Multiple myeloma, induction

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 Samuel M. Rubinstein, MD
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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!.
Note: due to its size/complexity, multiple myeloma has been split into sub-pages. This page covers induction regimens for both transplant eligible and ineligible patients. As this distinction can often be unclear, we do not separate regimens on this basis. Rather, the page is organized by doublets, triplets, quadruplets, and other combinations. The top-line inclusion criteria from each prospectively enrolling regimen are reported.

46 regimens on this page
107 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO/CCO

BSH/UKMF

European Myeloma Network (EMN)

EHA/ESMO

IMWG

NCCN

SITC

First-line therapy, doublets

Bortezomib & Dexamethasone (Vd)

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

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Niesvizky et al. 2015 (UPFRONT) 2007-2010 Phase 3b (E-de-esc) 1. VMP Did not meet primary endpoint of PFS
2. VTD Did not meet primary endpoint of PFS

Note: This regimen was meant for transplant ineligible patients.

Targeted therapy

Glucocorticoid therapy

  • 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

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2011 (IFM 2007-02) 2008-03 to 2009-01 Phase 3 (C) vtD Inferior VGPR rate

Note: 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).

Targeted therapy

Glucocorticoid therapy

  • 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

Subsequent treatment


Regimen variant #3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Harousseau et al. 2010 (IFM 2005-01) 2005-2008 Phase 3 (E-switch-ooc) VAD Might have superior PFS (secondary endpoint)

Note: 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).

Targeted therapy

Glucocorticoid therapy

  • 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 therapy

  • One of the following bisphosphonates recommended:
  • "Antibiotics, antifungal agents, and antiviral prophylaxis in accordance with local practice."

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #4, weekly bortezomib

Study Dates of enrollment Evidence
Girnius et al. 2014 (X05153) 2007-NR Phase 2

Targeted therapy

Glucocorticoid therapy

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 dosing details in manuscript PubMed NCT00200681
    1. Subgroup analysis: Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guérin-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. IFM 2007-02: 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 dosing details in manuscript PubMed NCT00910897
  3. X05153: 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 dosing details in manuscript PubMed NCT01090921
  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 dosing details in manuscript PubMed NCT00507416

Bortezomib & Prednisone (VP)

VP: Velcade (Bortezomib) & Prednisone

Regimen

Study Dates of enrollment Evidence
Larocca et al. 2016 (MMY2069) 2010-2012 Phase 2

Targeted therapy

Glucocorticoid therapy

28-day cycle for 9 cycles

Subsequent treatment

References

  1. MMY2069: 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. Epub 2016 Feb 22. link to original article contains dosing details in manuscript PubMed NCT01190787

Lenalidomide & Dexamethasone (Rd)

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

Regimen variant #1, limited duration (4 cycles)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rajkumar et al. 2009 (ECOG E4A03) 2004-2006 Phase 3 (E-de-esc) RD Superior OS (secondary endpoint)

Inconclusive whether non-inferior RR after 4 cycles (primary endpoint)
Gay et al. 2010 2004-2008 Retrospective
Palumbo et al. 2014 (MPRvsMEL200) 2007-2009 Non-randomized part of phase 3 RCT
Gay et al. 2015 (EMN-441) 2009-2011 Non-randomized part of phase 3 RCT

Note: 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. MPRvsMEL200 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.

Targeted therapy

Glucocorticoid therapy

Supportive therapy

(as described in Rajkumar et al. 2009):

  • One of the following bisphosphonates:
  • Thromboprophylaxis mandatory (added mid-protocol after excess rates of DVT)

28-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2, limited duration (6 cycles)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Durie et al. 2016 (SWOG S0777) 2008-2012 Phase 3 (C) VRd Inferior OS1

1Reported efficacy is based on the 2020 update.

Targeted therapy

Glucocorticoid therapy

28-day cycle for 6 cycles

Subsequent treatment

  • Rd maintenance


Regimen variant #3, limited duration (9 cycles)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Magarotto et al. 2016 (EMN01) 2009-2012 Phase 3 (E-de-esc) 1. CPR Did not meet primary endpoint of PFS
2. MPR Might have inferior PFS
Larocca et al. 2021 (RV-MM-PI-0752) 2014-2017 Phase 3 (E-de-esc) Rd; continuous Seems to have superior EFS (primary endpoint)
Median EFS: 10.4 vs 6.9 mo
(HR 0.70, 95% CI 0.51-0.95)

Note: In EMNO1, 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. In RV-MM-PI-0752, this regimen is intended for patients between 65 and 80 years of age who were ineligible for transplant.

Targeted therapy

Glucocorticoid therapy

  • Dexamethasone (Decadron) by the following study-specific criteria:
    • EMN01, age 65 to 75 years: 40 mg PO once per day on days 1, 8, 15, 22
    • EMN01, age greater than 75 years & RV-MM-PI-0752, all patients: 20 mg PO once per day on days 1, 8, 15, 22

Supportive therapy

28-day cycle for 9 cycles

Subsequent treatment


Regimen variant #4, limited duration (18 cycles, "Rd18")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Benboubker et al. 2014 (FIRSTMM) 2008-2011 Phase 3 (E-RT-switch-ooc) 1. MPT Superior OS1 (secondary endpoint)
Median OS: 62 vs 49 mo
(HR not reported)
2. Rd; continuous Did not meet primary endpoint of PFS1

1Reported efficacy is based on the 2017 update.
Note: 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.

Targeted therapy

  • Lenalidomide (Revlimid) by the following renal function-based criteria:
    • CrCl more than 50 mL/min/1.73m2: 25 mg PO once per day on days 1 to 21
    • CrCl 30 to 50 mL/min/1.73m2: 10 mg PO once per day on days 1 to 21
    • CrCl less than 30 mL/min/1.73m2: 15 mg PO once every other day on days 1 to 21

Glucocorticoid therapy

  • Dexamethasone (Decadron) by the following age-based criteria:
    • 75 years old or younger: 40 mg PO once per day on days 1, 8, 15, 22
    • Older than 75 years old: 20 mg PO once per day on days 1, 8, 15, 22

28-day cycle for 18 cycles


Regimen variant #5, indefinite 28-day cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Benboubker et al. 2014 (FIRSTMM) 2008-2011 Phase 3 (E-RT-switch-ooc) 1. MPT Superior PFS (primary endpoint)
Median PFS: 25.5 vs 21.2 mo
(HR 0.72, 95% CI 0.61-0.85)

Superior OS1 (secondary endpoint)
Median OS: 59 vs 49 mo
(HR 0.78, 95% CI 0.67-0.92)
2. Rd; Rd18 Did not meet primary endpoint of PFS1
Dimopoulos et al. 2022 (ELOQUENT-1) 2011-2014 Phase 3 (C) Elo-Rd Did not meet primary endpoint of PFS
Facon et al. 2019 (MAIA) 2015-2017 Phase 3 (C) Dara-Rd Inferior PFS (primary endpoint)

Inferior OS2 (secondary endpoint)
Puig et al. 2021 (GEM-CLARIDEX) 2015-2019 Phase 3 (C) BiRd Did not meet primary endpoint of PFS
Usmani et al. 2019 (KEYNOTE-185) 2016-01-07 to 2017-06-09 Phase 3 (C) Rd & Pembrolizumab Did not meet primary endpoint of PFS

1Reported efficacy for FIRST is based on the 2017 update.
2Reported efficacy for MAIA is based on the 2021 update.
Note: KEYNOTE-185 was closed early due to excess mortality in the experimental arm.

Eligibility criteria

  • FIRST: 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.
  • MAIA: 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.

Targeted therapy

  • Lenalidomide (Revlimid) by the following renal function-based criteria:
    • CrCl more than 50 mL/min/1.73m2: 25 mg PO once per day on days 1 to 21
    • CrCl 30 to 50 mL/min/1.73m2: 10 mg PO once per day on days 1 to 21
    • CrCl less than 30 mL/min/1.73m2: 15 mg PO once every other day on days 1 to 21

Glucocorticoid therapy

  • Dexamethasone (Decadron) by the following age-based criteria:
    • Younger than 75 years old: 40 mg PO once per day on days 1, 8, 15, 22
    • Older than 75 years old: 20 mg PO once per day on days 1, 8, 15, 22

28-day cycles

Dose and schedule modifications

  • FIRST: See supplemental appendix for further details of dose reductions from starting dose.
  • MAIA: Lenalidomide dosing for CrCl less than 30 mL/min/1.73m2 was not specified. Patients with BMI less than 18.5 were also given the reduced-dose dexamethasone.


Regimen variant #6, indefinite with 35-day induction cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zonder et al. 2010 (SWOG S0232) 2004-2007 Phase 3 (E-esc) Dexamethasone Superior PFS (primary endpoint)

Note: 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.

Targeted therapy

  • Lenalidomide (Revlimid) as follows:
    • Cycles 1 to 3: 25 mg PO once per day on days 1 to 28
    • Cycle 4 onwards: 25 mg PO once per day on days 1 to 21

Glucocorticoid therapy

  • 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
    • Cycle 4 onwards: 40 mg PO once per day on days 1 to 4

Supportive therapy

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

35-day cycle for 3 cycles, then 28-day cycles


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

Study Dates of enrollment Evidence
Rajkumar et al. 2005 2004 Phase 2

Targeted therapy

Glucocorticoid therapy

  • 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 therapy

  • Thromboprophylaxis: Aspirin 80 mg or 325 mg PO once per day

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 dosing details in abstract link to PMC article PubMed
  2. ECOG E4A03: Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; ECOG. 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 dosing details in manuscript link to PMC article PubMed NCT00098475
    1. Subgroup analysis: Jacobus SJ, Kumar S, Uno H, Van Wier SA, Ahmann GJ, Henderson KJ, Callander NS, Williams ME, Siegel DS, Greipp PR, Rajkumar SV, Fonseca R. Impact of high-risk classification by FISH: an eastern cooperative oncology group (ECOG) study E4A03. Br J Haematol. 2011 Nov;155(3):340-8. Epub 2011 Sep 9. link to original article 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 dosing details in manuscript link to PMC article PubMed
  4. SWOG S0232: 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 dosing details in manuscript PubMed NCT00064038
  5. MPRvsMEL200: 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 dosing details in manuscript PubMed NCT00551928
  6. FIRSTMM: 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 dosing details in manuscript PubMed NCT00689936
    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 link to PMC 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 dosing details in abstract PubMed NCT01091831
  8. 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 dosing details in manuscript PubMed NCT01093196
  9. SWOG S0777: 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 dosing details in manuscript link to PMC article PubMed NCT00644228
    1. Update: Durie BGM, Hoering A, Sexton R, Abidi MH, Epstein J, Rajkumar SV, Dispenzieri A, Kahanic SP, Thakuri MC, Reu FJ, Reynolds CM, Orlowski RZ, Barlogie B. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020 May 11;10(5):53. link to original article link to PMC article PubMed
  10. MAIA: Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Attal M, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Chiu C, Wang J, Van Rampelbergh R, Uhlar CM, Kobos R, Qi M, Usmani SZ; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019 May 30;380(22):2104-2115. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02252172
    1. HRQoL analysis: Perrot A, Facon T, Plesner T, Usmani SZ, Kumar S, Bahlis NJ, Hulin C, Orlowski RZ, Nahi H, Mollee P, Ramasamy K, Roussel M, Jaccard A, Delforge M, Karlin L, Arnulf B, Chari A, He J, Ho KF, Van Rampelbergh R, Uhlar CM, Wang J, Kobos R, Gries KS, Fastenau J, Weisel K. Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial. J Clin Oncol. 2021 Jan 20;39(3):227-237. Epub 2020 Dec 16. link to original article link to PMC article PubMed
    2. Update: Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Wang J, Van Rampelbergh R, Uhlar CM, Tromp B, Delioukina M, Vermeulen J, Usmani SZ. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1582-1596. Epub 2021 Oct 13. link to original article PubMed
  11. KEYNOTE-185: Usmani SZ, Schjesvold F, Oriol A, Karlin L, Cavo M, Rifkin RM, Yimer HA, LeBlanc R, Takezako N, McCroskey RD, Lim ABM, Suzuki K, Kosugi H, Grigoriadis G, Avivi I, Facon T, Jagannath S, Lonial S, Ghori RU, Farooqui MZH, Marinello P, San-Miguel J; KEYNOTE-185 Investigators. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019 Sep;6(9):e448-e458. Epub 2019 Jul 18. link to original article contains dosing details in abstract PubMed NCT02579863
  12. TOURMALINE-MM2: Facon T, Venner CP, Bahlis NJ, Offner F, White D, Karlin L, Benboubker L, Rigaudeau S, Rodon P, Voog E, Yoon SS, Suzuki K, Shibayama H, Zhang X, Twumasi-Ankrah P, Yung G, Rifkin RM, Moreau P, Lonial S, Kumar SK, Richardson PG, Rajkumar SV. Oral ixazomib, lenalidomide, and dexamethasone for newly diagnosed transplant-ineligible multiple myeloma patients. Blood. 2021 Jul 1;137(26):3616-3628. Epub 2021 Mar 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01850524
  13. GEM-CLARIDEX: Puig N, Hernández MT, Rosiñol L, González E, de Arriba F, Oriol A, González-Calle V, Escalante F, de la Rubia J, Gironella M, Ríos R, García-Sánchez R, Arguiñano JM, Alegre A, Martín J, Gutiérrez NC, Calasanz MJ, Martín ML, del Carmen Couto M, Casanova M, Arnao M, Pérez-Persona E, Garzón S, González MS, Martín-Sánchez G, Ocio EM, Coleman M, Encinas C, Vale AM, Teruel AI, Cortés-Rodríguez M, Paiva B, Cedena MT, San-Miguel JF, Lahuerta JJ, Bladé J, Niesvizky R, Mateos MV. Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial. Blood Cancer J. 2021 May 21;11(5):101. link to original article link to PMC article PubMed NCT02575144
  14. RV-MM-PI-0752: Larocca A, Bonello F, Gaidano G, D'Agostino M, Offidani M, Cascavilla N, Capra A, Benevolo G, Tosi P, Galli M, Marasca R, Giuliani N, Bernardini A, Antonioli E, Rota-Scalabrini D, Cellini C, Pompa A, Monaco F, Patriarca F, Caravita di Toritto T, Corradini P, Tacchetti P, Boccadoro M, Bringhen S. Dose/schedule-adjusted Rd-R vs continuous Rd for elderly, intermediate-fit patients with newly diagnosed multiple myeloma. Blood. 2021 Jun 3;137(22):3027-3036. link to original article contains dosing details in manuscript PubMed NCT02215980
  15. ELOQUENT-1: Dimopoulos MA, Richardson PG, Bahlis NJ, Grosicki S, Cavo M, Beksaç M, Legieć W, Liberati AM, Goldschmidt H, Belch A, Magen H, Larocca A, Laubach JP, Petrucci MT, Reece D, White D, Mateos MV, Špička I, Lazaroiu M, Berdeja J, Kaufman JL, Jou YM, Ganetsky A, Popa McKiver M, Lonial S, Weisel K; ELOQUENT-1 investigators. Addition of elotuzumab to lenalidomide and dexamethasone for patients with newly diagnosed, transplantation ineligible multiple myeloma (ELOQUENT-1): an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2022 Jun;9(6):e403-e414. Epub 2022 May 9. link to original article contains dosing details in abstract PubMed NCT01335399
  16. EMN20: NCT04096066
  17. King Faisal 2081-113: NCT01530594

Lenalidomide & Prednisone (RP)

RP: Revlimid (Lenalidomide) & Prednisone

Regimen

Study Dates of enrollment Evidence
Falco et al. 2012 2008-2009 Phase 2

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.

Targeted therapy

Glucocorticoid therapy

Supportive therapy

  • Thromboprophylaxis: Aspirin 100 mg PO once per day, taken during lenalidomide 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 dosing details in manuscript PubMed

Thalidomide & Dexamethasone (TD)

TD: Thalidomide & Dexamethasone
Thal-Dex: Thalidomide & Dexamethasone

Regimen variant #1, 50 -> 200 mg/d, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosiñol et al. 2012 (GEM05/MENOS65) 2006-2009 Phase 3 (C) 1. VTD Seems to have inferior PFS
2. VBMCP/VBAD, then B Not reported

Note: 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.

Targeted therapy

  • 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

Glucocorticoid therapy

Supportive therapy

28-day cycle for 6 cycles


Regimen variant #2, 50 -> 200 mg/d, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rajkumar et al. 2008 (THAL-MM-003) 2003-2005 Phase 3 (E-RT-esc) Dexamethasone Superior TTP (primary endpoint)
Median TTP: 22.6 vs 6.5 mo
(HR 0.43, 95% CI 0.32-0.58)

Note: 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.

Targeted therapy

  • 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

Glucocorticoid therapy

  • 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


Regimen variant #3, 100 -> 200 mg/d, 3 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cavo et al. 2010 (GIMEMA MM-BO2005) 2006-2008 Phase 3 (C) VTD Inferior OS1

1Reported efficacy is based on the 2020 update.
Note: This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma.

Targeted 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

Glucocorticoid therapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #4, 100 -> 200 mg/d, 4 cycles

Study Dates of enrollment Evidence
Cavo et al. 2004 (Bologna 2002) 2002-2003 Phase 2

Targeted 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 end of cycle
    • Cycles 2 to 4: 200 mg PO once per day

Glucocorticoid therapy

  • 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

1-month cycle for 4 cycles

Subsequent treatment


Regimen variant #5, 100 -> 400 mg/day

Study Dates of enrollment Evidence
Weber et al. 2003 1999-2001 Phase 1/2

Targeted therapy

  • Thalidomide (Thalomid) as follows:
    • Cycle 1: 100 mg PO once per day on days 1 to 7, then 200 mg PO once per day on days 8 to 14, then 300 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 29
    • Cycle 2 onwards: 400 mg PO once per day on days 1 to 29

Glucocorticoid therapy

29-day cycles


Regimen variant #6, 200 mg/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Rajkumar et al. 2002 NR Phase 2
Rajkumar et al. 2005 (ECOG E1A00) 2002-06 to 2003-04 Phase 3 (E-RT-esc) Dexamethasone Seems to have superior RR within 4 months (primary endpoint) Inferior toxicity

Note: In ECOG E1A00 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.

Targeted therapy

Glucocorticoid therapy

  • 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

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 dosing details in abstract PubMed
  2. 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 contains dosing details in abstract PubMed
  3. Bologna 2002: 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 dosing details in abstract 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 dosing details in abstract PubMed
  4. ECOG E1A00: Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; ECOG. 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 dosing details in abstract PubMed NCT00033332
  5. THAL-MM-003: 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 dosing details in manuscript link to PMC article PubMed NCT00057564
  6. 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. Erratum in: Lancet. 2011 Nov 26;378(9806):1846. link to original article PubMed NCT01134484
    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 dosing details in manuscript PubMed
    2. Update: Tacchetti P, Pantani L, Patriarca F, Petrucci MT, Zamagni E, Dozza L, Galli M, Di Raimondo F, Crippa C, Boccadoro M, Barbato S, Tosi P, Narni F, Montefusco V, Testoni N, Spadano A, Terragna C, Pescosta N, Marzocchi G, Cellini C, Galieni P, Ronconi S, Gobbi M, Catalano L, Lazzaro A, De Sabbata G, Cangialosi C, Ciambelli F, Musto P, Elice F, Cavo M; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto Italian Myeloma Network). Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. Lancet Haematol. 2020 Dec;7(12):e861-e873. link to original article PubMed
  7. GEM05/MENOS65: 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; PETHEMA; GEM. 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 dosing details in manuscript PubMed NCT00461747
    1. Update: 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 dosing details in manuscript PubMed

First-line therapy, triplets

BBD

BBD: Bendamustine, Bortezomib, Dexamethasone

Regimen

Study Dates of enrollment Evidence
Berdeja et al. 2017 (SCRI MM 23) 2010-2014 Phase 2

Note: this is the modified treatment schema.

Chemotherapy

Glucocorticoid therapy

Targeted therapy

Supportive therapy

  • Mandatory VZV prophylaxis

28-day cycle for 8 cycles

Subsequent treatment

  • Vd maintenance

References

  1. SCRI MM 23: 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 dosing details in manuscript PubMed NCT01056276

CPR

CPR: Cyclophosphamide, Prednisone, Revlimid (Lenalidomide)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Magarotto et al. 2016 (EMN01) 2009-2012 Phase 3 (E-esc) 1. MPR Might have inferior PFS (primary endpoint)
2. Rd Did not meet primary endpoint of PFS

Note: 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

Glucocorticoid therapy

Targeted therapy

Supportive therapy

28-day cycle for 9 cycles

Subsequent treatment

References

  1. 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 dosing details in manuscript PubMed NCT01093196

CRd

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

Regimen variant #1, Rdc

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jackson et al. 2021 (UK NCRI Myeloma XI+) 2013-2016 Phase 3 (C) 1. KRdc Inferior PFS
2. Tdc Not reported

Chemotherapy

Glucocorticoid therapy

Targeted therapy

28-day cycle for at least 4 cycles

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence
Kumar et al. 2011 (RV-MM-PI-0116) 2006-2008 Phase 2

Chemotherapy

Glucocorticoid therapy

Targeted therapy

Supportive therapy

28-day cycle for 4 to 12 cycles

Subsequent treatment

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

References

  1. RV-MM-PI-0116: 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. Epub 2011 May 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00478218
  2. UK NCRI Myeloma XI+: Jackson GH, Pawlyn C, Cairns DA, de Tute RM, Hockaday A, Collett C, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Rocci A, Snowden JA, Jenner MW, Cook G, Russell NH, Drayson MT, Gregory WM, Kaiser MF, Owen RG, Davies FE, Morgan GJ; UK NCRI Haemato-oncology Clinical Studies Group. Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial. PLoS Med. 2021 Jan 11;18(1):e1003454. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01554852

CTD

CTD: Cyclophosphamide, Thalidomide, Dexamethasone
CTDa: Cyclophosphamide, Thalidomide, Dexamethasone, attenuated
Tdc: Thalidomide, low-dose dexamethasone, low-dose cyclophosphamide

Regimen variant #1, CTD

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX) 2003-2007 Phase 3 (E-switch-ooc) CVAD Not reported

Note: This was an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference. Thalidomide dose was only increased if the starting dose was tolerated.

Chemotherapy

Glucocorticoid therapy

Targeted therapy

  • Thalidomide (Thalomid) as follows:
    • Cycle 1: 100 mg PO once per day on days 1 to 21
    • Cycle 2 onwards: 200 mg PO once per day on days 1 to 21

Supportive therapy

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

Subsequent treatment


Regimen variant #2, CTDa

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX) 2003-2007 Phase 3 (E-esc) MP Not reported

Note: This was a nonintensive treatment pathway, as determined by performance status, informed discussion, and patient preference. Thalidomide dose was increased only if the prior dose was tolerated.

Chemotherapy

Glucocorticoid therapy

Targeted therapy

  • Thalidomide (Thalomid) as follows:
    • Cycle 1: 50 mg PO once per day on days 1 to 28
    • Cycle 2: 100 mg PO once per day on days 1 to 28
    • Cycle 3: 150 mg PO once per day on days 1 to 28
    • Cycles 4 to 9: 200 mg PO once per day on days 1 to 28

Supportive therapy

28-day cycle for 6 to 9 cycles

Subsequent treatment


Regimen variant #3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hungria et al. 2015 (GBRAM0002) 2006-2013 Phase 3 (E-switch-ic) 1. MPT Might have superior ORR (primary endpoint)
2. TD Not reported

Note: the TD arm was close prematurely and no comparisons were made.

Chemotherapy

Glucocorticoid therapy

  • Dexamethasone (Decadron) as follows:
    • Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 15 to 18
    • Cycles 3 to 9: 40 mg PO once per day on days 1 to 4

Targeted therapy

28-day cycle for up to 9 cycles

References

  1. MRC Myeloma IX: Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. link to original article link to PMC article PubMed ISRCTN68454111
    1. Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article contains dosing details in manuscript link to PMC article PubMed
    2. Update: 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 dosing details in manuscript PubMed
    3. 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. link to original article contains dosing details in manuscript link to PMC article PubMed
    4. 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
  2. GBRAM0002: Hungria VT, Crusoé EQ, Maiolino A, Bittencourt R, Fantl D, Maciel JF, Pessoa de Magalhaes RJ, Almeida MS, Cury P, Hisgashi F, Peres AL, Chiattone CS. Phase 3 trial of three thalidomide-containing regimens in patients with newly diagnosed multiple myeloma not transplant-eligible. Ann Hematol. 2016 Jan;95(2):271-8. Epub 2015 Oct 30. link to original article contains dosing details in manuscript PubMed NCT01532856
  3. GBRAM003r: NCT03402295
  4. NCRI Myeloma XI: NCT01554852

Dara-Rd

Dara-Rd: Daratumumab, Revlimid (Lenalidomide), Dexamethasone
DRd: Daratumumab, Revlimid (Lenalidomide), Dexamethasone

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Facon et al. 2019 (MAIA) 2015-2017 Phase 3 (E-RT-esc) Rd Superior PFS (primary endpoint)
PFS30: 70.6% vs 55.6%
(HR 0.56, 95% CI 0.43-0.73)

Superior OS1 (secondary endpoint)
Median OS: NYR vs NYR
(HR 0.68, 95% CI 0.53-0.86)

1Reported efficacy is based on the 2021 update.
Note: 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.

Targeted therapy

  • Daratumumab (Darzalex) as follows:
    • Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22
    • Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15
    • Cycle 7 onwards: 16 mg/kg IV once on day 1
  • Lenalidomide (Revlimid) by the following renal function-based criteria:
    • CrCl more than 50 mL/min/1.73m2: 25 mg PO once per day on days 1 to 21
    • CrCl 30 to 50 mL/min/1.73 m2: 10 mg PO once per day on days 1 to 21

Glucocorticoid therapy

  • Dexamethasone (Decadron) by the following age- and BMI-based criteria:
    • 75 years old and younger AND BMI 18.5 or more: 40 mg PO once per day on days 1, 8, 15, 22
    • Older than 75 years old OR BMI less than 18.5: 20 mg PO once per day on days 1, 8, 15, 22

28-day cycles

References

  1. MAIA: Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Attal M, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Chiu C, Wang J, Van Rampelbergh R, Uhlar CM, Kobos R, Qi M, Usmani SZ; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019 May 30;380(22):2104-2115. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02252172
    1. HRQoL analysis: Perrot A, Facon T, Plesner T, Usmani SZ, Kumar S, Bahlis NJ, Hulin C, Orlowski RZ, Nahi H, Mollee P, Ramasamy K, Roussel M, Jaccard A, Delforge M, Karlin L, Arnulf B, Chari A, He J, Ho KF, Van Rampelbergh R, Uhlar CM, Wang J, Kobos R, Gries KS, Fastenau J, Weisel K. Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial. J Clin Oncol. 2021 Jan 20;39(3):227-237. Epub 2020 Dec 16. link to original article link to PMC article PubMed
    2. Update: Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Wang J, Van Rampelbergh R, Uhlar CM, Tromp B, Delioukina M, Vermeulen J, Usmani SZ. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1582-1596. Epub 2021 Oct 13. link to original article PubMed
  2. EQUATE: NCT04566328

IRd

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

Regimen variant #1, indefinite with dose-reduced dexamethasone

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Facon et al. 2021 (TOURMALINE-MM2) 2013-2015 Phase 3 (E-esc) Rd Might have superior PFS (primary endpoint)
Median PFS: 35.3 vs 21.8 mo
(HR 0.83, 95% CI 0.68-1.02)

Note: this variant was intended for patients older than 75 years. Patients were ineligible for autologous HSCT due to age or comorbidities.

Targeted therapy

  • Ixazomib (Ninlaro) as follows:
    • Cycles 1 to 18: 4 mg PO once per day on days 1, 8, 15
    • Cycle 19 onwards: 3 mg PO once per day on days 1, 8, 15
  • Lenalidomide (Revlimid) as follows:
    • Cycles 1 to 18: 25 mg PO once per day on days 1 to 21
    • Cycle 19 onwards: 10 mg PO once per day on days 1 to 21

Glucocorticoid therapy

28-day cycles


Regimen variant #2, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Facon et al. 2021 (TOURMALINE-MM2) 2013-2015 Phase 3 (E-esc) Rd Might have superior PFS (primary endpoint)
Median PFS: 35.3 vs 21.8 mo
(HR 0.83, 95% CI 0.68-1.02)

Note: Patients were ineligible for autologous HSCT due to age or comorbidities.

Targeted therapy

  • Ixazomib (Ninlaro) as follows:
    • Cycles 1 to 18: 4 mg PO once per day on days 1, 8, 15
    • Cycle 19 onwards: 3 mg PO once per day on days 1, 8, 15
  • Lenalidomide (Revlimid) as follows:
    • Cycles 1 to 18: 25 mg PO once per day on days 1 to 21
    • Cycle 19 onwards: 10 mg PO once per day on days 1 to 21

Glucocorticoid therapy

28-day cycles


Regimen variant #3, limited duration

Study Dates of enrollment Evidence
Kumar et al. 2014 (C16005) 2010-2012 Phase 1/2

Note: This is the MTD dose of C16005.

Targeted therapy

Glucocorticoid therapy

28-day cycle for up to 12 cycles

Subsequent treatment

References

  1. C16005: 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. Epub 2014 Nov 14. link to original article contains dosing details in abstract PubMed NCT01217957
  2. TOURMALINE-MM2: Facon T, Venner CP, Bahlis NJ, Offner F, White D, Karlin L, Benboubker L, Rigaudeau S, Rodon P, Voog E, Yoon SS, Suzuki K, Shibayama H, Zhang X, Twumasi-Ankrah P, Yung G, Rifkin RM, Moreau P, Lonial S, Kumar SK, Richardson PG, Rajkumar SV. Oral ixazomib, lenalidomide, and dexamethasone for newly diagnosed transplant-ineligible multiple myeloma patients. Blood. 2021 Jul 1;137(26):3616-3628. Epub 2021 Mar 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01850524
  3. FiTNEss: NCT03720041

KCD

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

Regimen variant #1, bi-weekly carfilzomib

Study Dates of enrollment Evidence
Bringhen et al. 2014 (IST-CAR-506) 2011-2012 Phase 2

Targeted therapy

  • 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

Chemotherapy

Glucocorticoid therapy

28-day cycle for 9 cycles

Subsequent treatment


Regimen variant #2, weekly carfilzomib ("wKCyd")

Study Dates of enrollment Evidence
Bringhen et al. 2017 (IST-CAR-561) 2013-2015 Phase 1/2

Note: this is the MTD established for the phase 2 portion of the trial.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

28-day cycle for 9 cycles

Subsequent treatment

References

  1. IST-CAR-506: 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 dosing details in manuscript PubMed NCT01346787
  2. IST-CAR-561: 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 contains dosing details in manuscript PubMed NCT01857115

KMP

KMP: Kyprolis (Carfilzomib), Melphalan, Prednisone
CMP: Carfilzomib, Melphalan, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2015 (CARMYSAP) 2010-2012 Phase 1/2
Facon et al. 2019 (CLARION) 2013-2015 Phase 3 (E-switch-ic) VMP Did not meet primary endpoint of PFS
Median PFS: 22.3 vs 22.1 mo
(HR 0.91, 95% CI 0.75-1.10)

Note: CARMYSAP 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 CARMYSAP. CLARION was open to transplant ineligible patients.

Targeted therapy

  • 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

Chemotherapy

Glucocorticoid therapy

42-day cycle for 9 cycles

References

  1. CARMYSAP: 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 dosing details in manuscript PubMed NCT01279694
  2. CLARION: Facon T, Lee JH, Moreau P, Niesvizky R, Dimopoulos M, Hajek R, Pour L, Jurczyszyn A, Qiu L, Klippel Z, Zahlten-Kumeli A, Osman M, Paiva B, San-Miguel J. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2019 May 2;133(18):1953-1963. Epub 2019 Feb 28. link to original article contains dosing details in abstract PubMed NCT01818752

KRd

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

Regimen variant #1


Study Dates of enrollment Evidence
Korde et al. 2016 (NCI 11-C-0221) 2011-2013 Phase 2

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

Targeted therapy

  • 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

Glucocorticoid therapy

  • Dexamethasone (Decadron) as follows:
    • Cycle 1: 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
    • Cycles 2 to 4: 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
    • Cycles 5 to 8: 10 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycle for 8 cycles

Subsequent treatment

  • 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 maintenance after the 8th cycle


Regimen variant #2

Study Dates of enrollment Evidence
Jakubowiak et al. 2012 (UMCC 2009.056) 2009-2011 Phase 1/2

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

Targeted therapy

  • 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

Glucocorticoid therapy

  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 4: 40 mg (route not specified) once per day on days 1, 8, 15, 22
    • Cycles 1 & 2; at clinician's discretion: 4 mg IV or PO once per day on days 2, 9, 16 (in addition to above)
    • Cycles 5 to 8: 20 mg (route not specified) once per day on days 1, 8, 15, 22

28-day cycle for 8 cycles

Subsequent treatment

  • 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


Regimen variant #3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kumar et al. 2020 (ENDURANCE) 2013-2019 Phase 3 (E-switch-ic) RVD Did not meet primary endpoint of PFS
Median PFS: 34.6 vs 34.4 mo
(HR 1.04, 95% CI 0.83-1.31)

Targeted therapy

  • 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

Glucocorticoid therapy

  • 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
    • Cycles 9 to 12: 10 mg PO once per day on days 1, 2, 8, 9

28-day cycle for 9 cycles

Subsequent treatment

References

  1. UMCC 2009.056: 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 dosing details in manuscript link to PMC article PubMed NCT01029054
  2. NCI 11-C-0221: 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 link to PMC article contains dosing details in manuscript PubMed NCT01402284
  3. ENDURANCE: Kumar SK, Jacobus SJ, Cohen AD, Weiss M, Callander N, Singh AK, Parker TL, Menter A, Yang X, Parsons B, Kumar P, Kapoor P, Rosenberg A, Zonder JA, Faber E Jr, Lonial S, Anderson KC, Richardson PG, Orlowski RZ, Wagner LI, Rajkumar SV. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020 Oct;21(10):1317-1330. Epub 2020 Aug 28. link to original article link to PMC article PubMed NCT01863550
  4. COBRA: NCT03729804
  5. EMN20: NCT04096066

KTD

KTd: Kyprolis (Carfilzomib), Thalidomide, Dexamethasone

Regimen variant #1, 20/27

Study Dates of enrollment Evidence
Sonneveld et al. 2014 (CARTHADEX) 2010-2013 Phase 2

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

Targeted therapy

  • 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 4: 27 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
  • Thalidomide (Thalomid) 200 mg PO once per day

Glucocorticoid therapy

28-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2, 20/36

Study Dates of enrollment Evidence
Sonneveld et al. 2014 (CARTHADEX) 2010-2013 Phase 2

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

Targeted therapy

  • 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 4: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
  • Thalidomide (Thalomid) 200 mg PO once per day

Glucocorticoid therapy

28-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3, 20/45

Study Dates of enrollment Evidence
Sonneveld et al. 2014 (CARTHADEX) 2010-2013 Phase 2

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

Targeted therapy

  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 45 mg/m2 IV once per day on days 8, 9, 15, 16
    • Cycles 2 to 4: 45 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
  • Thalidomide (Thalomid) 200 mg PO once per day

Glucocorticoid therapy

28-day cycle for 4 cycles

Subsequent treatment

References

  1. CARTHADEX: 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 dosing details in manuscript link to PMC article PubMed NTR2422

MPR

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

Regimen variant #1, 0.13/1.5/10

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Magarotto et al. 2016 (EMN01) 2009-2012 Phase 3 (E-esc) 1. CPR Might have superior PFS (primary endpoint)
2. Rd Might have superior PFS (primary endpoint)

Note: 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

Glucocorticoid therapy

Targeted therapy

Supportive therapy

28-day cycle for 9 cycles

Subsequent treatment


Regimen variant #2, 0.18/1.5/10

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Magarotto et al. 2016 (EMN01) 2009-2012 Phase 3 (E-esc) 1. CPR Might have superior PFS (primary endpoint)
2. Rd Might have superior PFS (primary endpoint)

Note: 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

Glucocorticoid therapy

Targeted therapy

Supportive therapy

28-day cycle for 9 cycles

Subsequent treatment


Regimen variant #3, 0.18/2/10

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Palumbo et al. 2007a 2005 Phase 2
Palumbo et al. 2012 (MM-015) 2007-02 to 2008-09 Phase 3 (E-esc) 1. MP Superior PFS (primary endpoint)
2. MPR Superior PFS (primary endpoint)
Zweegman et al. 2016 (HOVON87/NMSG18) 2009-2012 Phase 3 (E-switch-ic) MPT-T Might have superior PFS (primary endpoint)
Median PFS: 23 vs 20 mo
(HR 0.87, 95% CI 0.72-1.04)

Note: In Palumbo et al. 2007a 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

Glucocorticoid therapy

Targeted therapy

Supportive therapy

28-day cycle for 9 cycles

Subsequent treatment


Regimen variant #4, 5/100/10

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stewart et al. 2015 (ECOG E1A06) 2008-2011 Phase 3 (E-switch-ic) MPT-T Seems to have non-inferior PFS (primary endpoint)

Note: 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

Glucocorticoid therapy

Targeted therapy

Supportive therapy

  • 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

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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00405756
  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 dosing details in manuscript link to PMC article PubMed NCT00602641
  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 dosing details in manuscript PubMed NCT01093196
  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 dosing details in manuscript PubMed EudraCT 2007-004007-34

MPT

MPT: Melphalan, Prednisone, Thalidomide

Regimen variant #1, 0.72/8/200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zweegman et al. 2016 (HOVON87/NMSG18) 2009-2012 Phase 3 (C) MPR-R Did not meet primary endpoint of PFS

Note: 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

Glucocorticoid therapy

Targeted therapy

Supportive therapy

28-day cycle for 9 cycles

Subsequent treatment


Regimen variant #2, 36/400/100

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stewart et al. 2015 (ECOG E1A06) 2008-2011 Phase 3 (C) mPR-R Seems to have non-inferior PFS

Note: 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

Glucocorticoid therapy

Targeted therapy

Supportive therapy

  • 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


Regimen variant #3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Benboubker et al. 2014 (FIRSTMM) 2008-2011 Phase 3 (C) 1. Rd Inferior OS1
2. Rd18 Might have inferior OS

1Reported efficacy compared to Rd continuous is based on the 2017 update.
Note: 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.

Chemotherapy

  • Melphalan (Alkeran) by the following age- and laboratory-based criteria:
    • Younger than 75 years old AND ANC 1500/μL or more AND platelet count 100 x 109/L or more: 0.25 mg/kg PO once per day on days 1 to 4
    • Older than 75 years old AND ANC 1500/μL or more AND platelet count 100 x 109/L or more: 0.2 mg/kg PO once per day on days 1 to 4
    • Younger than 75 years old AND ANC 1000 up to 1500/μL OR platelet count 50 up to 100 x 109/L: 0.125 mg/kg PO once per day on days 1 to 4
    • Older than 75 years old AND ANC 1000 up to 1500/μL OR platelet count 50 up to 100 x 109/L: 0.1 mg/kg PO once per day on days 1 to 4

Glucocorticoid therapy

Targeted therapy

  • Thalidomide (Thalomid) by the following age-based criteria:
    • Younger than 75 years old: 200 mg PO once per day
    • Older than 75 years old: 100 mg PO once per day

42-day cycle for 12 cycles


Regimen variant #4, 36/240/100

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Beksac et al. 2010 (TMSG-2005-001) 2006-2009 Phase 3 (E-esc) MP Seems to have superior ORR (primary endpoint)

Note: 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

Glucocorticoid therapy

Targeted therapy

42-day cycle for 9 cycles


Regimen variant #5, 1/400/400

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Waage et al. 2010 (NMSG12) 2002-2007 Phase 3 (E-esc) MP Did not meet primary endpoint of OS

Note: 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

Glucocorticoid therapy

Targeted therapy

  • 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 until plateau phase

Subsequent treatment


Regimen variant #6, 1.25/5/200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wijermans et al. 2010 (HOVON 49) 2002-2007 Phase 3 (E-esc) MP Might have superior OS (secondary endpoint)
Median OS: 40 vs 31 mo

Superior EFS (primary endpoint)

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

Chemotherapy

Glucocorticoid therapy

Targeted therapy

Supportive therapy

28-day cycle for 9 cycles

Subsequent treatment


Regimen variant #7, 0.8/8/100

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hulin et al. 2009 (IFM 01/01) 2002-2006 Phase 3 (E-esc) MP Seems to have superior OS (primary endpoint)
Median OS: 44 vs 29.1 mo
(HR 0.68, 95% CI 0.48-0.96)

Note: 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. Note that 95% CI are not reported in the text and are calculated from P value and HR point estimate, assuming Wald P value.

Chemotherapy

Glucocorticoid therapy

Targeted therapy

42-day cycle for 12 cycles


Regimen variant #8, 1/8/400

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Facon et al. 2007 (IFM 99-06) 2000-2005 Phase 3 (E-esc) 1. MP Superior OS (primary endpoint)
Median OS: 51.6 vs 33.2 mo
(HR 0.59, 95% CI 0.46-0.81)
2. MEL100 Seems to have superior OS (primary endpoint)
Median OS: 51.6 vs 38.3 mo
(HR 0.69, 95% CI 0.49-0.96)

Note: This regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 75 years. Thalidomide dose was increased only if the prior dose was tolerated.

Chemotherapy

Glucocorticoid therapy

Targeted therapy

  • 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


Regimen variant #9, 28/280/100

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Palumbo et al. 2006 (GISMM2001-A) 2002-2005 Phase 3 (E-esc) MP Seems to have superior PFS1 (secondary endpoint)
Median PFS: 21.8 vs 14.5 mo
(HR 0.63, 95% CI 0.48-0.81)

Superior EFS (primary endpoint)

1Reported efficacy is based on the 2008 update.
Note: This regimen was intended for patients with newly diagnosed multiple myeloma aged 60 to 85 years.

Chemotherapy

Glucocorticoid therapy

Targeted therapy

Supportive therapy

28-day cycle for 6 cycles

Subsequent treatment

References

  1. GISMM2001-A: 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. 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 dosing details in abstract PubMed NCT00232934
    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 dosing details in abstract 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 dosing details in manuscript PubMed content property of HemOnc.org NCT00367185
  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 dosing details in manuscript PubMed NCT00644306
  4. NMSG12: 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 dosing details in manuscript PubMed NCT00218855
  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 dosing details in manuscript PubMed ISRCTN90692740
  6. TMSG-2005-001: 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 dosing details in abstract PubMed NCT00934154
  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. FIRSTMM: 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 dosing details in manuscript PubMed NCT00689936
    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 link to PMC 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 dosing details in manuscript link to PMC article PubMed NCT00602641
  10. 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 dosing details in manuscript PubMed EudraCT 2007-004007-34

PAD

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
BDD: Bortezomib, Doxorubicin, Dexamethasone

Regimen variant #1, 1/9/40, IV bortezomib

Study Dates of enrollment Evidence
Ludwig et al. 2010a 2006-2008 Phase 2

Note: This is not specifically a first-line regimen but most patients enrolled on the phase 2 trial were untreated (50 out of 68). The route of bortezomib was not clearly described in the manuscript but has been confirmed with the authors.

Targeted therapy

  • Bortezomib (Velcade) 1 mg/m2 IV 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

Chemotherapy

  • 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

Glucocorticoid therapy

21-day cycle for up to 8 cycles


Regimen variant #2, 1.3/9/20, SC bortezomib ("PAd")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mai et al. 2015 (GMMG-MM5) 2010-2012 Phase 3 (E-switch-ic) VCD Non-inferior VGPR or better rate (primary endpoint)

Note: 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.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

Supportive therapy

28-day cycle for 3 cycles

Subsequent treatment


Regimen variant #3, 1.3/9/40 x 3, IV bortezomib

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sonneveld et al. 2012 (HOVON-65) 2005-2008 Phase 3 (E-switch-ooc) VAD Superior PFS1 (primary endpoint)
Sonneveld et al. 2012 (GMMG-HD4) 2005-2008 Phase 3 (E-switch-ooc) VAD Superior PFS1 (primary endpoint)

1In the initial publication, this arm seemed to have an overall survival advantage; this was no longer present in the updated report of 2017.
Note: 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. Stem cells collected 4 to 6 weeks after induction therapy. HOVON-65/GMMG-HD4 was a single phase 3 RCT but the consolidation was different by group, so is reported here as 2 distinct trials.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

Supportive therapy

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

  • One of the following bisphosphonates recommended:
  • "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/day PO (did not specify whether taken once per day or as a divided twice per day dose)
    • Valacyclovir (Valtrex) 1000 mg/day PO (did not specify whether taken once per day or as a divided twice per day dose)

28-day cycle for 3 cycles

Subsequent treatment


Regimen variant #4, 1.3/9/40 x 4, IV bortezomib

Study Dates of enrollment Evidence
Oakervee et al. 2005 NR Phase 2, fewer than 20 pts

Note: While this was reported as a phase 2, it was also a dose-finding study; only 14 patients were treated at the dose here.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

  • 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

Subsequent treatment

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 dosing details in manuscript PubMed
  2. 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 dosing details in manuscript PubMed NCT00401804
  3. HOVON-65: 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 dosing details in manuscript PubMed ISRCTN64455289
    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
  4. 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 dosing details in manuscript PubMed ISRCTN64455289
    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
  5. GMMG-MM5: 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 dosing details in manuscript PubMed EudraCT 2010-019173-16
    1. Subgroup analysis: Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, Hielscher T, Blau IW, Scheid C, Hose D, Seckinger A, Jauch A, Hillengass J, Raab MS, Schurich B, Munder M, Schmidt-Wolf IG, Gerecke C, Lindemann HW, Zeis M, Weisel K, Duerig J, Goldschmidt H. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica. 2015 Jul;100(7):964-9. Epub 2015 Apr 3. link to original article link to PMC article PubMed
    2. Update: Goldschmidt H, Mai EK, Dürig J, Scheid C, Weisel KC, Kunz C, Bertsch U, Hielscher T, Merz M, Munder M, Lindemann HW, Hügle-Dörr B, Tichy D, Giesen N, Hose D, Seckinger A, Huhn S, Luntz S, Jauch A, Elmaagacli A, Rabold B, Fuhrmann S, Brossart P, Goerner M, Bernhard H, Hoffmann M, Hillengass J, Raab MS, Blau IW, Hänel M, Salwender HJ; German-speaking Myeloma Multicenter Group (GMMG). Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia. 2020 Jul;34(7):1853-1865. Epub 2020 Feb 7. link to original article PubMed
  6. SYSUCC-MM-308: NCT02362165

PAD (Pegylated liposomal doxorubicin substituted)

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

Regimen variant #1

Study Dates of enrollment Evidence
Berenson et al. 2011 (DOXILMMY2010) 2008-2010 Phase 2

Chemotherapy

Glucocorticoid therapy

Targeted therapy

28-day cycle for up to 8 cycles


Regimen variant #2

Study Dates of enrollment Evidence
Palumbo et al. 2010 2005-2007 Phase 2

Chemotherapy

Glucocorticoid therapy

  • 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

Targeted therapy

Supportive therapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3

Study Dates of enrollment Evidence
Jakubowiak et al. 2009 2005-2007 Phase 2

Chemotherapy

Glucocorticoid therapy

  • 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

Targeted therapy

Supportive therapy

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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript PubMed EudraCT 2005-004714-32
    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 dosing details in abstract PubMed
  3. DOXILMMY2010: 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 dosing details in manuscript PubMed NCT00742404

RVD

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

Synopsis

Induction therapy prior to autologous stem cell transplantation (ASCT) has evolved dramatically from early days, to its current form of lenalidomide, bortezomib, and dexamethasone (RVD). Both lenalidomide and bortezomib in combination with low-dose dexamethasone, demonstrated promising activity in relapsed/refractory multiple myeloma, before being studied in newly-diagnosed patients.

The most relevant studies that have informed clinical practice have demonstrated conclusively that the combination of an immunomodulatory agent (IMiD) and proteasome inhibitor (PI) are most efficacious for disease control and long term outcomes. Intergroup trial SWOG S0777 was a randomized study comparing RVD to Rd for patients with newly diagnosed multiple myeloma, without intention for ASCT (Durie B et al, Lancet 2017 Feb 4). This trial showed a median progression-free survival (PFS) of 75 months for the RVD arm, as compared with 64 months for the Rd arm. The IFM 2013-04, next, compared outcomes with an IMiD/PI combination induction (bortezomib, thalidomide, dexamethasone – VTD) with the standard at the time, bortezomib, cyclophosphamide and dexamethasone (VCD) (Moreau P et al Blood 2016 May 26). Responses to VTD were superior to those for VCD, including rates of CR (19% vs 6%), thus establishing the IMiD and PI combination as the preferred induction regimen. As of 2018, we lack randomized data regarding the addition of daratumumab to RVD vs RVD alone, and also whether carfilzomib, lenalidomide, and dexamethasone (KRd) is superior to RVD, though both of these questions are being examined in ongoing clinical trials.

Most variation in this protocol is based on whether it is intended as induction prior to transplant or whether it is part of a transplant-ineligible approach. For the former, 3 cycles are usually given; for the latter, up to 8 cycles are given before transition to maintenance. There is also some variation in how the steroid component is given. To our knowledge, none of the major published trials have used SC bortezomib, although this has been common practice in the clinic since 2010.


Regimen variant #1, 3 cycles, bi-weekly dexamethasone

Study Dates of enrollment Evidence
Attal et al. 2017 (IFM 2009) 2010-2012 Non-randomized part of phase 3 RCT

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

Targeted therapy

Glucocorticoid therapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2, 3 cycles, weekly dexamethasone

Study Dates of enrollment Evidence
Roussel et al. 2014 (IFM 2008) 2009 Phase 2

Targeted therapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #3, 6 cycles, q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosiñol et al. 2019 (PETHEMA/GEM2012) 2013-2015 Non-randomized part of phase 3 RCT
Sonneveld et al. 2023 (PERSEUS) 2019-01-19 to 2020-01-03 Phase 3 (C) Dara-RVD (SC daratumumab) Inferior PFS

Targeted therapy

Glucocorticoid therapy

Supportive therapy

28-day cycle for 6 cycles

Subsequent treatment


Regimen variant #4, 8 cycles, bi-weekly dexamethasone

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Durie et al. 2016 (SWOG S0777) 2008-2012 Phase 3 (E-esc) Rd Superior PFS (primary endpoint)
Median PFS: 43 vs 30 mo
(HR 0.71, 96% CI 0.56-0.91)

Superior OS1 (secondary endpoint)
Median OS: NYR vs 69 mo
(HR 0.71, 96% CI 0.54-0.93)

1Reported efficacy is based on the 2020 update.
Note: This regimen is intended for patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant.

Targeted therapy

Glucocorticoid therapy

21-day cycle for 8 cycles

Subsequent treatment

  • Rd maintenance


Regimen variant #5, 8 cycles, weekly dexamethasone

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kumar et al. 2012 (EVOLUTION) 2008-2009 Randomized Phase 2 (C) 1. VDC No formal comparison
2. VDC; modified No formal comparison
3. VDCR No formal comparison

Note: 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.

Targeted therapy

Glucocorticoid therapy

21-day cycle for 8 cycles

Subsequent treatment


Regimen variant #6, 8 cycles, tapered bi-weekly dexamethasone

Study Dates of enrollment Evidence
Richardson et al. 2010 (DFCI 06-150) 2006-2008 Phase 1/2

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

Targeted therapy

Glucocorticoid therapy

  • 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 therapy

21-day cycle for 8 cycles

Subsequent treatment

  • DFCI 06-150, patients who responded and tolerated therapy could optionally proceed to: RVD maintenance


Regimen variant #7, 12 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kumar et al. 2020 (ENDURANCE) 2013-2019 Phase 3 (C) KRd Did not meet primary endpoint of PFS

Targeted therapy

  • Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
  • Bortezomib (Velcade) as follows:
    • Cycles 1 to 8: 1.3 mg/m2 IV or SC once per day on days 1, 4, 8, 11
    • Cycles 9 to 12: 1.3 mg/m2 IV or SC once per day on days 1 & 8

Glucocorticoid therapy

  • 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
    • Cycles 9 to 12: 10 mg PO once per day on days 1, 2, 8, 9

21-day cycle for 12 cycles

Subsequent treatment

References

  1. DFCI 06-150: 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 dosing details in manuscript link to PMC article PubMed NCT00378105
  2. EVOLUTION: 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 dosing details in manuscript PubMed NCT00507442
  3. IFM 2008: 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 dosing details in manuscript PubMed NCT01206205
  4. SWOG S0777: 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 dosing details in manuscript link to PMC article PubMed NCT00644228
    1. Update: Durie BGM, Hoering A, Sexton R, Abidi MH, Epstein J, Rajkumar SV, Dispenzieri A, Kahanic SP, Thakuri MC, Reu FJ, Reynolds CM, Orlowski RZ, Barlogie B. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020 May 11;10(5):53. link to original article link to PMC article PubMed
  5. 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. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01191060
  6. PETHEMA/GEM2012: Rosiñol L, Oriol A, Rios R, Sureda A, Blanchard MJ, Hernández MT, Martínez-Martínez R, Moraleda JM, Jarque I, Bargay J, Gironella M, de Arriba F, Palomera L, González-Montes Y, Martí JM, Krsnik I, Arguiñano JM, González ME, González AP, Casado LF, López-Anglada L, Paiva B, Mateos MV, San Miguel JF, Lahuerta JJ, Bladé J. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma. Blood. 2019 Oct 17;134(16):1337-1345. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01916252
  7. ENDURANCE: Kumar SK, Jacobus SJ, Cohen AD, Weiss M, Callander N, Singh AK, Parker TL, Menter A, Yang X, Parsons B, Kumar P, Kapoor P, Rosenberg A, Zonder JA, Faber E Jr, Lonial S, Anderson KC, Richardson PG, Orlowski RZ, Wagner LI, Rajkumar SV. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020 Oct;21(10):1317-1330. Epub 2020 Aug 28. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01863550
  8. PERSEUS: Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Ho PJ, Beksac M, Hulin C, Antonioli E, Leleu X, Mangiacavalli S, Perrot A, Cavo M, Belotti A, Broijl A, Gay F, Mina R, Nijhof IS, van de Donk NWCJ, Katodritou E, Schjesvold F, Sureda Balari A, Rosiñol L, Delforge M, Roeloffzen W, Silzle T, Vangsted A, Einsele H, Spencer A, Hajek R, Jurczyszyn A, Lonergan S, Ahmadi T, Liu Y, Wang J, Vieyra D, van Brummelen EMJ, Vanquickelberghe V, Sitthi-Amorn A, de Boer CJ, Carson R, Rodriguez-Otero P, Bladé J, Moreau P; PERSEUS Trial Investigators. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Jan 25;390(4):301-313. Epub 2023 Dec 12. link to original article contains dosing details in manuscript PubMed NCT03710603
  9. CARTITUDE-5: NCT04923893
  10. CR108529: NCT03652064
  11. COBRA: NCT03729804
  12. DSMM XIV: NCT01685814
  13. GMMG-HD6: NCT02495922
  14. GMMG HD7: NCT03617731
  15. IMROZ: NCT03319667

TAD (Thalidomide)

TAD: Thalidomide, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lokhorst et al. 2009 (HOVON-50) 2001-2005 Phase 3 (E-switch-ooc) See link See link

Targeted therapy

Chemotherapy

Glucocorticoid therapy

28-day cycle for 3 cycles

Subsequent treatment

References

  1. HOVON-50: 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. 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 dosing details in manuscript PubMed NCT00028886
    1. Update: van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. link to original article PubMed

VDC

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

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2016 (IFM 2013-04) 2013-2015 Phase 3 (E-switch-ooc) VTD Seems to have inferior ORR (secondary endpoint)

Note: 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).

Targeted therapy

Chemotherapy

Glucocorticoid therapy

21-day cycle for 4 cycles

Subsequent treatment

  • Autologous hematopoietic cell transplant consolidation, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center


Regimen variant #2, "VCD"

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mai et al. 2015 (GMMG-MM5) 2010-2012 Phase 3 (E-switch-ic) PAD Non-inferior VGPR or better rate (primary endpoint)

Note: 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.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #3, "VDC"

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kumar et al. 2012 (EVOLUTION) 2008-2009 Randomized Phase 2 (E-esc) 1. VDCR No formal comparison
2. VDC; modified No formal comparison
3. VDR No formal comparison

Note: 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.

Targeted therapy

Glucocorticoid therapy

Chemotherapy

Supportive therapy

21-day cycle for 8 cycles

Subsequent treatment


Regimen variant #4, "VDC-mod"

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kumar et al. 2012 (EVOLUTION) 2008-2009 Randomized Phase 2 (E-esc) 1. VDCR No formal comparison
2. VDC No formal comparison
3. VDR No formal comparison

Note: 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.

Targeted therapy

Glucocorticoid therapy

Chemotherapy

Supportive therapy

21-day cycle for 8 cycles

Subsequent treatment


Regimen variant #5, "CyBorD", once per week bortezomib

Study Dates of enrollment Evidence
Reeder et al. 2010 NR Phase 2

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

Targeted therapy

Glucocorticoid therapy

  • 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 day on days 1, 8, 15, 22

Chemotherapy

28-day cycle for 4 cycles


Regimen variant #6, "CyBorD"

Study Dates of enrollment Evidence
Reeder et al. 2009 NR Phase 2

Targeted therapy

Glucocorticoid therapy

Chemotherapy

Supportive therapy

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 dosing details in manuscript 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 dosing details in manuscript PubMed
  3. EVOLUTION: 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 dosing details in manuscript PubMed NCT00507442
  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. GMMG-MM5: 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 dosing details in manuscript PubMed EudraCT 2010-019173-16
    1. Subgroup analysis: Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, Hielscher T, Blau IW, Scheid C, Hose D, Seckinger A, Jauch A, Hillengass J, Raab MS, Schurich B, Munder M, Schmidt-Wolf IG, Gerecke C, Lindemann HW, Zeis M, Weisel K, Duerig J, Goldschmidt H. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica. 2015 Jul;100(7):964-9. Epub 2015 Apr 3. link to original article link to PMC article PubMed
    2. Update: Goldschmidt H, Mai EK, Dürig J, Scheid C, Weisel KC, Kunz C, Bertsch U, Hielscher T, Merz M, Munder M, Lindemann HW, Hügle-Dörr B, Tichy D, Giesen N, Hose D, Seckinger A, Huhn S, Luntz S, Jauch A, Elmaagacli A, Rabold B, Fuhrmann S, Brossart P, Goerner M, Bernhard H, Hoffmann M, Hillengass J, Raab MS, Blau IW, Hänel M, Salwender HJ; German-speaking Myeloma Multicenter Group (GMMG). Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia. 2020 Jul;34(7):1853-1865. Epub 2020 Feb 7. link to original article PubMed
  6. IFM 2013-04: 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 dosing details in manuscript PubMed NCT01971658

VMP

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

Regimen variant #1, 4 cycles

Study Dates of enrollment Evidence
Mateos et al. 2006 2004-2005 Phase 1/2

Note: this was the phase 2 portion of this phase 1/2 study.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

42-day cycle for 4 cycles

Subsequent treatment

  • VMP consolidation


Regimen variant #2, 6 cycles, bi-weekly bortezomib

Study Dates of enrollment Evidence
Gasparetto et al. 2009 2004-08-05 to 2007-08-31 Phase 2

Targeted therapy

Chemotherapy

  • Melphalan (Alkeran) 6 mg/m2 PO once per day on days 1 to 7, given at least 1 hour prior to bortezomib

Glucocorticoid therapy

Supportive therapy

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


Regimen variant #3, 6 cycles, bi-weekly bortezomib x 1, then weekly bortezomib x 5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mateos et al. 2010 (GEM2005) 2006-2008 Phase 3 (C) VTP Seems to have superior OS1
Median OS: 63 vs 43 mo
(HR 0.67, 95% CI 0.49-0.91)

1Reported efficacy is based on the 2014 update.
Note: This regimen was intended for patients with untreated multiple myeloma, 65 years and older.

Targeted therapy

  • 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

Chemotherapy

Glucocorticoid therapy

Supportive therapy

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

Subsequent treatment

  • VP versus VT maintenance


Regimen variant #4, 8 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Niesvizky et al. 2015 (UPFRONT) 2007-2010 Phase 3b (E-esc) 1. Vd Did not meet primary endpoint of PFS
2. VTD Did not meet primary endpoint of PFS

Note: This regimen was meant for transplant ineligible patients.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

21-day cycle for 8 cycles

Subsequent treatment


Regimen variant #5, 9 cycles, bi-weekly bortezomib x 1, then weekly bortezomib x 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mateos et al. 2017 (ALCYONE) 2015-02-09 to 2016-07-14 Phase 3 (C) Dara-VMP Inferior OS1

1Reported efficacy is based on the 2019 update.
Note: 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.

Targeted therapy

  • 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

Chemotherapy

Glucocorticoid therapy

42-day cycle for 9 cycles


Regimen variant #6, 9 cycles, bi-weekly bortezomib x 4, then weekly bortezomib x 5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
San Miguel et al. 2008 (VISTA) 2004-2006 Phase 3 (E-RT-esc) MP Superior OS1 (secondary endpoint)
Median OS: 56.4 vs 43.1 mo
(HR 0.695, 95% CI 0.57-0.85)

Superior TTP (primary endpoint)
Median TTP: 24 vs 16.6 mo
(HR 0.48)
Palumbo et al. 2010 (GIMEMA MM-03-05) 2006-2009 Phase 3 (C) VMPT-VT Inferior OS2
San-Miguel et al. 2014 (CR015901) 2009-2011 Randomized Phase 2 (C) VMP & Siltuximab Did not meet primary endpoint of CR rate
Facon et al. 2019 (CLARION) 2013-2015 Phase 3 (C) KMP Did not meet primary endpoint of PFS

1Reported efficacy for VISTA is based on the 2012 update.
2Reported efficacy for GIMEMA MM-03-05 is based on the 2014 update.
Note: In GIMEMA MM-03-05, VISTA, and CLARION 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.

Targeted therapy

  • Bortezomib (Velcade) as follows:
    • Cycles 1 to 4: 1.3 mg/m2 IV or SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
    • Cycles 5 to 9: 1.3 mg/m2 IV or SC once per day on days 1, 8, 22, 29

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • 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


Regimen variant #7, 9 cycles, weekly bortezomib

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Palumbo et al. 2010 (GIMEMA MM-03-05) 2006-2009 Phase 3 (C) VMPT-VT Inferior OS1

1Reported efficacy is based on the 2014 update.
Note: 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.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

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 contains dosing details in manuscript 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. VISTA: 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 dosing details in abstract PubMed NCT00111319
    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 dosing details in abstract 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 dosing details in manuscript PubMed
  4. GEM2005: 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 dosing details in manuscript PubMed NCT00443235
    1. Subgroup analysis: Mateos MV, Gutiérrez NC, Martín-Ramos ML, Paiva B, Montalbán MA, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Martín A, Díaz-Mediavilla J, de Arriba F, Palomera L, Hernández JM, Sureda A, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, Fernández M, García-Sanz R, Vidriales MB, Bladé J, Lahuerta JJ, San Miguel JF. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood. 2011 Oct 27;118(17):4547-53. Epub 2011 Sep 6. link to original article PubMed
    2. 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
    3. 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 dosing details in manuscript PubMed
  5. GIMEMA MM-03-05: 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 dosing details in manuscript PubMed NCT01063179
    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 dosing details in manuscript PubMed
    2. Subgroup analysis: Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. link to original article PubMed
    3. Subgroup 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
    4. 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 dosing details in manuscript PubMed
  6. CR015901: 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 NCT00911859
  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 dosing details in manuscript PubMed NCT00507416
  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 dosing details in manuscript PubMed NCT02195479
    1. Update: Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Krevvata M, Chen Y, Wang J, Kudva A, Ukropec J, Wroblewski S, Qi M, Kobos R, San-Miguel J. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020 Jan 11;395(10218):132-141. Epub 2019 Dec 10. link to original article PubMed
  9. CLARION: Facon T, Lee JH, Moreau P, Niesvizky R, Dimopoulos M, Hajek R, Pour L, Jurczyszyn A, Qiu L, Klippel Z, Zahlten-Kumeli A, Osman M, Paiva B, San-Miguel J. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2019 May 2;133(18):1953-1963. Epub 2019 Feb 28. link to original article contains dosing details in manuscript PubMed NCT01818752

VTD

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

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2016 (IFM 2013-04) 2013-2015 Phase 3 (E-switch-ooc) VCD Seems to have superior ORR (secondary endpoint)
Moreau et al. 2019 (CASSIOPEIA part 1) 2015-2017 Phase 3 (C) Dara-VTD Inferior sCR rate

Note: The steroid dosing in CASSIOPEIA part 1 was not clearly described in the abstract; see paper for details.

Eligibility criteria

  • IFM 2013-04: 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)
  • CASSIOPEIA part 1: patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy with stem-cell transplantation

Targeted therapy

Glucocorticoid therapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Niesvizky et al. 2015 (UPFRONT) 2007-2010 Phase 3b (E-esc) 1. Vd Did not meet primary endpoint of PFS
2. VMP Did not meet primary endpoint of PFS

Note: 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.

Targeted therapy

Glucocorticoid therapy

  • 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

Subsequent treatment


Regimen variant #3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ludwig et al. 2012 (26866138-MMY-2043) 2007-2008 Randomized Phase 2 (C) VTDC Did not meet primary endpoint of nCR or better rate

Note: 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.

Targeted therapy

Glucocorticoid therapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosiñol et al. 2012 (GEM05/MENOS65) 2006-2009 Phase 3 (E-esc) 1. TD Seems to have superior PFS (secondary endpoint)

Superior CR rate (primary endpoint)
2. VBMCP/VBAD, then B Seems to have superior PFS (secondary endpoint)

Note: 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.

Targeted therapy

  • Bortezomib (Velcade) 1.3 mg/m2 IV 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

Glucocorticoid therapy

Supportive therapy

28-day cycle for 6 cycles

Subsequent treatment


Regimen variant #5, "vTD"

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2011 (IFM 2007-02) 2008-03 to 2009-01 Phase 3 (E-esc) Vd Superior VGPR rate (secondary endpoint)

Did not meet primary endpoint of CR rate after 4 cycles
Lok et al. 2014 2011-2013 Non-randomized

Note: 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.

Targeted therapy

Glucocorticoid therapy

  • 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

Subsequent treatment


Regimen variant #6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cavo et al. 2010 (GIMEMA MM-BO2005) 2006-2008 Phase 3 (E-esc) TD Superior OS1 (secondary endpoint)
Median OS: NYR vs 110 mo
(HR 0.68, 95% CI 0.51-0.90)

Superior composite primary endpoint of CR rate/nCR rate

1Reported efficacy is based on the 2020 update.
Note: This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma.

Targeted 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

Glucocorticoid therapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #7

Study Evidence
Kaufman et al. 2010 Retrospective

Targeted therapy

Glucocorticoid therapy

Supportive therapy

  • 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 dosing details in abstract 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 dosing details in abstract PubMed NCT01134484
    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 dosing details in manuscript PubMed
    2. Update: Tacchetti P, Pantani L, Patriarca F, Petrucci MT, Zamagni E, Dozza L, Galli M, Di Raimondo F, Crippa C, Boccadoro M, Barbato S, Tosi P, Narni F, Montefusco V, Testoni N, Spadano A, Terragna C, Pescosta N, Marzocchi G, Cellini C, Galieni P, Ronconi S, Gobbi M, Catalano L, Lazzaro A, De Sabbata G, Cangialosi C, Ciambelli F, Musto P, Elice F, Cavo M; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto Italian Myeloma Network). Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. Lancet Haematol. 2020 Dec;7(12):e861-e873. link to original article PubMed
  3. IFM 2007-02: 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 dosing details in manuscript PubMed NCT00910897
  4. GEM05/MENOS65: 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; PETHEMA; GEM. 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 dosing details in manuscript PubMed NCT00461747
    1. Update: 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 dosing details in manuscript PubMed
  5. 26866138-MMY-2043: 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 dosing details in manuscript PubMed NCT00531453
    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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00507416
  9. IFM 2013-04: 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 dosing details in manuscript PubMed NCT01971658
  10. CASSIOPEIA part 1: Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, Béné MC, Broijl A, Caillon H, Caillot D, Corre J, Delforge M, Dejoie T, Doyen C, Facon T, Sonntag C, Fontan J, Garderet L, Jie KS, Karlin L, Kuhnowski F, Lambert J, Leleu X, Lenain P, Macro M, Mathiot C, Orsini-Piocelle F, Perrot A, Stoppa AM, van de Donk NW, Wuilleme S, Zweegman S, Kolb B, Touzeau C, Roussel M, Tiab M, Marolleau JP, Meuleman N, Vekemans MC, Westerman M, Klein SK, Levin MD, Fermand JP, Escoffre-Barbe M, Eveillard JR, Garidi R, Ahmadi T, Zhuang S, Chiu C, Pei L, de Boer C, Smith E, Deraedt W, Kampfenkel T, Schecter J, Vermeulen J, Avet-Loiseau H, Sonneveld P. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019 Jul 6;394(10192):29-38. Epub 2019 Jun 3. Erratum in: Lancet. 2019 Jun 14. link to original article PubMed NCT02541383
  11. EMN18: NCT03896737

VTP

VTP: Velcade (Bortezomib), Thalidomide, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mateos et al. 2010 (GEM2005) 2006-2008 Phase 3 (E-switch-ooc) VMP Seems to have inferior OS1 (secondary endpoint)

1Reported efficacy is based on the 2014 update.
Note: This regimen was intended for patients with untreated multiple myeloma, 65 years and older.

Targeted therapy

  • 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 6: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
  • Thalidomide (Thalomid) as follows:
    • Cycle 1: 50 mg PO once per day on days 1 to 15, then 100 mg PO once per day on days 16 to 42
    • Cycles 2 to 6: 100 mg PO once per day

Glucocorticoid therapy

Supportive therapy

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

Subsequent treatment

  • VP versus VT maintenance

References

  1. GEM2005: 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 dosing details in manuscript PubMed NCT00443235
    1. Subgroup analysis: Mateos MV, Gutiérrez NC, Martín-Ramos ML, Paiva B, Montalbán MA, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Martín A, Díaz-Mediavilla J, de Arriba F, Palomera L, Hernández JM, Sureda A, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, Fernández M, García-Sanz R, Vidriales MB, Bladé J, Lahuerta JJ, San Miguel JF. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood. 2011 Oct 27;118(17):4547-53. Epub 2011 Sep 6. link to original article PubMed
    2. 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
    3. 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 dosing details in manuscript PubMed

First-line therapy, quadruplets

CYKLONE

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

Regimen

Study Dates of enrollment Evidence
Mikhael et al. 2015 (MC0982) 2010-2013 Phase 2

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

Chemotherapy

Glucocorticoid therapy

Targeted therapy

  • 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

Supportive therapy

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

28-day cycle for 4 to 12 cycles (see note)

References

  1. MC0982: 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 dosing details in manuscript link to PMC article PubMed NCT01057225

Dara-KRd

Dara-KRd: Daratumumab, Kyprolis (Carfilzomib), Revlimid (Lenalidomide), Dexamethasone

Regimen

Study Dates of enrollment Evidence
Landgren et al. 2021 (MANHATTAN) 2018-2019 Non-randomized

Note: The dosing of carfilzomib in the abstract (20/56) does not reconcile with the dosing on ClinicalTrials.gov (20/36). The authors have been contacted and have clarified that the weekly dosing as replicated here is correct.

Targeted therapy

  • Daratumumab (Darzalex) as follows:
    • Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22
    • Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15
    • Cycles 7 & 8: 16 mg/kg IV once on day 1
  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV once on day 1, then 56 mg/m2 IV once per day on days 8 & 15
    • Cycles 2 to 8: 56 mg/m2 IV once per day on days 1, 8, 15
  • Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

Glucocorticoid therapy

  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 4: 40 mg PO or IV once per day on days 1, 8, 15, 22
    • Cycles 5 to 8: 20 mg PO once per day on days 1, 8, 15, 22
    • Patients older than 75 years or underweight (BMI less than 18.5) received 20 mg weekly

28-day cycle for 8 cycles

References

  1. MANHATTAN: Landgren O, Hultcrantz M, Diamond B, Lesokhin AM, Mailankody S, Hassoun H, Tan C, Shah UA, Lu SX, Salcedo M, Werner K, Rispoli J, Caple J, Sams A, Verducci D, Jones K, Concepcion I, Ciardello A, Chansakul A, Schlossman J, Tavitian E, Shekarkhand T, Harrison A, Piacentini C, Rustad EH, Yellapantula V, Maclaughlan K, Maura F, Landau HJ, Scordo M, Chung DJ, Shah G, Lahoud OB, Thoren K, Murata K, Ramanathan L, Arcila ME, Ho C, Roshal M, Dogan A, Derkach A, Giralt SA, Korde N. Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial. JAMA Oncol. 2021 Jun 1;7(6):862-868. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03290950
  2. ADVANCE: NCT04268498

Dara-RVd

Dara-RVd: Daratumumab, Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
D-RVd: Daratumumab, Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone

Synopsis

Introduction: The evolution of front line therapy with Dara-RVd (daratumumab, lenalidomide, bortezomib, and dexamethasone) for multiple myeloma has progressed through several stages, involving a shift from traditional treatment approaches to the incorporation of monoclonal antibodies and immunomodulatory drugs. This summary highlights the key developments in the use of Dara-RVd as a front line therapy for multiple myeloma, supported by relevant literature.

Initial Combination Therapy: The combination of lenalidomide, bortezomib, and dexamethasone (RVd) emerged as a standard of care for the treatment of newly diagnosed multiple myeloma patients ([1] Richardson et al., 2010). This regimen showed significant improvement in progression-free survival and overall survival compared to previous therapies.

Introduction of Daratumumab: Daratumumab, a monoclonal antibody targeting CD38, demonstrated significant efficacy as a single agent in relapsed/refractory multiple myeloma ([2] Lonial et al., 2016). The success of daratumumab led to its incorporation into combination regimens with existing therapies.

Development of Dara-RVd: The addition of daratumumab to the RVd regimen (Dara-RVd) was investigated in the randomized phase 2 GRIFFIN trial, which compared Dara-RVd to RVd alone in newly diagnosed multiple myeloma patients ([3] Voorhees et al., 2020). The trial results demonstrated improved response rates and minimal residual disease negativity for Dara-RVd, indicating its potential as a more effective front line therapy.

Conclusion: The evolution of front line therapy with Dara-RVd for multiple myeloma has been marked by the successful integration of daratumumab with established treatment regimens, offering improved clinical outcomes for newly diagnosed patients.

Practical Considerations Although the GRIFFIN trial utilized bortezomib dosing on days 1, 4, 8, and 11 of a 21 day cycle, in practice, many oncologists are utilizing weekly bortezomib dosing of 1.3 - 1.5 mg/m2 SQ on days 1, 8, and 15, of a 28 day cycle. Although this has not been investigated in a randomized clinical trial, given prior prospective data such as published by O'Donnell et al [4], RVD-Lite, where weekly bortezomib dosing was utilized, there is some evidence that bortezomib can be given weekly in an induction context and demonstrate comparable response rates.
The draft for this synopsis was generated by a large language model and then manually edited by the page editor for accuracy and style. See this page for more information about this pilot project.


Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Voorhees et al. 2020 (GRIFFIN) 2016-2018 Randomized Phase 2 (E-esc) RVd Might have superior sCR rate (primary endpoint)

Note: This regimen was intended for patients with newly diagnosed multiple myeloma aged 18-70 and eligible for stem cell transplant.

Targeted therapy

Glucocorticoid therapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. GRIFFIN: Voorhees PM, Kaufman JL, Laubach J, Sborov DW, Reeves B, Rodriguez C, Chari A, Silbermann R, Costa LJ, Anderson LD Jr, Nathwani N, Shah N, Efebera YA, Holstein SA, Costello C, Jakubowiak A, Wildes TM, Orlowski RZ, Shain KH, Cowan AJ, Murphy S, Lutska Y, Pei H, Ukropec J, Vermeulen J, de Boer C, Hoehn D, Lin TS, Richardson PG. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020 Aug 20;136(8):936-945. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02874742
    1. Update: Voorhees PM, Sborov DW, Laubach J, Kaufman JL, Reeves B, Rodriguez C, Chari A, Silbermann R, Costa LJ, Anderson LD Jr, Nathwani N, Shah N, Bumma N, Efebera YA, Holstein SA, Costello C, Jakubowiak A, Wildes TM, Orlowski RZ, Shain KH, Cowan AJ, Dinner S, Pei H, Cortoos A, Patel S, Lin TS, Usmani SZ, Richardson PG. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023 Oct;10(10):e825-e837. Epub 2023 Sep 11. link to original article PubMed

Dara-RVd (SC daratumumab)

Dara-RVd: SC Daratumumab, Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sonneveld et al. 2023 (PERSEUS) 2019-01-19 to 2020-01-03 Phase 3 (E-esc) RVD Superior PFS (primary endpoint)
PFS48: 84.3% vs 67.7%
(HR 0.42, 95% CI 0.30-0.59)

Targeted therapy

Glucocorticoid therapy

28-day cycle for 6 cycles

Subsequent treatment

References

  1. PERSEUS: Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Ho PJ, Beksac M, Hulin C, Antonioli E, Leleu X, Mangiacavalli S, Perrot A, Cavo M, Belotti A, Broijl A, Gay F, Mina R, Nijhof IS, van de Donk NWCJ, Katodritou E, Schjesvold F, Sureda Balari A, Rosiñol L, Delforge M, Roeloffzen W, Silzle T, Vangsted A, Einsele H, Spencer A, Hajek R, Jurczyszyn A, Lonergan S, Ahmadi T, Liu Y, Wang J, Vieyra D, van Brummelen EMJ, Vanquickelberghe V, Sitthi-Amorn A, de Boer CJ, Carson R, Rodriguez-Otero P, Bladé J, Moreau P; PERSEUS Trial Investigators. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Jan 25;390(4):301-313. Epub 2023 Dec 12. link to original article contains dosing details in manuscript PubMed NCT03710603

Dara-VMP

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mateos et al. 2017 (ALCYONE) 2015-02-09 to 2016-07-14 Phase 3 (E-RT-esc) VMP Superior PFS (primary endpoint)
PFS18: 71.6% vs 50.2%
(HR 0.50, 95% CI 0.38-0.65)

Superior OS1 (secondary endpoint)
OS36: 78% vs 68%
(HR 0.60, 95% CI 0.46-0.80)

1Reported OS efficacy is based on the 2019 update.
Note: This regimen was intended for patients with newly diagnosed 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 substituted for prednisone on day 1.

Targeted therapy

  • 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

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Dexamethasone (Decadron) as follows:
    • Cycle 1: 20 mg IV or PO once per day on days 1, 8, 15, 22, 29, 36, prior to daratumumab
    • Cycles 2 to 9: 20 mg IV or PO once per day on days 1 & 22, prior to daratumumab

42-day cycle for 9 cycles

Subsequent treatment

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 dosing details in manuscript PubMed NCT02195479
    1. Update: Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Krevvata M, Chen Y, Wang J, Kudva A, Ukropec J, Wroblewski S, Qi M, Kobos R, San-Miguel J. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020 Jan 11;395(10218):132-141. Epub 2019 Dec 10. link to original article PubMed

Dara-VMP (SC daratumumab)

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

Regimen

Study Dates of enrollment Evidence
Chari et al. 2020 (PLEIADES) 2018-NR Phase 2 (RT)

Targeted therapy

  • Daratumumab and hyaluronidase (Darzalex Faspro) as follows:
    • Cycle 1: 1800 mg SC once per day on days 1, 8, 15, 22, 29, 36
    • Cycles 2 to 9: 1800 mg SC once per day on days 1 & 22
    • Cycle 10 onwards: 1800 mg SC once on day 1
  • 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

Chemotherapy

Glucocorticoid therapy

42-day cycle for 9 cycles, then 28-day cycles

References

  1. PLEIADES: Chari A, Rodriguez-Otero P, McCarthy H, Suzuki K, Hungria V, Sureda Balari A, Perrot A, Hulin C, Magen H, Iida S, Maisnar V, Karlin L, Pour L, Parasrampuria DA, Masterson T, Kosh M, Yang S, Delioukina M, Qi M, Carson R, Touzeau C. Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open-label Phase II study. Br J Haematol. 2021 Mar;192(5):869-878. Epub 2020 Jul 30. link to original article contains dosing details in manuscript PubMed NCT03412565

Dara-VTD

Dara-VTD: Daratumumab, Velcade (Bortezomib), Thalidomide, Dexamethasone
D-VTD: Daratumumab, Velcade (Bortezomib), Thalidomide, Dexamethasone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2019 (CASSIOPEIA part 1) 2015-2017 Phase 3 (E-RT-esc) VTD Superior sCR rate (primary endpoint)

Superior PFS (secondary endpoint)
Median PFS: NYR vs NYR
(HR 0.47, 95% CI 0.33-0.67)

Note: This regimen was intended for patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy with stem-cell transplantation.

Targeted therapy

Glucocorticoid therapy

  • Dexamethasone (Decadron) as follows:
    • Cycles 1 & 2: 40 mg PO or IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
    • Cycles 3 & 4: 40 mg PO or IV once per day on days 1 & 2, then 20 mg PO or IV once per day on days 8, 9, 15, 16

28-day cycle for 4 cycles

Subsequent treatment

References

  1. CASSIOPEIA part 1: Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, Béné MC, Broijl A, Caillon H, Caillot D, Corre J, Delforge M, Dejoie T, Doyen C, Facon T, Sonntag C, Fontan J, Garderet L, Jie KS, Karlin L, Kuhnowski F, Lambert J, Leleu X, Lenain P, Macro M, Mathiot C, Orsini-Piocelle F, Perrot A, Stoppa AM, van de Donk NW, Wuilleme S, Zweegman S, Kolb B, Touzeau C, Roussel M, Tiab M, Marolleau JP, Meuleman N, Vekemans MC, Westerman M, Klein SK, Levin MD, Fermand JP, Escoffre-Barbe M, Eveillard JR, Garidi R, Ahmadi T, Zhuang S, Chiu C, Pei L, de Boer C, Smith E, Deraedt W, Kampfenkel T, Schecter J, Vermeulen J, Avet-Loiseau H, Sonneveld P. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019 Jul 6;394(10192):29-38. Epub 2019 Jun 3. Erratum in: Lancet. 2019 Jun 14. link to original article contains dosing details in manuscript PubMed NCT02541383

Isa-RVd

Isa-RVd: Isatuximab, Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Goldschmidt et al. 2022 (GMMG-HD7) 2018-2020 Phase 3 (E-esc) RVd Superior MRD negativity (primary endpoint)
MRD negativity: 50% vs 36%
(OR 1.82, 95% CI 1.33-2.48)

Note: This regimen was intended for patients with newly diagnosed multiple myeloma aged 18-70, WHO performance status 0-2, and eligible for stem cell transplant.

Targeted therapy

Glucocorticoid therapy

42-day cycle for 3 cycles

Subsequent treatment

References

  1. GMMG-HD7: Goldschmidt H, Mai EK, Bertsch U, Fenk R, Nievergall E, Tichy D, Besemer B, Dürig J, Schroers R, von Metzler I, Hänel M, Mann C, Asemissen AM, Heilmeier B, Weinhold N, Huhn S, Kriegsmann K, Luntz SP, Holderried TAW, Trautmann-Grill K, Gezer D, Klaiber-Hakimi M, Müller M, Khandanpour C, Knauf W, Scheid C, Munder M, Geer T, Riesenberg H, Thomalla J, Hoffmann M, Raab MS, Salwender HJ, Weisel KC; German-Speaking Myeloma Multicenter Group (GMMG) HD7 investigators. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial. Lancet Haematol. 2022 Nov;9(11):e810-e821. link to original article contains dosing details in abstract PubMed NCT03617731

KRdc

KRdc: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), low-dose dexamethasone, low-dose cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jackson et al. 2021 (UK NCRI Myeloma XI+) 2013-2016 Phase 3 (E-esc) 1. Rdc
2. Tdc 		Superior PFS (co-primary endpoint)
Median PFS: NYR vs 36.1 mo
(HR 0.63, 95% CI 0.51-0.76)

Chemotherapy

Glucocorticoid therapy

Targeted therapy

  • 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
    • Cycle 2 onwards: 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

28-day cycle for at least 4 cycles

Subsequent treatment

References

  1. UK NCRI Myeloma XI+: Jackson GH, Pawlyn C, Cairns DA, de Tute RM, Hockaday A, Collett C, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Rocci A, Snowden JA, Jenner MW, Cook G, Russell NH, Drayson MT, Gregory WM, Kaiser MF, Owen RG, Davies FE, Morgan GJ; UK NCRI Haemato-oncology Clinical Studies Group. Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial. PLoS Med. 2021 Jan 11;18(1):e1003454. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01554852

RVDC

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kumar et al. 2012 (EVOLUTION) 2008-2009 Randomized Phase 2 (E-esc) 1. VDC No formal comparison
2. VDC; modified No formal comparison
3. VDR No formal comparison

Note: 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.

Targeted therapy

Glucocorticoid therapy

Chemotherapy

Supportive therapy

21-day cycle for 8 cycles

Subsequent treatment

References

  1. EVOLUTION: 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 dosing details in manuscript PubMed NCT00507442

VMPT

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

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Palumbo et al. 2010 (GIMEMA MM-03-05) 2006-2009 Phase 3 (E-esc) VMP Superior PFS (primary endpoint)
PFS36: 56% vs 41%
(HR 0.67, 95% CI 0.50-0.90)

Superior OS1 (secondary endpoint)
OS60: 61% vs 51%
(HR 0.70, 95% CI 0.52-0.92)

1Reported OS efficacy is based on the 2014 update.
Note: 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.

Targeted therapy

  • 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
  • Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 42

Chemotherapy

Glucocorticoid therapy

42-day cycle for 9 cycles

Subsequent treatment

  • VT maintenance


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Palumbo et al. 2010 (GIMEMA MM-03-05) 2006-2009 Phase 3 (E-esc) VMP Superior OS1 (secondary endpoint)
OS60: 61% vs 51%
(HR 0.70, 95% CI 0.52-0.92)

1Reported efficacy is based on the 2014 update.
Note: 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.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

42-day cycle for 9 cycles

Subsequent treatment

  • VT maintenance

References

  1. GIMEMA MM-03-05: 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 dosing details in manuscript PubMed NCT01063179
    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 dosing details in manuscript PubMed
    2. Subgroup analysis: Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. link to original article PubMed
    3. Subgroup 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
    4. 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 dosing details in manuscript PubMed

First-line therapy, other

CVAD

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX) 2003-2007 Phase 3 (C) CTD Not reported

Note: This was an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

Glucocorticoid therapy

Supportive therapy

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

Subsequent treatment

References

  1. MRC Myeloma IX: Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. link to original article link to PMC article PubMed ISRCTN68454111
    1. Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article contains dosing details in manuscript link to PMC article PubMed
    2. Update: 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 dosing details in manuscript PubMed
    3. 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. link to original article contains dosing details in manuscript link to PMC article PubMed
    4. 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

TVAD (Pegylated liposomal doxorubicin substituted)

TVAD doxil: Thalidomide, Vincristine, pegylated liposomal Adriamycin (Doxil), Dexamethasone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zervas et al. 2007 2002-2006 Phase 3 (E-esc) VAD doxil Seems to have superior OS (secondary endpoint)

Superior ORR (primary endpoint)

Note: This trial was open to patients aged 18 to 75 years old with previously untreated symptomatic MM and a life expectancy of greater than 6 months.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

  • 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

28-day cycle for 4 cycles

References

  1. 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 dosing details in manuscript PubMed

VAD (Pegylated liposomal doxorubicin substituted)

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

Regimen variant #1, indefinite ("DVd")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rifkin et al. 2006 (CR002434) 2001-2003 Phase 3 (E-switch-ic) VAd Non-inferior ORR (co-primary endpoint)

Note: 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

Glucocorticoid therapy

28-day cycles


Regimen variant #2, limited duration (4 cycles)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dimopoulos et al. 2003 1999-2001 Phase 3 (E-switch-ic) VAD Did not meet primary endpoint of ORR
Zervas et al. 2007 2002-2006 Phase 3 (C) TVAD-Doxil Seems to have inferior OS

Note: 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

Glucocorticoid therapy

  • 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 therapy

28-day cycle for 4 cycles


Regimen variant #3, limited duration (6 to 8 cycles)

Study Dates of enrollment Evidence
Hussein et al. 2002 NR Phase 2

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • 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 dosing details in abstract 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 dosing details in abstract PubMed
  3. CR002434: 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 dosing details in manuscript PubMed NCT00344422
  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 dosing details in manuscript PubMed

VAD-P

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Berenson et al. 2002 (SWOG 9210) 1993-1997 Phase 3 (C) VAD-P/Q Did not meet primary endpoint

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

  • Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg)
  • Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (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

Glucocorticoid therapy

21-day cycle for at least 9 cycles (6 months) or until at least 25% regression of disease

Subsequent treatment

  • SWOG 9210, patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy: prednisone; low-dose versus prednisone; high-dose maintenance

References

  1. SWOG 9210: 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 dosing details in abstract PubMed

VAD-P/Q

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Berenson et al. 2002 (SWOG 9210) 1993-1997 Phase 3 (E-esc) VAD-P Did not meet primary endpoint

Chemotherapy

  • Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 2 (total dose per cycle: 1.6 mg)
  • Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 2 (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
  • Quinine (Qualaquin) 400 mg PO three times per day on days 1 to 6

Glucocorticoid therapy

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

Subsequent treatment

  • SWOG 9210, patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy: prednisone; low-dose versus prednisone; high-dose maintenance

References

  1. SWOG 9210: 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 dosing details in abstract PubMed

VMP, then Rd

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mateos et al. 2015 (PETHEMA GEM05) 2005-NR Phase 3 (E-switch-ic) VMP/Rd Did not meet primary endpoint of PFS18

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

Targeted therapy, VMP portion

  • 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 9: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22

Chemotherapy, VMP portion (cycles 1 to 9)

Glucocorticoid therapy, VMP portion (cycles 1 to 9)

Supportive therapy, VMP portion (cycles 1 to 9)

Targeted therapy, Rd portion (cycles 10 to 18)

Glucocorticoid therapy, Rd portion (cycles 10 to 18)

Supportive therapy, Rd portion (cycles 10 to 18)

42-day course, 28-day cycle for 17 cycles (VMP x 9; Rd x 9)

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 dosing details in manuscript PubMed NCT00443235

VMP/Rd

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mateos et al. 2015 (PETHEMA GEM05) 2005-NR Phase 3 (E-switch-ic) VMP, then Rd Did not meet primary endpoint of PFS18

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

Targeted therapy, VMP portion

  • 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 3, 5, 7, 9, 11, 13, 15, 17: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22

Chemotherapy, VMP portion (cycles 1, 3, 5, 7, 9, 11, 13, 15, 17)

Glucocorticoid therapy, VMP portion (cycles 1, 3, 5, 7, 9, 11, 13, 15, 17)

Supportive therapy, VMP portion (cycles 1, 3, 5, 7, 9, 11, 13, 15, 17)

Targeted therapy, Rd portion (cycles 2, 4, 6, 8, 10, 12, 14, 16, 18)

Glucocorticoid therapy, Rd portion (cycles 2, 4, 6, 8, 10, 12, 14, 16, 18)

Supportive therapy, Rd portion (cycles 2, 4, 6, 8, 10, 12, 14, 16, 18)

42-day course, then 28-day cycle for 17 cycles

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 dosing details in manuscript PubMed NCT00443235

Zoledronic acid therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX) 2003-2007 Phase 3 (E-switch-ic) Clodronic acid Seems to have superior OS (co-primary endpoint)

Note: this agent was not given as monotherapy, but is included separately from the regimens that it was given with, based on the RCT design.

Supportive therapy

  • Zoledronic acid (Zometa) as follows:
    • During induction: 4 mg IV over 15 minutes once every 3 to 4 weeks
    • Consolidation onwards: 4 mg IV over 15 minutes once every 4 weeks

Continued indefinitely

References

  1. MRC Myeloma IX: Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. link to original article link to PMC article PubMed ISRCTN68454111
    1. Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article contains dosing details in manuscript link to PMC article PubMed
    2. Update: 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 dosing details in manuscript PubMed
    3. 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. link to original article contains dosing details in manuscript link to PMC article PubMed
    4. 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

Total Therapy

Study Dates of enrollment Evidence
Barlogie et al. 1997 (Total Therapy 1) 1990-1994 Non-randomized
Barlogie et al. 2006 (Total Therapy 2) 1998-2004 Prospective with randomization
Barlogie et al. 2007 (Total Therapy 3) 2004-2006 Prospective

Note: Total Therapy is a very complicated protocol, you are highly recommended to refer to the original manuscripts 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, VTD-PACE

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

Targeted therapy

Glucocorticoid therapy=

Chemotherapy=

  • Cisplatin (Platinol) 10 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m2)
  • Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m2)
  • Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 1600 mg/m2)
  • Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (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.

Supportive therapy

  • 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

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:


Interim maintenance, between cycles 1 and 2 of induction

Targeted therapy

Glucocorticoid therapy

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.


Consolidation, auto HSCT

Chemotherapy

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


Interim maintenance, between transplant 1 and transplant 2

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

Targeted therapy

Glucocorticoid therapy

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. 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.


Consolidation, VTD-PACE

Targeted therapy

Glucocorticoid therapy

Chemotherapy

  • Cisplatin (Platinol) 7.5 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 30 mg/m2)
  • Doxorubicin (Adriamycin) 7.5 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 30 mg/m2)
  • Cyclophosphamide (Cytoxan) 300 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1200 mg/m2)
  • Etoposide (Vepesid) 30 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 120 mg/m2)

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


Interim maintenance, between consolidation cycles 1 & 2

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:

Targeted therapy

Glucocorticoid therapy

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 therapy

  • 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, year 1 (VTD)

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

Targeted therapy

VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

Glucocorticoid therapy

28-day cycle for 13 cycles (1 year), then proceed to maintenance therapy years 2 to 3


Maintenance, years 2 & 3

TD: Thalidomide, Dexamethasone

Targeted therapy

Glucocorticoid therapy

28-day cycle for 26 cycles (2 years)

References

  1. Total Therapy 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, 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 dosing details in manuscript PubMed
    2. Pooled 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. Total Therapy 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 NCT00083551
    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. Pooled 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. Total Therapy 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 dosing details in manuscript 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. Pooled 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

VTD-PACE

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

Synopsis

The evolution of Total Therapy trials for multiple myeloma at UAMS from Total Therapy 1 (TT1) through Total Therapy 3 (TT3) were historically important innovations in treatment of multiple myeloma, with each trial incorporating advancements in understanding and available therapies for this disease.

Total Therapy 1 (TT1) set the foundation set the foundation for these regimens for newly diagnosed multiple myeloma. The focus was on developing a treatment resulting in deep and durable remissions([5] Barlogie et al., 1999).

The regimen for TT1 included several components: Remission Induction: This phase used VAD (vincristine, doxorubicin, and dexamethasone) administered three times. High-Dose Cyclophosphamide with PBSC Collection: Cyclophosphamide was used in high doses (at doses of 1.5 g/m2 every 4 hours ×4 for a total of 6 g/m2 along with mesna 6 g/m2 followed by subcutaneous administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) 250 μg/m2 beginning on day 2) along with the collection of peripheral blood stem cells (PBSC). EDAP (aka DECA) Regimen: This included etoposide, dexamethasone, cytarabine, and cisplatin. Autotransplants: Two autologous stem cell transplants were performed. The preparative regimens for these transplants involved melphalan at a dose of 200 mg/m², or a combination of melphalan at 140 mg/m² and total body irradiation (TBI) ranging from 850 to 1120 cGy, depending on the patient's response to the first transplant.

This aggressive and comprehensive approach was designed to induce remission and then reinforce it with high-dose therapy and stem cell transplantation. The success of TT1, as evidenced by higher event-free and overall survival rates compared to standard treatments, established the foundation for the subsequent Total Therapy regimens (TT2 and TT3), which incorporated new drugs and strategies based on emerging research and clinical experience.

Total Therapy 2 (TT2) built on the foundation of TT1, with significant changes including the optional addition of thalidomide. Thalidomide was introduced as a new class of medication at the time – immunomodulatory agent therapy, changing the therapeutic landscape of multiple myeloma ([6] Barlogie et al., 2006).

Total Therapy 3 (TT3) further evolved the treatment approach by adding bortezomib and altering the induction and consolidation phases. TT3 applied two cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone; 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide) as induction before and, at reduced doses, as consolidation after melphalan-based tandem transplantation. Maintenance therapy in TT3 comprised VTD (bortezomib [V], thalidomide [T], and dexamethasone [D]) in the first year and TD without V in years 2 and 3​​ ([7] van Rhee et al., 2010).

The evolution from TT1 to TT3 demonstrates an increasingly sophisticated approach to multiple myeloma treatment, integrating new drugs and regimens as medical knowledge and technologies advanced. Each successive trial showed improvements in overall survival, progression-free survival, and complete-response duration


The draft for this synopsis was generated by a large language model and then manually edited by the page editor for accuracy and style. See this page for more information about this pilot project.


Regimen

Study Dates of enrollment Evidence
Barlogie et al. 2007 (Total Therapy 3) 2004-2006 Prospective

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

Targeted therapy

Glucocorticoid therapy

Chemotherapy

  • Cisplatin (Platinol) 10 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m2)
  • Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m2)
  • Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 1600 mg/m2)
  • Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (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. Total Therapy 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 dosing details in manuscript PubMed

First-line therapy, intensification

VDC

VDC: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
CVD: Cyclophosphamide, Velcade (Bortezomib), Dexamethasone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jackson et al. 2018 (UK NCRI Myeloma XI) 2011-01-13 to 2017-08-11 Phase 3 (E-esc) No intensification Superior PFS1 (co-primary endpoint)
Median PFS: 30 vs 20 mo
(HR 0.60, 95% CI 0.48-0.75)

1Reported efficacy is based on the 2019 manuscript specifically addressing the issue of intensification.

Preceding treatment

  • CTD versus CRD induction, with minimal or partial response

Targeted therapy

Glucocorticoid therapy

Chemotherapy

21-day cycle for up to 8 cycles

Subsequent treatment

  • See paper for details

References

  1. UK NCRI Myeloma XI: Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Hockaday A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Jenner MW, Cook G, Russell NH, Kaiser MF, Drayson MT, Owen RG, Gregory WM, Morgan GJ; UK NCRI Haemato-oncology Clinical Studies Group. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):57-73. Epub 2018 Dec 14. link to original article link to PMC article PubMed NCT01554852
    1. Update: Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Waterhouse A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Wilson JN, Jenner MW, Cook G, Kaiser MF, Drayson MT, Owen RG, Russell NH, Gregory WM, Morgan GJ; UK NCRI Haematological Oncology Clinical Studies Group. Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol. 2019 Dec;6(12):e616-e629. Epub 2019 Oct 14. link to original article contains dosing details in abstract link to PMC article PubMed


Response criteria

Prognosis

Durie-Salmon Staging System - 1975

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

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 original article link to PMC article PubMed

IMWG consensus on risk stratification - 2013

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, San Miguel J, 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. link to original article PubMed

Revised International Staging System (R-ISS) - 2015

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 PubMed

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

References

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