2014 Jan 15. link to original article contains verified protocol link to PMC article PubMed

Thalidomide monotherapy

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Regimen

Study	Evidence
Singhal et al. 1999	Non-randomized

Chemotherapy

• Thalidomide (Thalomid) 200 mg PO once per day, increased by 200 mg every two weeks for six weeks, to final dose of 800 mg per day

Continued until progression

References

1. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. Erratum in: N Engl J Med 2000 Feb 3;342(5):364. link to original article contains protocol PubMed

Vemurafenib monotherapy

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Regimen

Study	Evidence
Andrulis et al. 2013	Case report

Note that Andrulis et al. 2013 is a single patient case report with a good response. Sharman et al. reports two patients with good response. In the Hyman et al. 2015 trial, there were 5 patients with multiple myeloma; "No patients with multiple myeloma have had a response to date."

Chemotherapy

• Vemurafenib (Zelboraf) 480 mg PO BID for one week, then increased to 720 mg PO BID

References

1. Andrulis M, Lehners N, Capper D, Penzel R, Heining C, Huellein J, Zenz T, von Deimling A, Schirmacher P, Ho AD, Goldschmidt H, Neben K, Raab MS. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013 Aug;3(8):862-9. Epub 2013 Apr 23. link to original article contains protocol PubMed
2. Sharman JP, Chmielecki J, Morosini D, Palmer GA, Ross JS, Stephens PJ, Stafl J, Miller VA, Ali SM. Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma. Clin Lymphoma Myeloma Leuk. 2014 Oct;14(5):e161-3. Epub 2014 Jun 11. link to original article PubMed
3. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015 Aug 20;373(8):726-36. link to original article link to PMC article PubMed

VMPT

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VMPT: Velcade (Bortezomib), Melphalan, Prednisone, Thalidomide

Regimen

Study	Evidence
Palumbo et al. 2007	Phase II

Chemotherapy

• Bortezomib (Velcade) 1 to 1.3 mg/m² IV bolus once per day on days 1, 4, 15, 22
• Melphalan (Alkeran) 6 mg/m² PO once per day on days 1 to 5
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 35

35-day cycle for 6 cycles

References

1. Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, Cangialosi C, Caravita T, Morabito F, Musto P, Bringhen S, Falco P, Avonto I, Cavallo F, Boccadoro M; Italian Multiple Myeloma Network; Gruppo Italiano Malattie Ematologicche dell'Adulto. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood. 2007 Apr 1;109(7):2767-72. link to original article contains protocol PubMed

ZRd

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ZRd: Zolinza (Vorinostat), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Evidence
Sanchez et al. 2016	Phase IIb

Chemotherapy

• Vorinostat (Zolinza) 400 mg PO once per day on days 1 to 7, 15 to 21
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

28-day cycles

References

1. Sanchez L, Vesole DH, Richter JR, Biran N, Bilotti E, McBride L, Anand P, Ivanovski K, Siegel DS. A phase IIb trial of vorinostat in combination with lenalidomide and dexamethasone in patients with multiple myeloma refractory to previous lenalidomide-containing regimens. Br J Haematol. 2017 Feb;176(3):440-447. Epub 2016 Nov 18. link to original article contains protocol PubMed

Consolidation after second-line therapy

Melphalan, then auto HSCT

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Regimen

Study	Evidence	Comparator	Efficacy
Cook et al. 2014 (NCRI Myeloma X Relapse)	Phase III	Cyclophosphamide	Seems to have superior OS (*)

Efficacy reported is based on the 2016 update.

Preceding treatment

• PAD x 4

Preparative regimen

• Melphalan (Alkeran) 200 mg/m² IV on day -2

Stem cells re-infused on day 0

References

1. Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. Epub 2014 Jun 16. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Dosage error in article text. link to original article PubMed
   1. Update: Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. link to original article contains protocol PubMed

Maintenance after second-line therapy

Bortezomib & Cyclophosphamide

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Regimen

Study	Evidence
de Waal et al. 2015	Phase II

Preceding treatment

• Bortezomib, Cyclophosphamide, Dexamethasone x 6

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV/SC every 2 weeks
• Cyclophosphamide (Cytoxan) 50 mg PO once per day (continuous)

Supportive medications

• Pneumococccal and anti-fungal prophylaxis "according to local protocols"
• Valacyclovir (Valtrex) (dose not specified) for herpes prophylaxis

1-year course

References

1. de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. link to original article contains verified protocol PubMed

CPD

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CPD: Carfilzomib, Pomalidomide, Dexamethasone
KPD: Kyprolis (Carfilzomib), Pomalidomide, Dexamethasone

Regimen

Study	Evidence
Shah et al. 2015	Phase I (*)

Note, although this is described as a Phase I trial, an additional 20 patients were enrolled at the MTD, which is the dose reported here.

Preceding treatment

• CPD x 6

Chemotherapy

• Carfilzomib (Kyprolis) 27 mg/m² IV over 30 minutes once per day on days 1, 2, 15, 16
• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 20 mg PO/IV once per week on days 1, 8, 15, 22

Supportive medications

• "Anti-viral therapy"
• Aspirin 81 mg PO once per day
  • Low molecular weight heparin was used in patients intolerant of aspirin

28-day cycles, given until disease progression, or unacceptable toxicity

References

1. Phase I: Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. Epub 2015 Sep 17. link to original article contains verified protocol link to PMC article PubMed

Daratumumab monotherapy

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Regimen

Study	Evidence
Palumbo et al. 2016 (CASTOR)	Non-randomized portion of RCT

Preceding treatment

• DVd x 8

Chemotherapy

• Daratumumab (Darzalex) 16 mg/kg IV once on day 1

28-day cycles until progression

References

1. CASTOR: Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed

Pomalidomide monotherapy

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Regimen

Study	Evidence	ORR
Paludo et al. 2017	Phase I/II	86%

Preceding treatment

• PVD x 8

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Supportive medications

• Aspirin 325 mg PO once per day
  • Full dose anticoagulation with LMWH or Warfarin (Coumadin) could be substituted at physician discretion
• Acyclovir (Zovirax) or equivalent for VZV prophylaxis

28-day cycles

References

1. Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1198-1204. Epub 2017 Jul 6. link to original article contains verified protocol PubMed

Pomalidomide & Prednisone

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Regimen

Study	Evidence	ORR
Larocca et al. 2013	Phase I/II	51%

Details are for the phase II portion of the published phase I/II trial.

Preceding treatment

• PCP x 6

Chemotherapy

• Pomalidomide (Pomalyst) 1 mg PO once per day
• Prednisone (Sterapred) 25 mg PO once every other day

Supportive medications

• Aspirin 100 mg PO once per day or low-molecular-weight heparin "according to patient risk"

Continuously until any signs of relapse or progression

References

1. Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A. Pomalidomide, cyclophosphamide and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013 Oct 17;122(16):2799-806. Epub 2013 Aug 16. link to original article contains verified protocol PubMed

RVD

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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
VRd: Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Evidence
Richardson et al. 2014	Phase II

Preceding treatment

• Salvage RVD

Chemotherapy

• Lenalidomide (Revlimid) (at previously tolerated dose) PO once per day on days 1 to 14
• Bortezomib (Velcade) (at previously tolerated dose) IV once per day on days 1 & 8
• Dexamethasone (Decadron) 10 mg PO once per day on days 1, 2, 8, 9

Supportive medications

• Aspirin 81 mg or 325 mg PO once per day
• Antiviral therapy for VZV prophylaxis

21-day cycles until progression or intolerance

References

1. Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial IM, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9. Epub 2014 Jan 15. link to original article contains verified protocol link to PMC article PubMed

Investigational agents

These are drugs under study with at least some promising results for this disease.

• Afuresertib (GSK2110183)
• Dinaciclib (SCH 727965)
• Isatuximab (SAR-650984)
• MOR202
• Perifosine (KRX-0401)
• Ricolinostat (ACY-1215, Rocilinostat)
• Selinexor (KPT-330)

Response criteria

• IMWG international uniform response criteria for multiple myeloma. (Durie et al. Leukemia 2006) PubMed
  • Make note of these errors which remain in the online version of the IMWG criteria as of 7/7/2013.
  • Clarification of the definition of complete response in multiple myeloma (Leukemia 2015) PubMed
• Disease progression criteria (Durie et al. Leukemia 2006).
• European Blood and Marrow Transplant (EBMT) criteria. (Bladé et al. Br J Hematol 1998) PubMed

Prognosis

Durie-Salmon Staging System - 1975

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Composed of four factors with a modifier based on renal function

• Serum levels of monoclonal protein (only defined for IgM, IgA, and Bence-Jones)
• Number of lytic bone lesions
• Hemoglobin
• Serum calcium level

Risk stratification

• Stage I: (must meet ALL criteria)
  • Hemoglobin greater than 10 g/dL
  • Calcium normal or less than or equal to 12 mg/dL
  • Skeletal survey with normal bone structure (scale 0) or solitary bone plasmacytoma only
  • Monoclonal protein relatively small (IgG M-spike value less than 5 g/dL OR IgA M-spike value less than 3 g/dL OR urine light chain protein less than 4 g/24 hr)
• Stage II: not stage I or stage III
• Stage III: (if meets ANY of the criteria)
  • Hemoglobin less than 8.5 g/dL
  • Calcium greater than 12 mg/dL
  • Skeletal survey with extensive skeletal destruction and major fractures
  • Monoclonal protein relatively large (IgG M-spike value greater than 7 g/dL OR IgA M-spike value greater than 5 g/dL OR urine light chain protein greater than 12 g/24 hr)

Modifier

• A: relatively normal creatinine (less than 2 mg/dL)
• B: creatinine greater than or equal to 2 mg/dL

References

1. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975 Sep;36(3):842-54. link to original article PubMed

International Staging System (ISS) - 2005

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Composed of two factors

• Serum albumin level
• Serum beta-2 microglobulin level

Risk stratification

• Stage I: Median survival of 62 months
  • Beta-2 microglobulin less than 3.5 mg/l
  • Albumin greater than or equal to 3.5 g/dl
• Stage II: Median survival of 44 months
  • Not meeting stage I or stage III criteria
• Stage III: Median survival of 29 months
  • Beta-2 microglobulin greater than or equal to 5.5 mg/l

References

1. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J. International staging system for multiple myeloma. J Clin Oncol. 2005 May 20;23(15):3412-20. Epub 2005 Apr 4. link to original article PubMed
2. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009 Jan;23(1):3-9. Epub 2008 Oct 30. link to PMC article PubMed

IMWG consensus on risk stratification - 2013

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Composed of four factors

• Serum albumin level
• Serum beta-2 microglobulin level
• Age
• Chromosomal abnormalities detected by interphase fluorescent in situ hybridization (FISH)

Risk stratification

• Low risk: (must meet all criteria) Median survival of greater than 10 years
  • ISS Stage I or II
  • Age less than 55 years
  • Absence of the following: del(17p13), t(4;14), +1q21
• Standard risk: Median survival of 7 years
  • Not meeting low risk or high risk criteria
• High risk: (if meets both criteria) Median survival of 2 years
  • ISS Stage II or III
  • Either of the following: del(17p13) or t(4;14)

References

1. Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, Miguel JS, Sonneveld P, Cavo M, Usmani S, Durie BG, Avet-Loiseau H; International Myeloma Working Group. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014 Feb;28(2):269-77. Epub 2013 Aug 26. Review. link to original article PubMed

Revised International Staging System (R-ISS) - 2015

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Composed of four factors

• Serum albumin level
• Serum beta-2 microglobulin level
• Serum LDH
• Chromosomal abnormalities detected by interphase fluorescent in situ hybridization (FISH)

Risk stratification

• Low risk: 5-year overall survival = 82%
  • Beta-2 microglobulin less than 3.5 mg/l
  • Albumin less than or equal to 3.5 g/dl
  • LDH less than the upper limit of normal range
  • Absence of the following: del(17p), t(4;14), t(14;16)
• Intermediate risk: 5-year overall survival = 62%
  • Not meeting low risk or high risk criteria
• High risk: (if meets ANY of the criteria) 5-year overall survival = 40%
  • Beta-2 microglobulin greater than or equal to 5.5 mg/l
  • LDH greater than the upper limit of normal range
  • Any of the following: del(17p), t(4;14), t(14;16)

References

1. Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P. Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015 Sep 10;33(26):2863-9. Epub 2015 Aug 3. link to original article link to PMC article

Miscellaneous

1. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007 Apr 15;109(8):3489-95. Epub 2007 Jan 5. link to original article PubMed
2. Avet-Loiseau H, Hulin C, Campion L, Rodon P, Marit G, Attal M, Royer B, Dib M, Voillat L, Bouscary D, Caillot D, Wetterwald M, Pegourie B, Lepeu G, Corront B, Karlin L, Stoppa AM, Fuzibet JG, Delbrel X, Guilhot F, Kolb B, Decaux O, Lamy T, Garderet L, Allangba O, Lifermann F, Anglaret B, Moreau P, Harousseau JL, Facon T. Chromosomal abnormalities are major prognostic factors in elderly patients with multiple myeloma: the Intergroupe Francophone du Myélome experience. J Clin Oncol. 2013 Aug 1;31(22):2806-9. Epub 2013 Jun 24. link to original article link to PMC article PubMed

External links

• Mayo Clinic mSMART (Stratification for Myeloma And Risk-adapted Therapy)