Difference between revisions of "Multiple myeloma, relapsed-refractory"

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KRD-PACE: '''<u>K</u>'''yprolis (Carfilzomib) '''<u>R</u>'''evlimid (Lenalidomide)-'''<u>D</u>'''examethasone, '''<u>C</u>'''isplatin (Platinol), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide (Toposar)
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KRD-PACE: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>R</u>'''evlimid (Lenalidomide),'''<u>D</u>'''examethasone - '''<u>C</u>'''isplatin (Platinol), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide (Toposar)
 
===Regimen variant #1 {{#subobject:0ndbe92|Variant=1}}===
 
===Regimen variant #1 {{#subobject:0ndbe92|Variant=1}}===
 
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Revision as of 22:49, 14 December 2020

Section editor
Headshot Cowan.jpg
 Andrew J. Cowan, MD
University of Washington
Seattle, WA
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LinkedIn

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:

80 regimens on this page
122 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

Relapsed or refractory, randomized data

Bortezomib monotherapy

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Regimen variant #1, 1 mg/m2, 21-day cycle x 8

Study Years of enrollment Evidence Comparator Comparative Efficacy
Jagannath et al. 2004 (CREST) 2001-2002 Randomized Phase II (E-de-esc) Bortezomib +/- Dexamethasone; 1.3 mg/m2 Did not meet primary endpoint of ORR
Petrucci et al. 2013 (RETRIEVE) NR Phase II (RT)

Note: RETRIEVE was a re-treatment trial; the dose used was the same as in the initial treatment (1.0 or 1.3 mg/m2).

Targeted therapy

21-day cycle for 8 cycles

Subsequent treatment

Regimen variant #2, 1.3 mg/m2, 21-day cycle x 8 (IV)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Jagannath et al. 2004 (CREST) 2001-2002 Randomized Phase II (E-esc) Bortezomib +/- Dexamethasone; 1.0 mg/m2 Did not meet primary endpoint of ORR
Richardson et al. 2005 (APEX) 2002-2003 Phase III (E-RT-switch-ooc) High-dose dexamethasone Seems to have superior OS (*)
Orlowski et al. 2015 2006-2009 Randomized Phase II (C) Bortezomib & Siltuximab Did not meet primary endpoint of PFS
White et al. 2012 (AMBER) 2007-2009 Randomized Phase II (C) Bortezomib & Bevacizumab Did not meet primary endpoint of PFS
Moreau et al. 2011 (MMY-3021) 2008-2010 Phase III (C) Bortezomib +/- Dexamethasone; SC Non-inferior ORR
Petrucci et al. 2013 (RETRIEVE) NR Phase II (RT)

Note: RETRIEVE was a re-treatment trial; the dose used was the same as in the initial treatment (1.0 or 1.3 mg/m2).

Targeted therapy

Supportive medications

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

21-day cycle for 8 cycles (see note)

Subsequent treatment

Regimen variant #3, 1.3 mg/m2, 21-day cycle x 8 (SC)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2011 (MMY-3021) 2008-2010 Phase III (E-RT-switch-ic) Bortezomib +/- Dexamethasone; IV Non-inferior ORR

Targeted therapy

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

Supportive medications

21-day cycle for 8 cycles (see note)

Subsequent treatment

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

Regimen variant #4, indefinite 21-day cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Richardson et al. 2003 (SUMMIT) 2001 Phase II (RT)
Orlowski et al. 2007 (MMY-3001) 2004-2006 Phase III (C) Bortezomib & Doxorubicin liposomal Inferior TTP
Dimopoulos et al. 2013 (VANTAGE 088) 2008-2011 Phase III (C) Bortezomib & Vorinostat Seems to have inferior PFS

Note: SUMMIT and MMY-3001 specified a total of 8 cycles, but those who were deriving clinical benefit could continue beyond this.

Targeted therapy

21-day cycles (see note)

Subsequent treatment

Regimen variant #5, 1.6 mg/m2, 35-day cycle x 10

Study Evidence
Hainsworth et al. 2008 Phase II

Targeted therapy

35-day cycle for up to 10 cycles

References

  1. SUMMIT: Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains protocol PubMed
    2. Pooled subgroup analysis: Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM, Anderson KC. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007 Jan;21(1):151-7. Epub 2006 Nov 9. link to original article PubMed
  2. CREST: Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004 Oct;127(2):165-72. link to original article contains verified protocol PubMed
    1. Subgroup Analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains protocol PubMed
    2. Update: Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Esseltine DL, Anderson KC. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol. 2008 Nov;143(4):537-40. Epub 2008 Sep 6. link to original article PubMed
  3. APEX: Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. link to original article contains verified protocol PubMed
    1. Pooled subgroup analysis: Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM, Anderson KC. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007 Jan;21(1):151-7. Epub 2006 Nov 9. link to original article PubMed
    2. Update: Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San Miguel J, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007 Nov 15;110(10):3557-60. Epub 2007 Aug 9. link to original article contains verified protocol PubMed
  4. MMY-3001: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. link to original article contains verified protocol PubMed
    1. Update: Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009 Jan;144(2):169-75. Epub 2008 Nov 19. link to original article contains verified protocol PubMed
    2. Update: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. link to original article PubMed
  5. Hainsworth JD, Spigel DR, Barton J, Farley C, Schreeder M, Hon J, Greco FA. Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network. Cancer. 2008 Aug 15;113(4):765-71. link to original article contains verified protocol PubMed
  6. MMY-3021: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. Epub 2011 Apr 18. link to original article contains verified protocol PubMed
    1. Update: Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, Feng H, Cakana A, Deraedt W, Moreau P. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec;97(12):1925-8. Epub 2012 Jun 11. link to original article link to PMC article PubMed
    2. Subgroup analysis: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Rekhtman G, Masliak Z, Robak P, Esseltine DL, Feng H, Deraedt W, van de Velde H, Arnulf B. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica. 2015 May;100(5):e207-10. Epub 2015 Jan 16. link to original article link to PMC article PubMed
  7. AMBER: White D, Kassim A, Bhaskar B, Yi J, Wamstad K, Paton VE. Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma. Cancer. 2013 Jan 15;119(2):339-47. Epub 2012 Jul 18. link to original article contains protocol PubMed
  8. RETRIEVE: Petrucci MT, Giraldo P, Corradini P, Teixeira A, Dimopoulos MA, Blau IW, Drach J, Angermund R, Allietta N, Broer E, Mitchell V, Bladé J. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol. 2013 Mar;160(5):649-59. Epub 2013 Jan 7. link to original article contains verified protocol PubMed
  9. VANTAGE 088: Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, Rosinol L, Williams C, Blacklock H, Goldschmidt H, Hungria V, Spencer A, Palumbo A, Graef T, Eid JE, Houp J, Sun L, Vuocolo S, Anderson KC. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013 Oct;14(11):1129-1140. Epub 2013 Sep 19. link to original article contains verified protocol PubMed
  10. Orlowski RZ, Gercheva L, Williams C, Sutherland H, Robak T, Masszi T, Goranova-Marinova V, Dimopoulos MA, Cavenagh JD, Špička I, Maiolino A, Suvorov A, Bladé J, Samoylova O, Puchalski TA, Reddy M, Bandekar R, van de Velde H, Xie H, Rossi JF. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol. 2015 Jan;90(1):42-9. contains verified protocol link to PMC article PubMed

Bortezomib, Dexamethasone, Panobinostat

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Protocol

Study Years of enrollment Evidence Comparator Comparative Efficacy
Richardson et al. 2013 (PANORAMA 2) 2010-2011 Phase II
San-Miguel et al. 2014 (PANORAMA 1) 2010-2012 Phase III (E-RT-esc) Bortezomib & Dexamethasone Superior PFS

Targeted therapy, phase 1

21-day cycle for 8 cycles

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

Targeted therapy, phase 2

42-day cycle for 4 cycles (PANORAMA 1) or indefinitely (PANORAMA 2)

References

  1. PANORAMA 2: Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, Mukhopadhyay S, Ondovik MS, Khan M, Paley CS, Lonial S. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013 Oct 3;122(14):2331-7. link to original article contains verified protocol PubMed
  2. PANORAMA 1: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. Epub 2014 Sep 18. Erratum in: Lancet Oncol. 2015 Jan;16(1):e6. link to original article contains verified protocol PubMed NCT01023308
    1. Subgroup analysis: Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. link to original article link to PMC article PubMed
    2. Update: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Nov;3(11):e506-e515. Epub 2016 Oct 14. link to original article PubMed

Bortezomib & Doxorubicin liposomal

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Orlowski et al. 2007 (MMY-3001) 2004-2006 Phase III (E-RT-esc) Bortezomib Superior TTP

Targeted therapy

Chemotherapy

Supportive medications

21-day cycle for 8 or more cycles

References

  1. MMY-3001: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. link to original article contains verified protocol PubMed
    1. Update: Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009 Jan;144(2):169-75. Epub 2008 Nov 19. link to original article contains verified protocol PubMed
    2. Update: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. link to original article PubMed

Bortezomib & Vorinostat

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Dimopoulos et al. 2013 (VANTAGE 088) 2008-2011 Phase III (E-esc) Bortezomib Seems to have superior PFS

Targeted therapy

21-day cycles

References

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

BTD

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BTD: Bendamustine, Thalidomide, Dexamethasone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Schey et al. 2015 (MUKone) 2011-2012 Randomized Phase II (E-de-esc) BTD; higher-dose benadmustine See below

This study involved two doses of bendamustine but the higher dose was too toxic, leading to premature closure. Note that while this study was randomized, it was "not powered to directly compare the two arms for statistically significant superiority." Dosage listed is the lower dose.

Chemotherapy

Targeted therapy

Supportive medications

  • Thromboprophylaxis (not specified)
  • Anti-infective prophylaxis (not specified)

28-day cycle for 6 to 9 cycles (2 cycles past best response)

References

  1. MUKone: Schey S, Brown SR, Tillotson AL, Yong K, Williams C, Davies F, Morgan G, Cavenagh J, Cook G, Cook M, Orti G, Morris C, Sherratt D, Flanagan L, Gregory W, Cavet J; Myeloma UK Early Phase Clinical Trial Network. Bendamustine, thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial. Br J Haematol. 2015 Aug;170(3):336-48. Epub 2015 Apr 20. link to original article contains verified protocol PubMed

Carfilzomib monotherapy

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Regimen variant #1, 15/20/27 dosing, for renal impairment

Study Evidence Efficacy
Badros et al. 2013 (PX-171-005) Phase II ORR: 25.5%

Targeted therapy

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

Supportive medications

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

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

Subsequent treatment

Regimen variant #2, 20/20 dosing

Study Evidence Efficacy
Vij et al. 2012b (PX-171-004 bortezomib-exposed) Phase II ORR: 17%
Jagannath et al. 2012 (PX-171-003-A0) Phase II ORR: 17%

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

Targeted therapy

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

Regimen variant #3, 20/27 dosing, variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hájek et al. 2016 (FOCUS) 2010-2012 Phase III (E-switch-ooc) 1. Cyclophosphamide & Dexamethasone
2. CP 		Did not meet primary endpoint of OS

Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have ORRs greater than 20%.

Targeted therapy

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

Supportive medications

28-day cycles

Regimen variant #4, 20/27 dosing, variant #2

Study Evidence Efficacy
Watanabe et al. 2016 Phase I/II ORR: 22.5%

This is the maximum predetermined dose, there was no MTD; ORR is reported for the phase II portion.

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
    • Cycle 2 onwards: 27 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16

Supportive medications

  • IV and PO hydration required for cycle 1, then as needed
  • Dexamethasone (Decadron) as follows:
  • Prophylactic antibiotics (not specified) in cycle 1
  • Acyclovir (Zovirax) for patients with history of herpes infection, in cycle 1

28-day cycles

Regimen variant #5, 20/27 dosing, with BSA cap

Study Years of enrollment Evidence Efficacy
Vij et al. 2012a (PX-171-004 bortezomib-naive) 2007-2010 Phase II (RT) ORR: 42-52%
Siegel et al. 2012 (PX-171-003-A1) 2008-2009 Phase II (RT) ORR: 24%

Note: Neither Vij et al. 2012a nor Siegel et al. 2012 specify that carfilzomib is capped at a body surface area of 2.2 m2, but the package insert specifies that: "The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%."

Targeted therapy

  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 (body surface area capped at 2.2 m2) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
    • Cycle 2 onwards: 27 mg/m2 (body surface area capped at 2.2 m2) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16

Supportive medications

  • Dexamethasone (Decadron) as follows:
    • Cycle 1: 4 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, prior to Carfilzomib (Kyprolis)
    • Cycle 2: 4 mg IV or PO once on day 1, prior to Carfilzomib (Kyprolis) (Vij et al. 2012a only)
      • Restart dexamethasone premedication if patients experience infusion reactions: "fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina."
  • "All patients were to receive oral and intravenous fluids before dosing to assure adequate hydration."

28-day cycle for up to 12 cycles

Dose modifications

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

Regimen variant #6, 20/56 dosing

Study Years of enrollment Evidence Efficacy
Papadopoulos et al. 2014 (PX-171-007) 2009-2013 Phase 1 (RT)
Lendvai et al. 2014 (MSK 10-228) 2011-2013 Phase II ORR: 55%

Targeted therapy

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

Supportive medications

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

28-day cycles

References

  1. PX-171-004 bortezomib-naive: Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012 Jun 14;119(24):5661-70. Epub 2012 May 3. link to original article contains verified protocol link to PMC article PubMed
  2. PX-171-004 bortezomib-exposed: Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, Bahlis N, Belch A, Kunkel LA, Wear S, Wong AF, Wang M. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012 Sep;158(6):739-48. Epub 2012 Jul 30. link to original article link to PMC article PubMed
  3. PX-171-003-A0: Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T, Somlo G, Bahlis N, Lonial S, Kunkel LA, Wong A, Orlowski RZ, Siegel DS. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8. link to original article contains protocol PubMed
  4. PX-171-003-A1: Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012 Oct 4;120(14):2817-25. Epub 2012 Jul 25. link to original article contains verified protocol link to PMC article PubMed Pivotal trial for accelerated FDA approval
    1. Subgroup analysis: Jakubowiak AJ, Siegel DS, Martin T, Wang M, Vij R, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Harrison BL, Wong AF, Orlowski RZ, Jagannath S. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leukemia. 2013 Dec;27(12):2351-6. Epub 2013 May 14. link to original article link to PMC article PubMed
  5. PX-171-005: Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, Lee S, Wong AF, Niesvizky R. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013 Aug;27(8):1707-14. Epub 2013 Jan 31. contains verified protocol link to PMC article PubMed
  6. Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, Tsakos I, Redling K, Koehne G, Chung DJ, Schaffer WL, Giralt SA. A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma. Blood. 2014 Aug 7;124(6):899-906. Epub 2014 Jun 24. link to original article contains verified protocol link to PMC article PubMed
  7. PX-171-007: Papadopoulos KP, Siegel DS, Vesole DH, Lee P, Rosen ST, Zojwalla N, Holahan JR, Lee S, Wang Z, Badros A. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2015 Mar 1;33(7):732-9. Epub 2014 Sep 15. link to original article contains protocol PubMed
  8. Watanabe T, Tobinai K, Matsumoto M, Suzuki K, Sunami K, Ishida T, Ando K, Chou T, Ozaki S, Taniwaki M, Uike N, Shibayama H, Hatake K, Izutsu K, Ishikawa T, Shumiya Y, Kashihara T, Iida S. A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma. Br J Haematol. 2016 Mar;172(5):745-56. Epub 2016 Jan 5. link to original article contains verified protocol link to PMC article PubMed
  9. FOCUS: Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. link to original article link to PMC article contains verified protocol PubMed NCT01302392

Cyclophosphamide & Dexamethasone

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hájek et al. 2016 (FOCUS) 2010-2012 Phase III (C) Carfilzomib Did not meet primary endpoint of OS

Note: cyclophosphamide was described as optional for the control arm but 95% of patients received it. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

Continued indefinitely

References

  1. FOCUS: Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. link to original article link to PMC article contains verified protocol PubMed NCT01302392

Cyclophosphamide & Prednisone

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CP: Cyclophosphamide & Prednisone
CyPred: Cyclophosphamide & Prednisone

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hájek et al. 2016 (FOCUS) 2010-2012 Phase III (C) Carfilzomib Did not meet primary endpoint of OS

Note: cyclophosphamide was described as optional for the control arm but 95% of patients received it. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

Continued indefinitely

Regimen variant #2

Study Evidence
de Weerdt et al. 2001 Non-randomized

Chemotherapy

Continued indefinitely

References

  1. de Weerdt O, van de Donk NW, Veth G, Bloem AC, Hagenbeek A, Lokhorst HM. Continuous low-dose cyclophosphamide-prednisone is effective and well tolerated in patients with advanced multiple myeloma. Neth J Med. 2001 Aug;59(2):50-6. link to original article contains protocol PubMed
  2. FOCUS: Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. link to original article link to PMC article contains verified protocol PubMed NCT01302392

Daratumumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lokhorst et al. 2015 (GEN501 part 2) 2008-NR Phase I/II (RT)
Lonial et al. 2016 (SIRIUS) 2013-NR Phase II (RT)
Mateos et al. 2020 (COLUMBA) 2017-2018 Phase III (C) Daratumumab and hyaluronidase Non-inferior ORR

Note: although SIRIUS was a randomized phase II trial, the randomization was to choose the dose for further assessment in an expansion cohort; the dose chosen (16 mg/kg from the start) is the one reported here:

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
    • Per the package insert, daratumumab infusion should complete within 15 hours. In Lokhorst et al. 2015, daratumumab was given over 8 hours.

Supportive medications

This is a combination of what is listed in the daratumumab package insert and Lokhorst et al. 2015. There were protocol amendments in Lokhorst et al. 2015; listed medications are what was eventually used.

28-day cycles

References

  1. GEN501: Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. link to original article contains verified protocol link to supplementary appendix link to study protocol PubMed NCT00574288
    1. Pooled update: Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, Lokhorst HM, Voorhees PM, Richardson PG, Chari A, Sasser AK, Axel A, Feng H, Uhlar CM, Wang J, Khan I, Ahmadi T, Nahi H. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. Epub 2016 May 23. link to original article link to PMC article PubMed
  2. SIRIUS: Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Bladé J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. Epub 2016 Jan 7. link to original article contains protocol PubMed NCT01985126
    1. Pooled update: Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, Lokhorst HM, Voorhees PM, Richardson PG, Chari A, Sasser AK, Axel A, Feng H, Uhlar CM, Wang J, Khan I, Ahmadi T, Nahi H. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. Epub 2016 May 23. link to original article link to PMC article PubMed
  3. COLUMBA: Mateos MV, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, Hungria V, Korenkova S, Bahlis N, Flogegard M, Bladé J, Moreau P, Kaiser M, Iida S, Laubach J, Magen H, Cavo M, Hulin C, White D, De Stefano V, Clemens PL, Masterson T, Lantz K, O'Rourke L, Heuck C, Qin X, Parasrampuria DA, Yuan Z, Xu S, Qi M, Usmani SZ. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020 Mar 23:S2352-3026(20)30070-3. Epub ahead of print. link to original article PubMed NCT03277105

Daratumumab and hyaluronidase monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mateos et al. 2020 (COLUMBA) 2017-2018 Phase III (E-RT-switch-ic) Daratumumab Non-inferior ORR

Targeted therapy

28-day cycles

References

  1. COLUMBA: Mateos MV, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, Hungria V, Korenkova S, Bahlis N, Flogegard M, Bladé J, Moreau P, Kaiser M, Iida S, Laubach J, Magen H, Cavo M, Hulin C, White D, De Stefano V, Clemens PL, Masterson T, Lantz K, O'Rourke L, Heuck C, Qin X, Parasrampuria DA, Yuan Z, Xu S, Qi M, Usmani SZ. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020 Mar 23:S2352-3026(20)30070-3. Epub ahead of print. link to original article PubMed NCT03277105

Dara-Kd

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Dara-Kd: Daratumumab, Kyprolis (Carfilzomib), low-dose dexamethasone
KdD: Kyprolis (Carfilzomib), low-dose dexamethasone, Daratumumab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Dimopoulos et al. 2020 (CANDOR) 2017-2018 Phase III (E-RT-esc) Kd Superior PFS

Targeted therapy

References

  1. CANDOR: Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Yang H, Klippel Z, Zahlten-Kumeli A, Usmani SZ. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020 Jul 18;396(10245):186-197. link to original article PubMed NCT03158688

Dara-Rd

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Dara-Rd: Daratumumab, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Plesner et al. 2016 (GEN503) 2012-NR Phase I/II
Dimopoulos et al. 2016 (POLLUX) 2014-2015 Phase III (E-RT-esc) Rd Superior PFS

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

28-day cycle for up to 26 cycles (Plesner et al. 2014) or indefinitely (POLLUX)

References

  1. GEN503: Plesner T, Arkenau HT, Gimsing P, Krejcik J, Lemech C, Minnema MC, Lassen U, Laubach JP, Palumbo A, Lisby S, Basse L, Wang J, Sasser AK, Guckert ME, de Boer C, Khokhar NZ, Yeh H, Clemens PL, Ahmadi T, Lokhorst HM, Richardson PG. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016 Oct 6;128(14):1821-8. Epub 2016 Aug 16. link to original article contains verified protocol link to PMC article PubMed
  2. POLLUX: Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. link to original article link to original protocol contains verified protocol PubMed NCT02076009
    1. Update: Dimopoulos MA, San-Miguel J, Belch A, White D, Benboubker L, Cook G, Leiba M, Morton J, Ho PJ, Kim K, Takezako N, Moreau P, Kaufman JL, Sutherland HJ, Lalancette M, Magen H, Iida S, Kim JS, Prince HM, Cochrane T, Oriol A, Bahlis NJ, Chari A, O' Rourke L, Wu K, Schecter JM, Casneuf T, Chiu C, Soong D, Sasser AK, Khokhar NZ, Avet-Loiseau H, Usmani SZ. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica. 2018 Dec;103(12):2088-96. Epub 2018 Sep 20. link to original article PubMed
    2. Update:' Bahlis NJ, Dimopoulos MA, White DJ, Benboubker L, Cook G, Leiba M, Ho PJ, Kim K, Takezako N, Moreau P, Kaufman JL, Krevvata M, Chiu C, Qin X, Okonkwo L, Trivedi S, Ukropec J, Qi M, San-Miguel J. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020 Jul;34(7):1875-1884. Epub 2020 Jan 30. PubMed

Dara-VD

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Dara-VD: Daratumumab, Velcade (Bortezomib), Dexamethasone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Palumbo et al. 2016 (CASTOR) 2014-2015 Phase III (E-RT-esc) VD Superior PFS

Targeted therapy

  • Daratumumab (Darzalex) as follows:
    • Cycles 1 to 3: 16 mg/kg IV once per day on days 1, 8, 15
    • Cycles 4 to 8: 16 mg/kg IV once on day 1
  • Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
  • Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
    • Can be dose-reduced to 20 mg IV or PO once per day on days 1, 8, 15 for patients greater than 75 years, with BMI less than 18.5, or with previous side effects

21-day cycle for 8 cycles

Subsequent treatment

References

  1. CASTOR: Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed
    1. Update: Spencer A, Lentzsch S, Weisel K, Avet-Loiseau H, Mark TM, Spicka I, Masszi T, Lauri B, Levin MD, Bosi A, Hungria V, Cavo M, Lee JJ, Nooka AK, Quach H, Lee C, Barreto W, Corradini P, Min CK, Scott EC, Chanan-Khan AA, Horvath N, Capra M, Beksac M, Ovilla R, Jo JC, Shin HJ, Sonneveld P, Soong D, Casneuf T, Chiu C, Amin H, Qi M, Thiyagarajah P, Sasser AK, Schecter JM, Mateos MV. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018 Dec;103(12):2079-87. Epub 2018 Sep 20. link to original article PubMed

Elo-PD

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Elo-PD: Elotuzumab, Pomalidomide, Dexamethasone

Regimen variant #1, lower-dose dexamethasone

Study Years of enrollment Evidence Comparator Comparative Efficacy
Dimopoulos et al. 2018 (ELOQUENT-3) 2016-2017 Phase III (E-RT-esc) Pomalidomide & Dexamethasone Superior PFS

Note: this variant was intended for patients older than 75 years.

Targeted therapy

  • Elotuzumab (Empliciti) as follows:
    • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15, 22
    • Cycle 3 onwards: 20 mg/kg IV once on day 1
  • Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
  • Dexamethasone (Decadron) as follows:
    • Weeks without elotuzumab: 20 mg PO once per week
    • Weeks with elotuzumab: 8 mg PO once per infusion, prior to Elotuzumab (Empliciti), then 8 mg IV once per infusion, on days when Elotuzumab (Empliciti) is administered
      • According to the elotuzumab package insert, the first dose should be given between 3 and 24 hours before elotuzumab; the second dose should be given 45 to 90 minutes before elotuzumab.

Supportive medications

28-day cycles

Regimen variant #2, standard-dose dexamethasone

Study Years of enrollment Evidence Comparator Comparative Efficacy
Dimopoulos et al. 2018 (ELOQUENT-3) 2016-2017 Phase III (E-esc) Pomalidomide & Dexamethasone Superior PFS

Note: this variant was intended for patients up to 75 years.

Targeted therapy

  • Elotuzumab (Empliciti) as follows:
    • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15, 22
    • Cycle 3 onwards: 20 mg/kg IV once on day 1
  • Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
  • Dexamethasone (Decadron) as follows:
    • Weeks without elotuzumab: 40 mg PO once per week
    • Weeks with elotuzumab: 28 mg PO once per infusion, prior to Elotuzumab (Empliciti), then 8 mg IV once per infusion, on days when Elotuzumab (Empliciti) is administered
      • According to the elotuzumab package insert, the first dose should be given between 3 and 24 hours before elotuzumab; the second dose should be given 45 to 90 minutes before elotuzumab.

Supportive medications

28-day cycles

References

  1. ELOQUENT-3: Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, Leleu X, LeBlanc R, Suzuki K, Raab MS, Richardson PG, Popa McKiver M, Jou YM, Shelat SG, Robbins M, Rafferty B, San-Miguel J. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018 Nov 8;379(19):1811-1822. link to original article contains verified protocol PubMed

Elo-Rd

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Elo-Rd: Elotuzumab, Revlimid (Lenalidomide), low-dose dexamethasone
ELd: Elotuzumab, Lenalidomide, low-dose dexamethasone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lonial et al. 2012 (1703 Study) 2008-NR Phase Ib/II
Lonial et al. 2015 (ELOQUENT-2) 2011-2012 Phase III (E-RT-esc) Rd Seems to have superior OS (*)

Note: Reported efficacy for ELOQUENT-2 is based on the 2017 update.

Targeted therapy

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

Supportive medications

28-day cycles

References

  1. 1703 Study: Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK, Jagannath S. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012 Jun 1;30(16):1953-9. link to original article contains verified protocol PubMed NCT00742560
    1. Update: Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, Vij R, White D, Reece DE, Benboubker L, Zonder J, Tsao LC, Anderson KC, Bleickardt E, Singhal AK, Lonial S; 1703 study investigators. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015 Dec;2(12):e516-27. Epub 2015 Nov 16. link to original article contains protocol PubMed
  2. ELOQUENT-2: Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. Epub 2015 Jun 2. link to original article contains verified protocol PubMed
    1. Update: Dimopoulos MA, Lonial S, White D, Moreau P, Palumbo A, San-Miguel J, Shpilberg O, Anderson K, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Bleickardt E, Poulart V, Sheng J, Sy O, Katz J, Singhal A, Richardson P. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017 Sep;178(6):896-905. Epub 2017 Jul 5. link to original article PubMed
    2. Update: Dimopoulos MA, Lonial S, Betts KA, Chen C, Zichlin ML, Brun A, Signorovitch JE, Makenbaeva D, Mekan S, Sy O, Weisel K, Richardson PG. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018 Oct 15;124(20):4032-4043. Epub 2018 Sep 11. link to original article PubMed

Elo-VD

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Elo-VD: Elotuzumab, Velcade (Bortezomib), low-dose dexamethasone
EBd: Elotuzumab, Bortezomib, low-dose dexamethasone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Jakubowiak et al. 2016 (CA204-009) 2012-2013 Randomized Phase II (E-esc) VD Might have superior PFS

Targeted therapy

  • Elotuzumab (Empliciti) as follows:
    • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15
    • Cycles 3 to 8: 10 mg/kg IV once per day on days 1 & 11
    • Cycle 9 onwards: 10 mg/kg IV once per day on days 1 & 15
  • Bortezomib (Velcade) as follows:
    • Cycles 1 to 8: 1.3 mg/m2 IV or SC once per day on days 1, 4, 8, 11
    • Cycle 9 onwards: 1.3 mg/m2 IV or SC once per day on days 1, 8, 15
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 & 2:
    • Cycles 3 to 8:
    • Cycle 9 onwards:

Supportive medications

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

References

  1. CA204-009: Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016 Jun 9;127(23):2833-40. Epub 2016 Apr 18. link to original article contains verified protocol in supplement link to PMC article PubMed NCT01478048

IRd

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2016 (TOURMALINE-MM1) 2012-2014 Phase III (E-RT-esc) Rd Superior PFS
Hou et al. 2017 (TOURMALINE-MM1 China Continuation) 2014-2015 Phase III (E-esc) Rd Superior OS

Targeted therapy

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

Supportive medications

  • Thromboprophylaxis required

28-day cycles

References

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

Isa-PD

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Isa-PD: Isatuximab, Pomalidomide, Dexamethasone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Attal et al. 2019 (ICARIA-MM) 2017-2018 Phase III (E-RT-esc) PD Might have superior OS

Targeted therapy

  • Isatuximab (Sarclisa) as follows:
    • Cycle 1: 10 mg/kg IV once per day on days 1, 8, 15, 22
    • Cycle 2 onwards: 10 mg/kg IV once per day on days 1 & 15
  • Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
  • Dexamethasone (Decadron) as follows:
    • Age less than or equal to 75: 40 mg PO once per day on days 1, 8, 15, 22
    • Age greater than 75: 20 mg PO once per day on days 1, 8, 15, 22

Supportive medications

28-day cycles

References

  1. ICARIA-MM: Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang JS, Minarik J, Cavo M, Prince HM, Macé S, Corzo KP, Campana F, Le-Guennec S, Dubin F, Anderson KC; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019 Dec 7;394(10214):2096-2107. Epub 2019 Nov 14. Erratum in: Lancet. 2019 Dec 7;394(10214):2072. link to original article contains protocol PubMed NCT02990338

Ixazomib & Dexamethasone

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Regimen variant #1, 4/20

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kumar et al. 2016 (MC1181) 2013-2015 Randomized Phase II (E-de-esc) Ixazomib & Dexamethasone; 5.5/20 Might have inferior ORR

Targeted therapy

Supportive medications

  • Herpes zoster prophylaxis

28-day cycles

Regimen variant #2, 5.5/20

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kumar et al. 2016 (MC1181) 2013-2015 Randomized Phase II (E-esc) Ixazomib & Dexamethasone; 4/20 Might have superior ORR

Targeted therapy

Supportive medications

  • Herpes zoster prophylaxis

28-day cycles

References

  1. MC1181: Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338. link to original article contains verified protocol link to PMC article PubMed NCT01415882
    1. Update: Kumar SK, LaPlant BR, Reeder CB, Roy V, Halvorson AE, Buadi F, Gertz MA, Bergsagel PL, Dispenzieri A, Thompson MA, Crawley J, Kapoor P, Mikhael J, Stewart K, Hayman SR, Hwa YL, Gonsalves W, Witzig TE, Ailawadhi S, Dingli D, Go RS, Lin Y, Rivera CE, Rajkumar SV, Lacy MQ. Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib. Blood. 2016 Nov 17;128(20):2415-2422. link to original article contains verified protocol link to PMC article PubMed

KD

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KD: Kyprolis (Carfilzomib) & low-dose dexamethasone

Regimen variant #1, 20/27

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2018 (ARROW) 2015-2016 Phase III (C) KD; weekly Inferior PFS

Targeted therapy

  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV over 10 minutes once per day on days 1 & 2, then 27 mg/m2 IV over 10 minutes once per day on days 8, 9, 15, 16
    • Cycle 2 onwards: 27 mg/m2 IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 8: 40 mg IV or PO once per day on days 1, 8, 15, 22
    • Cycle 10 onwards: 40 mg IV or PO once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 20/56 dosing

Study Years of enrollment Evidence Comparator Comparative Efficacy
Dimopoulos et al. 2015 (ENDEAVOR) 2012-2014 Phase III (E-RT-switch-ic) VD Superior OS (*)

Note: reported efficacy is based on the 2019 update.

Targeted therapy

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

28-day cycles

Regimen variant #3, 20/70 dosing (weekly)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Berenson et al. 2016 (CHAMPION-1) 2012-2014 Phase I/II
Moreau et al. 2018 (ARROW) 2015-2016 Phase III (E-RT-switch-ic) KD; twice-weekly Superior PFS

Targeted therapy

  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV over 30 minutes once on day 1, then 70 mg/m2 IV over 30 minutes once per day on days 8 & 15
    • Cycle 2 onwards: 70 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 8: 40 mg IV or PO once per day on days 1, 8, 15, 22
    • Cycle 10 onwards: 40 mg IV or PO once per day on days 1, 8, 15

28-day cycles

Regimen variant #4, 27 dosing

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

Preceding treatment

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

Targeted therapy

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

References

  1. PX-171-005: Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, Lee S, Wong AF, Niesvizky R. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013 Aug;27(8):1707-14. Epub 2013 Jan 31. contains verified protocol link to PMC article PubMed
  2. ENDEAVOR: Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. Epub 2015 Dec 5. link to original article contains verified protocol PubMed NCT01568866
    1. Subgroup analysis: Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017 Jun;31(6):1368-1374. Epub 2016 Dec 27. link to original article link to PMC article PubMed
    2. Update: Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1327-1337. Epub 2017 Aug 23. link to original article PubMed
    3. Update: Orlowski RZ, Moreau P, Niesvizky R, Ludwig H, Oriol A, Chng WJ, Goldschmidt H, Yang Z, Kimball AS, Dimopoulos M. Carfilzomib-Dexamethasone Versus Bortezomib-Dexamethasone in Relapsed or Refractory Multiple Myeloma: Updated Overall Survival, Safety, and Subgroups. Clin Lymphoma Myeloma Leuk. 2019 Aug;19(8):522-530.e1. Epub 2019 May 2. link to original article PubMed
  3. CHAMPION-1: Berenson JR, Cartmell A, Bessudo A, Lyons RM, Harb W, Tzachanis D, Agajanian R, Boccia R, Coleman M, Moss RA, Rifkin RM, Patel P, Dixon S, Ou Y, Anderl J, Aggarwal S, Berdeja JG. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016 Jun 30;127(26):3360-8. Epub 2016 May 12. link to original article contains verified protocol link to PMC article PubMed NCT01677858
  4. ARROW: Moreau P, Mateos MV, Berenson JR, Weisel K, Lazzaro A, Song K, Dimopoulos MA, Huang M, Zahlten-Kumeli A, Stewart AK. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (ARROW): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018 Jul;19(7):953-964. Epub 2018 Jun 1. Erratum in: Lancet Oncol. 2018 Aug;19(8):e382. link to original article contains protocol PubMed

KRd

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

Regimen variant #1, bi-weekly carfilzomib

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Wang et al. 2013 (PX-171-006) 2008-2010 Phase II
Stewart et al. 2014 (ASPIRE) 2010-2012 Phase III (E-RT-esc) Rd Superior OS (*) Superior GHS/QoL

Note: In PX-171-006, patients with at least SD after 4 cycles received up to 12 cycles; patients with at least SD after 12 cycles received up to 18 cycles. Reported efficacy for ASPIRE is based on the 2018 update.

Targeted therapy

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

Supportive medications

28-day cycle for 18 cycles

Subsequent treatment

  • ASPIRE, no progression: Rd maintenance

Regimen variant #2, weekly carfilzomib

Study Evidence
Biran et al. 2019 (CFZ013) Phase 1b

Note: this is the dose that is being explore in phase III studies.

Targeted therapy

  • 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 18: 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
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 8: 40 mg PO once per day on days 1, 8, 15, 22
    • Cycles 9 to 18: 40 mg PO once per day on days 1, 8, 15

28-day cycle for up to 18 cycles

References

  1. PX-171-006: Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E, Huang M, Orlowski RZ, Niesvizky R. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013 Oct 31;122(18):3122-8. Epub 2013 Sep 6. link to original article contains verified protocol link to PMC article PubMed
  2. ASPIRE: Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. link to original article link to PMC article PubMed
    2. HRQoL analysis: Stewart AK, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Buchanan J, Cocks K, Yang X, Xing B, Zojwalla N, Tonda M, Moreau P, Palumbo A. Health-related quality-of-life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol. 2016 Nov 10;34(32):3921-3930. link to original article PubMed
    3. Update: Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, San-Miguel J, Obreja M, Blaedel J, Stewart AK. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 10;36(8):728-734. Epub 2018 Jan 17. link to original article PubMed
  3. CFZ013: Biran N, Siegel D, Berdeja JG, Raje N, Cornell RF, Alsina M, Kovacsovics T, Fang B, Kimball AS, Landgren O. Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a phase 1b study. Am J Hematol. 2019 Jul;94(7):794-802. Epub 2019 May 13. link to original article link to PMC article contains verified protocol PubMed

Lenalidomide monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Richardson et al. 2006 2002-2003 Randomized Phase II (E-switch-ic) Lenalidomide; 15 mg PO twice per day Did not meet primary endpoint of ORR
Richardson et al. 2009 2003-2004 Phase II

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

Targeted therapy

28-day cycles

Subsequent treatment

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

References

  1. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. link to original article contains verified protocol link to PMC article PubMed
  2. Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, Williams SF, Bensinger W, Badros AZ, Vescio R, Kenvin L, Yu Z, Olesnyckyj M, Zeldis J, Knight R, Anderson KC. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009 Jul 23;114(4):772-8. Epub 2009 May 26. link to original article contains verified protocol PubMed NCT00065351

PCD

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PCD: Pomalidomide, Cyclophosphamide, Dexamethasone
PomCyDex: Pomalidomide, Cyclophosphamide, Dexamethasone

Regimen variant #1, 4/300/40

Study Evidence
Garderet et al. 2018 (IC 2013-05) Phase II

Targeted therapy

Chemotherapy

28-day cycle for 4 to 9 cycles, depending on plan for transplant

Subsequent treatment

  • Pomalidomide & Dexamethasone maintenance

Regimen variant #2, 4/400/40

Study Years of enrollment Evidence Comparator Comparative Efficacy
Baz et al. 2016 (PO-MM-PI-0039) 2011-2014 Randomized Phase I/II (E-esc) PomDex Seems to have superior ORR rate

Targeted therapy

Chemotherapy

Supportive medications

  • Aspirin 81 mg PO once per day unless contraindicated

28-day cycles

References

  1. PO-MM-PI-0039: Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. link to original article contains verified protocol PubMed NCT01432600
  2. IC 2013-05: Garderet L, Kuhnowski F, Berge B, Roussel M, Escoffre-Barbe M, Lafon I, Facon T, Leleu X, Karlin L, Perrot A, Moreau P, Marit G, Stoppa AM, Royer B, Chaleteix C, Tiab M, Araujo C, Lenain P, Macro M, Voog E, Benboubker L, Allangba O, Jourdan E, Orsini-Piocelle F, Brechignac S, Eveillard JR, Belhadj K, Wetterwald M, Pegourie B, Jaccard A, Eisenmann JC, Glaisner S, Mohty M, Hulin C, Loiseau HA, Mathiot C, Attal M. Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma. Blood. 2018 Dec 13;132(24):2555-2563. Epub 2018 Oct 3. link to original article contains verified protocol PubMed

PD

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PD: Pomalidomide & Dexamethasone
Pd: Pomalidomide & low-dose dexamethasone
PomDex: Pomalidomide & Dexamethasone
Pom + LoDEX: Pomalidomide & Low-dose Dexamethasone

Regimen variant #1, 4 mg 21/28

Study Years of enrollment Evidence Comparator Comparative Efficacy
San Miguel et al. 2013 (NIMBUS) 2011-2012 Phase III (E-RT-esc) Dexamethasone Superior OS (*)
Leleu et al. 2013 (IFM 2009-02) 2009-2010 Randomized Phase II (E-de-esc) Pom-Dex; 28/28 Did not meet primary endpoint of ORR
Richardson et al. 2014 (CC-4047-MM-002) 2009-NR Randomized Phase II (E-RT-esc) Pomalidomide Seems to have superior PFS
Baz et al. 2016 (PO-MM-PI-0039) 2011-2014 Randomized Phase I/II (C) PomCyDex Seems to have inferior ORR rate
Leleu et al. 2015 (IFM 2010-02) 2012-2013 Phase II
Dimopoulos et al. 2016 (STRATUS) 2012-2014 Phase IIIb
Mateos et al. 2019 (KEYNOTE-183) 2016-2017 Phase III (C) PD & Pembrolizumab Did not meet primary endpoints of PFS/OS
Attal et al. 2019 (ICARIA-MM) 2017-2018 Phase III (C) Isa-PD Might have inferior OS

Note: efficacy reported for NIMBUS is based on the 2015 update.

Targeted therapy

Supportive medications

  • San Miguel et al. 2013: Thromboprohpylaxis required. "Choice of thromboprophylaxis and use of myeloid and erythroid growth factors was left to the physician's discretion."
  • Leleu et al. 2013: Thromboprophylaxis "at the physician's discretion"
  • CC-4047-MM-002: Aspirin 81 to 100 mg PO once per day unless contraindicated
  • Baz et al. 2016: Aspirin 81 mg PO once per day unless contraindicated
  • STRATUS: Thromboprophylaxis with low-dose Aspirin, |LMWH, or equivalent was required
  • Leleu et al. 2013: G-CSF allowed beginning with cycle 2 and on
  • ICARIA-MM: mandatory Aspirin or |LMWH

28-day cycles

Regimen variant #2, 4 mg continuous

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lacy et al. 2011 (MC0789) 2009 Phase II
Leleu et al. 2013 (IFM 2009-02) 2009-2010 Randomized phase II, >20 patients (E-esc) Pom-Dex; 21/28 Did not meet primary endpoint of ORR

Targeted therapy

Supportive medications

28-day cycles

Regimen variant #3, 2 mg continuous

Study Evidence
Lacy et al. 2009 Phase II
Lacy et al. 2010 Phase II
Lacy et al. 2011 (MC0789) Phase II

Targeted therapy

Supportive medications

28-day cycles

References

  1. Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Kyle RA, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009 Oct 20;27(30):5008-14. Epub 2009 Aug 31. link to original article contains verified protocol PubMed
  2. Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV, Buadi F. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010 Nov;24(11):1934-9. Epub 2010 Sep 9. link to original article contains verified protocol link to PMC article PubMed NCT00558896
  3. MC0789: Lacy MQ, Allred JB, Gertz MA, Hayman SR, Short KD, Buadi F, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Stewart AK, Laumann K, Mandrekar SJ, Reeder C, Rajkumar SV, Mikhael JR. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011 Sep 15;118(11):2970-5. Epub 2011 Jun 20. link to original article contains verified protocol link to PMC article PubMed NCT00558896
  4. IFM 2009-02: Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, Mathiot C, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B, Stoppa AM, Hennache B, Bréchignac S, Meuleman N, Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L, Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, Fermand JP, Avet-Loiseau H, Facon T. Pomalidomide plus low dose dexamethasone is active and well tolerated in bortezomib and lenalidomide refractory multiple myeloma: IFM 2009-02. Blood. 2013 Mar 14;121(11):1968-1975. Epub 2013 Jan 14. link to original article contains verified protocol PubMed NCT01053949
  5. NIMBUS: San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-66. Epub 2013 Sep 3. link to original article contains verified protocol PubMed
    1. Update: Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Spencer A, Knop S, Bahlis NJ, Renner C, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel JF. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015 Oct;100(10):1327-33. Epub 2015 Aug 6. link to original article link to PMC article PubMed
  6. CC-4047-MM-002: Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article contains verified protocol link to PMC article PubMed
  7. IFM 2010-02: Leleu X, Karlin L, Macro M, Hulin C, Garderet L, Roussel M, Arnulf B, Pegourie B, Kolb B, Stoppa AM, Brechiniac S, Marit G, Thielemans B, Onraed B, Mathiot C, Banos A, Lacotte L, Tiab M, Dib M, Fuzibet JG, Petillon MO, Rodon P, Wetterwald M, Royer B, Legros L, Benboubker L, Decaux O, Escoffre-Barbe M, Caillot D, Fermand JP, Moreau P, Attal M, Avet-Loiseau H, Facon T; Intergroupe Francophone du Myélome. Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015 Feb 26;125(9):1411-7. Epub 2015 Jan 9. link to original article contains verified protocol PubMed NCT01745640
  8. PO-MM-PI-0039: Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. link to original article contains verified protocol PubMed NCT01432600
  9. STRATUS: Dimopoulos MA, Palumbo A, Corradini P, Cavo M, Delforge M, Di Raimondo F, Weisel KC, Oriol A, Hansson M, Vacca A, Blanchard MJ, Goldschmidt H, Doyen C, Kaiser M, Petrini M, Anttila P, Cafro AM, Raymakers R, San-Miguel J, de Arriba F, Knop S, Röllig C, Ocio EM, Morgan G, Miller N, Simcock M, Peluso T, Herring J, Sternas L, Zaki MH, Moreau P. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016 Jul 28;128(4):497-503. Epub 2016 May 25. link to original article contains verified protocol link to PMC article PubMed NCT01712789
  10. ELOQUENT-3: Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, Leleu X, LeBlanc R, Suzuki K, Raab MS, Richardson PG, Popa McKiver M, Jou YM, Shelat SG, Robbins M, Rafferty B, San-Miguel J. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018 Nov 8;379(19):1811-1822. link to original article contains verified protocol PubMed
  11. KEYNOTE-183: Mateos MV, Blacklock H, Schjesvold F, Oriol A, Simpson D, George A, Goldschmidt H, Larocca A, Chanan-Khan A, Sherbenou D, Avivi I, Benyamini N, Iida S, Matsumoto M, Suzuki K, Ribrag V, Usmani SZ, Jagannath S, Ocio EM, Rodriguez-Otero P, San Miguel J, Kher U, Farooqui M, Liao J, Marinello P, Lonial S; KEYNOTE-183 Investigators. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019 Jul 18. [Epub ahead of print] link to original article contains protocol PubMed NCT02576977
  12. ICARIA-MM: Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang JS, Minarik J, Cavo M, Prince HM, Macé S, Corzo KP, Campana F, Le-Guennec S, Dubin F, Anderson KC; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019 Dec 7;394(10214):2096-2107. Epub 2019 Nov 14. Erratum in: Lancet. 2019 Dec 7;394(10214):2072. link to original article contains verified protocol PubMed NCT02990338

Pomalidomide monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Richardson et al. 2014 (CC-4047-MM-002) 2009-NR Randomized Phase II (C) POM+LoDEX Seems to have inferior PFS

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

Targeted therapy

Supportive medications

  • Aspirin 81 to 100 mg PO once per day (unless contraindicated)

28-day cycles

References

  1. CC-4047-MM-002: Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article contains verified protocol link to PMC article PubMed

PVD

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PVD: Pomalidomide, Velcade (Bortezomib), Dexamethasone

Regimen variant #1, 21-day cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Richardson et al. 2019 (OPTIMISMM) 2013-2017 Phase III (E-esc) VD Superior PFS

Targeted therapy

  • Pomalidomide (Pomalyst) 4 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
    • Cycle 9 onwards: 1.3 mg/m2 IV or SC once per day on days 1 & 8
  • Dexamethasone (Decadron) as follows:
    • Age up to 75 years, cycles 1 to 8: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
    • Age up to 75 years, cycle 9 onwards: 20 mg PO once per day on days 1, 2, 8, 9
    • Older than 75 years, cycles 1 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
    • Older than 75 years, cycle 9 onwards: 10 mg PO once per day on days 1, 2, 8, 9

21-day cycles

Regimen variant #2, 28-day cycles

Study Evidence Efficacy
Paludo et al. 2017 (MC1082) Phase I/II ORR: 86%

This is the MTD used in the phase II portion of the trial.

Targeted therapy

Supportive medications

28-day cycle for 8 cycles

Subsequent treatment

References

  1. MC1082: Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1198-1204. Epub 2017 Jul 6. link to original article contains verified protocol link to PMC article PubMed
  2. OPTIMISMM: Richardson PG, Oriol A, Beksac M, Liberati AM, Galli M, Schjesvold F, Lindsay J, Weisel K, White D, Facon T, San Miguel J, Sunami K, O'Gorman P, Sonneveld P, Robak P, Semochkin S, Schey S, Yu X, Doerr T, Bensmaine A, Biyukov T, Peluso T, Zaki M, Anderson K, Dimopoulos M; OPTIMISMM trial investigators. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jun;20(6):781-794. Epub 2019 May 13. link to original article contains protocol PubMed NCT01734928

Rd

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

Regimen variant #1, Len @ 25 mg 21/28

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Stewart et al. 2014 (ASPIRE) 2010-2012 Phase III (C) KRd Inferior OS (*) Inferior GHS/QoL
Lonial et al. 2015 (ELOQUENT-2) 2011-2012 Phase III (C) Elo-Rd Seems to have inferior OS (*)
Moreau et al. 2016 (TOURMALINE-MM1) 2012-2014 Phase III (C) IRd Inferior PFS
Dimopoulos et al. 2016 (POLLUX) 2014-2015 Phase III (C) Dara-Rd Inferior PFS
Hou et al. 2017 (TOURMALINE-MM1 China Continuation) 2014-2015 Phase III (C) IRd Inferior OS

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

Targeted therapy

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

Supportive medications

Best described by ASPIRE:

28-day cycles

Regimen variant #2, Len @ 25 mg 21/28, with high-dose dex lead-in

Study Years of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2007 (MM-009) 2003-2004 Phase III (E-RT-esc) Dexamethasone Seems to have superior OS (*)
Dimopoulos et al. 2007 (MM-010) 2003-2004 Phase III (E-RT-esc) Dexamethasone Seems to have superior OS

Note: MM-009 is "Study 1" and MM-010 is "Study 2" listed in the package insert. Reported efficacy of MM-009 is based on the 2009 pooled update.

Targeted therapy

28-day cycles

Regimen variant #3, Len @ 30 mg 21/28

Study Years of enrollment Evidence Comparator Comparative Efficacy
Richardson et al. 2006 2002-2003 Randomized Phase II (E-switch-ic) Rd; twice-daily Lenalidomide Did not meet primary endpoint of ORR

This regimen is essentially of historical interest.

Preceding treatment

Targeted therapy

28-day cycles

Regimen variant #4, Len @ 15 mg 21/28 ("RevLite")

Study Evidence
Quach et al. 2017 (RevLite) Phase II

Targeted therapy

28-day cycles

References

  1. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. link to original article contains verified protocol link to PMC article PubMed
  2. MM-010: Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32. link to original article contains verified protocol PubMed
    1. Update: Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. link to original article PubMed
  3. MM-009: Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007 Nov 22;357(21):2133-42. link to original article contains verified protocol PubMed
    1. Update: Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. link to original article PubMed
  4. ASPIRE: Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. link to original article link to PMC article PubMed
    2. HRQoL analysis: Stewart AK, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Buchanan J, Cocks K, Yang X, Xing B, Zojwalla N, Tonda M, Moreau P, Palumbo A. Health-related quality-of-life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol. 2016 Nov 10;34(32):3921-3930. link to original article PubMed
    3. Update: Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, San-Miguel J, Obreja M, Blaedel J, Stewart AK. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 10;36(8):728-734. Epub 2018 Jan 17. link to original article PubMed
  5. ELOQUENT-2: Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. Epub 2015 Jun 2. link to original article contains verified protocol PubMed
    1. Update: Dimopoulos MA, Lonial S, White D, Moreau P, Palumbo A, San-Miguel J, Shpilberg O, Anderson K, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Bleickardt E, Poulart V, Sheng J, Sy O, Katz J, Singhal A, Richardson P. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017 Sep;178(6):896-905. Epub 2017 Jul 5. link to original article PubMed
    2. Update: Dimopoulos MA, Lonial S, Betts KA, Chen C, Zichlin ML, Brun A, Signorovitch JE, Makenbaeva D, Mekan S, Sy O, Weisel K, Richardson PG. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018 Oct 15;124(20):4032-4043. Epub 2018 Sep 11. link to original article PubMed
  6. TOURMALINE-MM1: Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-1634. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, Ganly P, Palumbo A, Cavo M, Langer C, Pluta A, Nagler A, Kumar S, Ben-Yehuda D, Rajkumar SV, San-Miguel J, Berg D, Lin J, van de Velde H, Esseltine DL, di Bacco A, Moreau P, Richardson PG. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017 Dec 14;130(24):2610-2618. Epub 2017 Oct 20. link to original article PubMed
  7. POLLUX: Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. link to original article link to original protocol contains verified protocol PubMed NCT02076009
    1. Update: Dimopoulos MA, San-Miguel J, Belch A, White D, Benboubker L, Cook G, Leiba M, Morton J, Ho PJ, Kim K, Takezako N, Moreau P, Kaufman JL, Sutherland HJ, Lalancette M, Magen H, Iida S, Kim JS, Prince HM, Cochrane T, Oriol A, Bahlis NJ, Chari A, O' Rourke L, Wu K, Schecter JM, Casneuf T, Chiu C, Soong D, Sasser AK, Khokhar NZ, Avet-Loiseau H, Usmani SZ. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica. 2018 Dec;103(12):2088-96. Epub 2018 Sep 20. PubMed
    2. Update:' Bahlis NJ, Dimopoulos MA, White DJ, Benboubker L, Cook G, Leiba M, Ho PJ, Kim K, Takezako N, Moreau P, Kaufman JL, Krevvata M, Chiu C, Qin X, Okonkwo L, Trivedi S, Ukropec J, Qi M, San-Miguel J. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020 Jul;34(7):1875-1884. Epub 2020 Jan 30. PubMed
  8. RevLite: Quach H, Fernyhough L, Henderson R, Corbett G, Baker B, Browett P, Blacklock H, Forsyth C, Underhill C, Cannell P, Trotman J, Neylon A, Harrison S, Link E, Swern A, Cowan L, Dimopoulos MA, Miles Prince H. Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study. Br J Haematol. 2017 May;177(3):441-448. Epub 2017 Feb 15. link to original articlecontains verified protocol PubMed
  9. TOURMALINE-MM1 China Continuation: Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, Lu J, Du X, Chen X, Li J, Liu J, Gupta N, Hanley MJ, Li H, Hua Z, Wang B, Zhang X, Wang H, van de Velde H, Richardson PG, Moreau P. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study. J Hematol Oncol. 2017 Jul 6;10(1):137. link to original article link to PMC article contains protocol PubMed

TD

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

Regimen variant #1, thalidomide 200, with lead-in

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hjorth et al. 2012 (NMSG 17/07) 2007-2010 Phase III (E-switch-ooc) Bort-Dex Did not meet primary endpoint of PFS

Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

Targeted therapy

Supportive medications

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

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

Regimen variant #2, thalidomide 200

Study Years of enrollment Evidence Comparator Comparative Efficacy
Garderet et al. 2012 (MMVAR/IFM 2005-04) 2006-2010 Phase III (C) VTD Inferior TTP

Intended for patients who have relapsed after an autologous stem-cell transplant

Targeted therapy

Supportive medications

21-day cycle for 18 cycles (1 year)

Regimen variant #3, thalidomide 400, with lead-in

Study Evidence
Dimopoulos et al. 2001 Phase II

Targeted therapy

  • Thalidomide (Thalomid) as follows:
    • Cycle 1: 200 mg PO once per day for 14 days, then 400 mg PO once per day
    • Cycle 2 onwards: 400 mg PO once per day
  • Dexamethasone (Decadron) as follows:
    • Cycle 1: 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
    • Cycle 2 onwards: 20 mg PO once per day on days 1 to 4

1-month cycles

References

  1. Dimopoulos MA, Zervas K, Kouvatseas G, Galani E, Grigoraki V, Kiamouris C, Vervessou E, Samantas E, Papadimitriou C, Economou O, Gika D, Panayiotidis P, Christakis I, Anagnostopoulos N. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol. 2001 Jul;12(7):991-5. link to original article contains verified protocol PubMed
  2. NMSG 17/07: Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group. Thalidomide and dexamethasone vs bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. Epub 2012 Mar 30. link to original article contains verified protocol link to PMC article PubMed NCT00602511
  3. MMVAR/IFM 2005-04: Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012 Jul 10;30(20):2475-82. Epub 2012 May 14. Erratum in: J Clin Oncol. 2012 Sep 20;30(27):3429. link to original article contains verified protocol PubMed NCT00256776

VD

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

Regimen variant #1, indefinite 21-day then 28-day cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Jakubowiak et al. 2016 (CA204-009) 2012-2013 Randomized Phase II (C) Elo-VD Might have inferior PFS

Targeted therapy

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

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

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Moreau et al. 2011 (MMY-3021) 2008-2010 Phase III (E-RT-switch-ic) Bort-Dex; IV Non-inferior ORR
Terpos et al. 2017 (OPTIMRETREAT) 2013-2016 Phase III (C) Bort-Dex x 6, then bortezomib maint. Did not meet primary endpoint of PFS
Palumbo et al. 2016 (CASTOR) 2014-2015 Phase III (C) Dara-VD Inferior PFS

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

Preceding treatment

Targeted therapy

21-day cycle for 8 cycles (see note)

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
San-Miguel et al. 2014 (PANORAMA 1) 2010-2012 Phase III (C) Bortezomib, Dexamethasone, Panobinostat Inferior PFS

Note: Patients who had clinical benefit per the modified European Group for Blood and Marrow Transplantation [EBMT] criteria on day 1 of cycle 8 proceeded to the last four cycles.

Targeted therapy

  • Bortezomib (Velcade) as follows:
    • Cycles 1 to 8: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
    • Cycles 9 to 12: 1.3 mg/m2 IV once per day on days 1, 8, 22, 29
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 8: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
    • Cycles 9 to 12: 20 mg PO once per day on days 1, 2, 8, 9, 22, 23, 29, 30

21-day cycle for 8 cycles, then 42-day cycle for 4 cycles

Regimen variant #4, 21-day cycles, response-adapted

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hjorth et al. 2012 (NMSG 17/07) 2007-2010 Phase III (E-switch-ooc) Thal-Dex Did not meet primary endpoint of PFS
Dimopoulos et al. 2013 (CR013165) 2008-2009 Phase II Not evaluable

Targeted therapy

Supportive medications

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

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

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Jagannath et al. 2004 (CREST) 2001-2002 Randomized Phase II (E-esc) Bort-Dex; low-dose Did not meet primary endpoint of ORR
Moreau et al. 2011 (MMY-3021) 2008-2010 Phase III (C) Bort-Dex; SC Non-inferior ORR
Kropff et al. 2017 (CR015247) 2008-2010 Phase III (C) VCD Did not meet primary endpoint of TTP

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

Preceding treatment

Targeted therapy

21-day cycle for 8 cycles (see note)

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Jagannath et al. 2004 (CREST) 2001-2002 Randomized Phase II (E-de-esc) Bort-Dex; standard-dose Did not meet primary endpoint of ORR

Preceding treatment

Targeted therapy

21-day cycle for 8 cycles

Regimen variant #7, IV indefinite 21-day cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Richardson et al. 2003 (SUMMIT) 2001 Phase II (RT) RR: 35%
Orlowski et al. 2007 (MMY-3001) 2004-2006 Phase IIIb ORR: 67%
Dimopoulos et al. 2015 (ENDEAVOR) 2012-2014 Phase III (C) KD Inferior OS (*)

Note: SUMMIT & MMY-3001 specified a total of 8 cycles, but those who were deriving clinical benefit could continue beyond this. Reported efficacy for ENDEAVOR is based on the 2019 update.

Preceding treatment

Targeted therapy

21-day cycles

Regimen variant #8, SC indefinite 21-day cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Dimopoulos et al. 2015 (ENDEAVOR) 2012-2014 Phase III (C) KD Inferior OS (*)

Note: reported efficacy is based on the 2019 update.

Targeted therapy

21-day cycles

Regimen variant #9, indefinite 35-day cycles

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

Note: treatment could be stopped if CR was achieved.

Targeted therapy

35-day cycles

References

  1. SUMMIT: Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains protocol PubMed
    2. Subgroup analysis: Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM, Anderson KC. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007 Jan;21(1):151-7. Epub 2006 Nov 9. link to original article PubMed
  2. CREST: Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004 Oct;127(2):165-72. link to original article contains verified protocol PubMed
    1. Subgroup Analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains protocol PubMed
    2. Update: Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Esseltine DL, Anderson KC. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol. 2008 Nov;143(4):537-40. Epub 2008 Sep 6. link to original article PubMed
  3. MMY-3001: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. link to original article contains verified protocol PubMed
    1. Update: Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009 Jan;144(2):169-75. Epub 2008 Nov 19. link to original article contains verified protocol PubMed
    2. Update: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. link to original article PubMed
  4. MMY-3021: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. Epub 2011 Apr 18. link to original article contains verified protocol PubMed
    1. Update: Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, Feng H, Cakana A, Deraedt W, Moreau P. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec;97(12):1925-8. Epub 2012 Jun 11. link to original article link to PMC article PubMed
    2. Subgroup analysis: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Rekhtman G, Masliak Z, Robak P, Esseltine DL, Feng H, Deraedt W, van de Velde H, Arnulf B. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica. 2015 May;100(5):e207-10. Epub 2015 Jan 16. link to original article link to PMC article PubMed
  5. Fukushima T, Nakamura T, Iwao H, Nakajima A, Miki M, Sato T, Sakai T, Sawaki T, Fujita Y, Tanaka M, Masaki Y, Nakajima H, Motoo Y, Umehara H. Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events. Anticancer Res. 2011 Jun;31(6):2297-302. link to original article contains verified protocol PubMed
  6. NMSG 17/07: Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group. Thalidomide and dexamethasone vs bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. Epub 2012 Mar 30. link to original article contains verified protocol link to PMC article PubMed NCT00602511
  7. CR013165: Dimopoulos MA, Beksac M, Benboubker L, Roddie H, Allietta N, Broer E, Couturier C, Mazier MA, Angermund R, Facon T. Phase 2 study of bortezomib-dexamethasone alone or with added cyclophosphamide or lenalidomide for sub-optimal response as second-line treatment for patients with multiple myeloma. Haematologica. 2013 Aug;98(8):1264-72. Epub 2013 May 28. link to original article contains verified protocol link to PMC article PubMed NCT00908232
  8. PANORAMA 1: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. Epub 2014 Sep 18. Erratum in: Lancet Oncol. 2015 Jan;16(1):e6. link to original article contains verified protocol PubMed NCT01023308
    1. Subgroup analysis: Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. link to original article link to PMC article PubMed
    2. Update: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Nov;3(11):e506-e515. Epub 2016 Oct 14. link to original article PubMed
  9. ENDEAVOR: Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. Epub 2015 Dec 5. link to original article PubMed NCT01568866
    1. Subgroup analysis: Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017 Jun;31(6):1368-1374. Epub 2016 Dec 27. link to original article link to PMC article contains verified protocol PubMed
    2. Update: Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1327-1337. Epub 2017 Aug 23. link to original article PubMed
    3. Update: Orlowski RZ, Moreau P, Niesvizky R, Ludwig H, Oriol A, Chng WJ, Goldschmidt H, Yang Z, Kimball AS, Dimopoulos M. Carfilzomib-Dexamethasone Versus Bortezomib-Dexamethasone in Relapsed or Refractory Multiple Myeloma: Updated Overall Survival, Safety, and Subgroups. Clin Lymphoma Myeloma Leuk. 2019 Aug;19(8):522-530.e1. Epub 2019 May 2. link to original article PubMed
  10. CA204-009: Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016 Jun 9;127(23):2833-40. Epub 2016 Apr 18. link to original article contains verified protocol in supplement link to PMC article PubMed NCT01478048
  11. CASTOR: Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed
    1. Update: Spencer A, Lentzsch S, Weisel K, Avet-Loiseau H, Mark TM, Spicka I, Masszi T, Lauri B, Levin MD, Bosi A, Hungria V, Cavo M, Lee JJ, Nooka AK, Quach H, Lee C, Barreto W, Corradini P, Min CK, Scott EC, Chanan-Khan AA, Horvath N, Capra M, Beksac M, Ovilla R, Jo JC, Shin HJ, Sonneveld P, Soong D, Casneuf T, Chiu C, Amin H, Qi M, Thiyagarajah P, Sasser AK, Schecter JM, Mateos MV. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018 Dec;103(12):2079-87. Epub 2018 Sep 20. link to original article PubMed
  12. CR015247: Kropff M, Vogel M, Bisping G, Schlag R, Weide R, Knauf W, Fiechtner H, Kojouharoff G, Kremers S, Berdel WE. Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. Ann Hematol. 2017 Nov;96(11):1857-1866. Epub 2017 Sep 14. link to original article PubMed
  13. OPTIMRETREAT: Terpos E, Gobbi M, Potamianou A, Lahaye M, Couturier C, Cavo M. Retreatmentvand prolonged therapy with subcutaneous bortezomib in patients with relapsed multiple myeloma: a randomized, controlled, phase III study. Eur J Haematol. 2018 Jan;100(1):10-19. Epub 2017 Oct 30. link to original article PubMed NCT01910987

VDC

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VDC: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
VCD: Velcade (Bortezomib), Cyclophosphamide, Dexamethasone
CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kropff et al. 2017 (CR015247) 2008-2010 Phase III (E-esc) VD Did not meet primary endpoint of TTP

Treatment details are from the NCT record.

Targeted therapy

Chemotherapy

21-day cycle for up to 8 cycles

Regimen variant #2

Study Evidence
de Waal et al. 2015 Phase II

Treatment intended for bortezomib-naive patients.

Targeted therapy

  • Bortezomib (Velcade) as follows:
    • Cycles 1 to 3: 1.3 mg/m2 IV or SC once per day on days 1, 4, 8, 11
    • Cycles 4 to 6: 1.6 mg/m2 IV or SC once per day on days 1, 8, 15, 22

Chemotherapy

Supportive medications

  • Pneumococccal and anti-fungal prophylaxis "according to local protocols"
  • Valacyclovir (Valtrex) (dose not specified) for herpes prophylaxis

21-day cycle for 3 cycles then 35-day cycle for 3 cycles

Subsequent treatment

Regimen variant #3

Study Evidence
Kropff et al. 2007 Phase II

Treatment intended for bortezomib-naive patients.

Targeted therapy

  • Bortezomib (Velcade) as follows:
    • Cycles 1 to 3: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
    • Cycles 4 to 6: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22

Chemotherapy

21-day cycle for 3 cycles then 35-day cycle for 3 cycles

References

  1. Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, Dechow T, Kröger N, Salwender H, Metzner B, Sezer O, Engelhardt M, Wolf HH, Einsele H, Volpert S, Heinecke A, Berdel WE, Kienast J; Deutsche Studiengruppe Multiples Myelom,. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007 Aug;138(3):330-7. link to original article contains verified protocol PubMed
  2. de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. link to original article contains verified protocol PubMed
  3. CR015247: Kropff M, Vogel M, Bisping G, Schlag R, Weide R, Knauf W, Fiechtner H, Kojouharoff G, Kremers S, Berdel WE. Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. Ann Hematol. 2017 Nov;96(11):1857-1866. Epub 2017 Sep 14. link to original article PubMed

VTD

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VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Garderet et al. 2012 (MMVAR/IFM 2005-04) 2006-2010 Phase III (E-esc) TD Superior TTP

Intended for patients who have relapsed after an autologous stem-cell transplant

Targeted therapy

Supportive medications

21-day cycle for 8 cycles, then 42-day cycle for 4 cycles (1 year)

References

  1. MMVAR/IFM 2005-04: Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012 Jul 10;30(20):2475-82. Epub 2012 May 14. Erratum in: J Clin Oncol. 2012 Sep 20;30(27):3429. link to original article contains verified protocol PubMed NCT00256776

Relapsed or refractory, non-randomized or retrospective data

BBD

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BBD: Bendamustine, Bortezomib, Dexamethasone

Regimen

Study Evidence
Ludwig et al. 2013 (AFAC BBD) Phase II

Chemotherapy

Targeted therapy

28-day cycle for up to 8 cycles

References

  1. AFAC BBD: Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, Greil R, Seebacher A, Pour L, Weißmann A, Adam Z. Bendamustine-bortezomib-dexamethasone is an active and well tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood. 2014 Feb 13;123(7):985-91. Epub 2013 Nov 13. link to original article contains verified protocol link to PMC article PubMed

Belantamab mafodotin monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence
Lonial et al. 2019 (DREAMM-2) 2018-2019 Randomized Phase II (*)

Note: while this was a randomized trial, it was not comparative between the arms.

Targeted therapy

21-day cycles

References

  1. DREAMM-2: Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, Abdallah AO, Callander N, Lendvai N, Sborov D, Suvannasankha A, Weisel K, Karlin L, Libby E, Arnulf B, Facon T, Hulin C, Kortüm KM, Rodríguez-Otero P, Usmani SZ, Hari P, Baz R, Quach H, Moreau P, Voorhees PM, Gupta I, Hoos A, Zhi E, Baron J, Piontek T, Lewis E, Jewell RC, Dettman EJ, Popat R, Esposti SD, Opalinska J, Richardson P, Cohen AD. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020 Feb;21(2):207-221. Epub 2019 Dec 16. link to original article contains protocol PubMed NCT03525678

BID

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BID: Bendamustine, Ixazomib, Dexamethasone

Regimen

Study Evidence
Dhakal et al. 2019 (PRO00024991) Phase I/II, <20 pts in MTD cohort

Dosages listed are the determined maximally tolerated doses (MTD) of this phase I/II trial. Note that dexamethasone is not given in week 4; this has been confirmed with the authors.

Chemotherapy

Targeted therapy

28-day cycle for up to 8 cycles

References

  1. PRO00024991 Dhakal B, D'Souza A, Hamadani M, Arce-Lara C, Schroeder K, Chhabra S, Shah NN, Gauger K, Keaton T, Pasquini M, Hari P. Phase I/II trial of bendamustine, ixazomib, and dexamethasone in relapsed/refractory multiple myeloma. Blood Cancer J. 2019 Jul 29;9(8):56. link to original article link to original article contains verified protocol PubMed

BLD

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BLD: Bendamustine, Lenalidomide, Dexamethasone

Regimen

Study Evidence
Lentzsch et al. 2012 Phase I/II

Dosages listed are the determined maximally tolerated doses (MTD) of this phase I/II trial.

Chemotherapy

Targeted therapy

Supportive medications

28-day cycle for up to 8 cycles

References

  1. Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, Burt S, Boyiadzis M, Roodman GD, Mapara MY, Agha M, Waas J, Shuai Y, Normolle D, Zonder JA. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012 May 17;119(20):4608-13. Epub 2012 Mar 26. link to original article contains verified protocol link to PMC article PubMed

Bortezomib, Thalidomide, Dexamethasone, Panobinostat

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Regimen

Study Evidence
Popat et al. 2016 (MUK-six) Phase I/II

Note: this is the dose used in the phase II portion of the trial.

Targeted therapy

21-day cycle for 16 cycles

References

  1. Popat R, Brown SR, Flanagan L, Hall A, Gregory W, Kishore B, Streetly M, Oakervee H, Yong K, Cook G, Low E, Cavenagh J; Myeloma UK Early Phase Clinical Trial Network.. Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial. Lancet Haematol. 2016 Dec;3(12):e572-e580. link to original article contains protocol PubMed

Carfilzomib & Panobinostat

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Regimen

Study Evidence
Berdeja et al. 2015 Phase II

Targeted therapy

  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 45 mg/m2 IV over 30 minutes once per day on days 8, 9, 15, 16
    • Cycle 2 onwards: 45 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
  • Panobinostat (Farydak) 30 mg PO once per day on days 1, 3, 5, 15, 17, 19

28-day cycles

References

  1. Berdeja JG, Hart LL, Mace JR, Arrowsmith ER, Essell JH, Owera RS, Hainsworth JD, Flinn IW. Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma. Haematologica. 2015 May;100(5):670-6. Epub 2015 Feb 20. link to original article contains verified protocol link to PMC article PubMed

CPR

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CPR: Cyclophosphamide, Prednisone, Revlimid (Lenalidomide)
REP: Revlimid (Lenalidomide), Endoxan (Cyclophosphamide), Prednisone

Regimen variant #1, "REP"

Study Evidence
Nijhof et al. 2016 (REPEAT) Phase I/II

Details are for the MTD/phase II portion of the published phase I/II trial.

Targeted therapy

Chemotherapy

28-day cycles

Regimen variant #2, "CPR"

Study Evidence
Reece et al. 2014 Phase I/II

Details are for the phase II portion of the published phase I/II trial.

Chemotherapy

Targeted therapy

28-day cycles

References

  1. Reece DE, Masih-Khan E, Atenafu EG, Jimenez-Zepeda VH, Anglin P, Chen C, Kukreti V, Mikhael JR, Trudel S. Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma. Br J Haematol. 2015 Jan;168(1):46-54. Epub 2014 Aug 22. link to original article contains protocol PubMed
  2. Nijhof IS, Franssen LE, Levin MD, Bos GM, Broijl A, Klein SK, Koene HR, Bloem AC, Beeker A, Faber LM, van der Spek E, Ypma PF, Raymakers R, van Spronsen DJ, Westerweel PE, Oostvogels R, van Velzen J, van Kessel B, Mutis T, Sonneveld P, Zweegman S, Lokhorst HM, van de Donk NW. Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma. Blood. 2016 Nov;128(19), 2297-2306. Epub 2016 Sep 19. link to original article contains verified protocol PubMed

CRD

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CRD: Cyclophosphamide, Revlimid (Lenalidomide), Dexamethasone

Regimen

Study Evidence
Schey et al. 2010 Phase I/II

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

Chemotherapy

Targeted therapy

Supportive medications

28-day cycles

References

  1. Schey SA, Morgan GJ, Ramasamy K, Hazel B, Ladon D, Corderoy S, Jenner M, Phekoo K, Boyd K, Davies FE. The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study. Br J Haematol. 2010 Aug;150(3):326-33. link to original article contains verified protocol PubMed

CTD

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CTD: Cyclophosphamide, Thalidomide, Dexamethasone

Regimen

Study Evidence
Dimopoulos et al. 2004 Phase II

Chemotherapy

Targeted therapy

  • Thalidomide (Thalomid) as follows:
    • Cycles 1 to 3: 400 mg PO every evening on days 1 to 5, 14 to 18
    • Cycle 4 onwards: 400 mg PO every evening on days 1 to 5
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 3: 20 mg PO every morning after breakfast on days 1 to 5, 14 to 18
    • Cycle 4 onwards: 20 mg PO every morning after breakfast on days 1 to 5

28-day cycles

References

  1. Dimopoulos MA, Hamilos G, Zomas A, Gika D, Efstathiou E, Grigoraki V, Poziopoulos C, Xilouri I, Zorzou MP, Anagnostopoulos N, Anagnostopoulos A. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J. 2004;5(2):112-7. PubMed

Dara-KD

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Dara-KD: Daratumumab, Kyprolis (Carfilzomib), low-dose dexamethasone

Regimen

Study Evidence Efficacy
Chari et al. 2019 (MMY1001) Phase Ib ORR: 84%

Targeted therapy

  • Daratumumab (Darzalex) as follows:
    • Cycles 1 & 2: 16 mg/kg IV once per day on day 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
  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV once on day 1, then 70 mg/m2 IV once per day on days 8 & 15
    • Cycle 2 onwards: 70 mg/m2 IV once per day on days 1, 8, 15
  • Dexamethasone (Decadron) as follows:
    • Up to age 75: 40 mg PO once per day on days 1, 8, 15, 22
    • Older than 75: 20 mg PO once per day on days 1, 8, 15, 22

Supportive medications

28-day cycles

References

  1. MMY1001: Chari A, Martinez-Lopez J, Mateos MV, Bladé J, Benboubker L, Oriol A, Arnulf B, Rodriguez-Otero P, Pineiro L, Jakubowiak A, de Boer C, Wang J, Clemens PL, Ukropec J, Schecter J, Lonial S, Moreau P. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019 Aug 1;134(5):421-431. Epub 2019 May 21. link to original article contains verified protocol PubMed

Dara-PD

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Dara-PD: Daratumumab, Pomalidomide, Dexamethasone

Regimen

FDA-recommended dose
Study Years of enrollment Evidence Efficacy
Chari et al. 2017 (EQUULEUS) NR Phase Ib (RT) ORR: 59% (95% CI, 49-69)

Targeted therapy

  • Daratumumab (Darzalex) as follows:
    • Cycles 1 & 2: 16 mg/kg IV once per day on day 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
  • Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
  • Dexamethasone (Decadron) as follows:
    • Standard patients: 40 mg PO once per day on days 1, 8, 15, 22
    • Patients older than 75 years or BMI less than 18.5: 20 mg PO once per day on days 1, 8, 15, 22

Supportive medications

28-day cycles

References

  1. EQUULEUS: Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, Weiss BM, Krishnan A, Lentzsch S, Comenzo R, Wang J, Nottage K, Chiu C, Khokhar NZ, Ahmadi T, Lonial S. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017 Aug 24;130(8):974-981. Epub 2017 Jun 21. link to original article contains verified protocol PubMed

DCEP

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

Regimen variant #1

Study Evidence
Lazzarino et al. 2001 Phase II

Note: this protocol is reported as a mobilization regimen prior to high dose autologous transplant; all patients had received prior therapy.

Chemotherapy

Supportive medications

  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 48 hours after chemotherapy and continuing through stem cell collection

One course

Regimen variant #2

Study Evidence
Dadacaridou et al. 2007 Phase II, <20 patients reported

These limited details are based on the abstract's description only. Full article was not available for review.

Chemotherapy

Supportive medications

  • G-CSF SC once per day, starting on day 5, to continue until neutrophil recovery

28-day cycles

References

  1. Lazzarino M, Corso A, Barbarano L, Alessandrino EP, Cairoli R, Pinotti G, Ucci G, Uziel L, Rodeghiero F, Fava S, Ferrari D, Fiumanò M, Frigerio G, Isa L, Luraschi A, Montanara S, Morandi S, Perego D, Santagostino A, Savarè M, Vismara A, Morra E. DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) is an effective regimen for peripheral blood stem cell collection in multiple myeloma. Bone Marrow Transplant. 2001 Nov;28(9):835-9. link to original article contains verified protocol PubMed
  2. Dadacaridou M, Papanicolaou X, Maltesas D, Megalakaki C, Patos P, Panteli K, Repousis P, Mitsouli-Mentzikof C. Dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) for relapsed or refractory multiple myeloma patients. J BUON. 2007 Jan-Mar;12(1):41 to 4. PubMed

DTPACE

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DTPACE: Dexamethasone, Thalidomide, Platinol (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide

Regimen

Study Evidence
Lee et al. 2003 Prospective

To be completed

Targeted therapy

Chemotherapy

References

  1. Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, van Rhee F, Cottler-Fox M, Muwalla F, Tricot G. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol. 2003 Jul 15;21(14):2732-9. Erratum in: J Clin Oncol. 2008 Apr 20;26(12): 2066. link to original article PubMed

FRD

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FRD: Farydak (Panobinostat), Revlimid (Lenalidomide), Dexamethasone

Regimen

Study Evidence
Chari et al. 2017 Phase II

Targeted therapy

28-day cycles

References

  1. Chari A, Cho HJ, Dhadwal A, Morgan G, La L, Zarychta K, Catamero D, Florendo E, Stevens N, Verina D, Chan E, Leshchenko V, Laganà A, Perumal D, Mei AH, Tung K, Fukui J, Jagannath S, Parekh S. A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. Blood Adv. 2017 Aug 21;1(19):1575-1583. eCollection 2017 Aug 22. link to original article contains verified protocol link to PMC article PubMed

Hyper-CVAD

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Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen variant #1

Study Evidence
Dimopoulos et al. 1996 Phase II

To be completed.

Chemotherapy

Regimen variant #2, modified

Study Evidence
Saraceni et al. 2018 Retrospective

Note that vincristine is a flat dose.

Chemotherapy

Supportive Medications

  • Pegfilgrastim (Neulasta) 6 mg SC once on day 5 or 6
  • Mesna (Mesnex) 350 mg/m2/day IV continuous infusion over 96 hours, started on day 1
  • Antiviral prophylaxis with Valacyclovir (Valtrex) daily (dose not specified)
  • "Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"

Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks

References

  1. Dimopoulos MA, Weber D, Kantarjian H, Delasalle KB, Alexanian R. HyperCVAD for VAD-resistant multiple myeloma. Am J Hematol. 1996 Jun;52(2):77-81. link to original article PubMed
  2. Retrospective: Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, Medvedova E. Modified hyperCVAD versus bortezomib-hyperCAD in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e77-e84. link to original article contains verified protocol PubMed

Ixazomib monotherapy

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Regimen variant #1, bi-weekly, 2 out of 3 weeks

Study Evidence
Richardson et al. 2014 (C16003) Phase I/II

Note: this is the dosing used in the expansion cohort.

Targeted therapy

21-day cycle for up to 12 cycles

Regimen variant #2, 3 out of 4 weeks

Study Evidence
Kumar et al. 2015 (MC1181) Phase II

Targeted therapy

28-day cycles

Subsequent treatment

References

  1. C16003: Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, Talpaz M, Berg D, Liu G, Yu J, Gupta N, Di Bacco A, Hui AM, Lonial S. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 Aug 14;124(7):1038-46. Epub 2014 Jun 11. link to original article link to PMC article contains verified protocol PubMed
  2. MC1181: Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338. link to original article contains verified protocol link to PMC article PubMed NCT01415882

KPD

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KPD: Kyprolis (Carfilzomib), Pomalidomide, Dexamethasone
CPD: Carfilzomib, Pomalidomide, Dexamethasone

Regimen

Study Evidence
Shah et al. 2015 (PO-MM-PI-0034) Phase I (*)

Note, although this is described as a Phase I trial, an additional 20 patients were enrolled at the MTD, which is the dose reported here.

Targeted therapy

  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV over 30 minutes once per day on days 1 & 2, then 27 mg/m2 IV over 30 minutes once per day on days 8, 9, 15, 16
    • Cycles 2 to 6: 27 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 4: 40 mg IV or PO once per day on days 1, 8, 15, 22
    • Cycles 5 to 6: 20 mg IV or PO once per day on days 1, 8, 15, 22

Supportive medications

28-day cycle for 6 cycles

Subsequent treatment

References

  1. PO-MM-PI-0034: Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. Epub 2015 Sep 17. link to original article contains verified protocol link to PMC article PubMed

KRD-PACE

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KRD-PACE: Kyprolis (Carfilzomib), Revlimid (Lenalidomide),Dexamethasone - Cisplatin (Platinol), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide (Toposar)

Regimen variant #1

Study Evidence
Cowan et al. 2020 Retrospective

Note that PACE was administered as a continuous infusion.

Chemotherapy

Regimen variant #2, modified

Study Evidence
Cowan et al. 2020 Retrospective

Note that PACE was administered as a continuous infusion.

Chemotherapy

Supportive Medications

  • Neupogen (Filgrastim) 10 ug/kg per day S.C. was begun onday 10.
  • Antiviral prophylaxis with Valacyclovir (Valtrex) daily (dose not specified)
  • "Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"
  • All patients received anticoagulation therapy; individuals not receiving systemic therapeutic anticoagulation for another reason received enoxaparin 40 mg per day subcutaneously for DVT prophylaxis during chemotherapy

Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks

References

  1. Retrospective: Cowan AJ, Green DJ, Karami M, Becker PS, Tuazon S, Coffey DG, Hyun TS, Libby EN, Gopal AK, Holmberg LA. KRD-PACE Mobilization for Multiple Myeloma Patients With Significant Residual Disease Before Autologous Stem-Cell Transplantation. Clin Lymphoma Myeloma Leuk. 2020 Sep;20(9):602-609. doi: 10.1016/j.clml.2020.04.002. [1] contains verified protocol PubMed

PAD

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

Regimen

Study Evidence
Cook et al. 2014 (NCRI Myeloma X Relapse) Non-randomized portion of RCT

Note: length of cycle is not reported in the manuscript, but presumably is 28 days, similar to other PAD regimens.

Targeted therapy

Chemotherapy

  • Doxorubicin (Adriamycin) 9 mg/m2 IV once per day on days 1 to 4
    • Could be given as a 4-day continuous infusion or as bolus injections
  • Dexamethasone (Decadron) as follows:
    • Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
    • Cycles 2 to 4: 40 mg PO once per day on days 1 to 4

28-day cycle for 2 to 4 cycles

Subsequent treatment

References

  1. NCRI Myeloma X Relapse: Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. Epub 2014 Jun 16. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Dosage error in article text. link to original article PubMed NCT00747877
    1. Update: Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. link to original article contains protocol PubMed
    2. Subgroup analysis: Cook G, Royle KL, O'Connor S, Cairns DA, Ashcroft AJ, Williams CD, Hockaday A, Cavenagh JD, Snowden JA, Ademokun D, Tholouli E, Andrews VE, Jenner M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Drayson MT, Brown JM, Morris TCM; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long-term follow-up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Br J Haematol. 2019 May;185(3):450-467. Epub 2019 Feb 6. link to original article link to PMC article PubMed

PCP

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PCP: Pomalidomide, Cyclophosphamide, Prednisone

Regimen

Study Evidence
Larocca et al. 2013 Phase I/II

Details are for the phase II portion of the published phase I/II trial.

Targeted therapy

Chemotherapy

Supportive medications

28-day cycle for 6 cycles

Subsequent treatment

References

  1. Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A. Pomalidomide, cyclophosphamide and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013 Oct 17;122(16):2799-806. Epub 2013 Aug 16. link to original article contains verified protocol PubMed

RVD

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

Regimen

Study Evidence ORR
Richardson et al. 2014 (DFCI 06-147) Phase II 64%

Targeted therapy

Supportive medications

21-day cycle for 8 cycles

Subsequent treatment

References

  1. DFCI 06-147: Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial IM, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9. Epub 2014 Jan 15. link to original article contains verified protocol link to PMC article PubMed

Selinexor & Dexamethasone

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence
Vogl et al. 2018 (STORM) NR Phase II (RT)

Targeted therapy

28-day cycles

References

  1. STORM: Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D, Zonder J, Baz R, Nooka A, Richter J, Cole C, Vij R, Jakubowiak A, Abonour R, Schiller G, Parker TL, Costa LJ, Kaminetzky D, Hoffman JE, Yee AJ, Chari A, Siegel D, Fonseca R, Van Wier S, Ahmann G, Lopez I, Kauffman M, Shacham S, Saint-Martin JR, Picklesimer CD, Choe-Juliak C, Stewart AK. Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 20;36(9):859-866. Epub 2018 Jan 30. link to original article contains verified protocol PubMed
    1. Update: Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, Moreau P, Dingli D, Cole C, Lonial S, Dimopoulos M, Stewart AK, Richter J, Vij R, Tuchman S, Raab MS, Weisel KC, Delforge M, Cornell RF, Kaminetzky D, Hoffman JE, Costa LJ, Parker TL, Levy M, Schreder M, Meuleman N, Frenzel L, Mohty M, Choquet S, Schiller G, Comenzo RL, Engelhardt M, Illmer T, Vlummens P, Doyen C, Facon T, Karlin L, Perrot A, Podar K, Kauffman MG, Shacham S, Li L, Tang S, Picklesimer C, Saint-Martin JR, Crochiere M, Chang H, Parekh S, Landesman Y, Shah J, Richardson PG, Jagannath S. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019 Aug 22;381(8):727-738. link to original article PubMed

Thalidomide monotherapy

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Regimen

Study Evidence
Singhal et al. 1999 Non-randomized

Targeted therapy

  • Thalidomide (Thalomid) 200 mg PO once per day, increased by 200 mg every two weeks for six weeks, to final dose of 800 mg per day

Continued indefinitely

References

  1. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. Erratum in: N Engl J Med 2000 Feb 3;342(5):364. link to original article contains protocol PubMed

Vemurafenib monotherapy

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Regimen

Study Evidence
Hyman et al. 2015 (VE-BASKET) Basket trial, <20 pts in subgroup

Note that Andrulis et al. 2013 is a single patient case report with a good response. Sharman et al. reports two patients with good response. In the Hyman et al. 2015 trial, there were 5 patients with multiple myeloma; "No patients with multiple myeloma have had a response to date."

Targeted therapy

Continued indefinitely

References

  1. Case report: Andrulis M, Lehners N, Capper D, Penzel R, Heining C, Huellein J, Zenz T, von Deimling A, Schirmacher P, Ho AD, Goldschmidt H, Neben K, Raab MS. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013 Aug;3(8):862-9. Epub 2013 Apr 23. link to original article contains protocol PubMed
  2. Case series: Sharman JP, Chmielecki J, Morosini D, Palmer GA, Ross JS, Stephens PJ, Stafl J, Miller VA, Ali SM. Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma. Clin Lymphoma Myeloma Leuk. 2014 Oct;14(5):e161-3. Epub 2014 Jun 11. link to original article PubMed
  3. VE-BASKET: Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015 Aug 20;373(8):726-36. link to original article link to PMC article contains verified protocol PubMed

V-HyperCAD

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V-HyperCAD: Velcade (Bortezomib), Hyperfractionated Cyclophosphamide, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study Evidence
Saraceni et al. 2018 Retrospective

Targeted therapy

Chemotherapy

Supportive Medications

  • Pegfilgrastim (Neulasta) 6 mg SC once on day 5 or 6
  • Mesna (Mesnex) 350 mg/m2/day IV continuous infusion over 96 hours, started on day 1
  • Antiviral prophylaxis with Acyclovir (Zovirax) daily (dose not specified)
  • "Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"

Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks

References

  1. Retrospective: Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, Medvedova E. Modified hyperCVAD versus bortezomib-hyperCAD in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e77-e84. link to original article contains verified protocol PubMed

VMPT

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

Regimen

Study Evidence
Palumbo et al. 2007 Phase I/II

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

Targeted therapy

Chemotherapy

35-day cycle for 6 cycles

References

  1. Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, Cangialosi C, Caravita T, Morabito F, Musto P, Bringhen S, Falco P, Avonto I, Cavallo F, Boccadoro M; Italian Multiple Myeloma Network; Gruppo Italiano Malattie Ematologicche dell'Adulto. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood. 2007 Apr 1;109(7):2767-72. link to original article contains protocol PubMed

ZRd

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ZRd: Zolinza (Vorinostat), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study Evidence
Sanchez et al. 2016 Phase IIb

Targeted therapy

28-day cycles

References

  1. Sanchez L, Vesole DH, Richter JR, Biran N, Bilotti E, McBride L, Anand P, Ivanovski K, Siegel DS. A phase IIb trial of vorinostat in combination with lenalidomide and dexamethasone in patients with multiple myeloma refractory to previous lenalidomide-containing regimens. Br J Haematol. 2017 Feb;176(3):440-447. Epub 2016 Nov 18. link to original article contains protocol PubMed

Consolidation after second-line therapy

Bortezomib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Richardson et al. 2005 (APEX) 2002-2003 Phase III (E-RT-switch-ooc) High-dose dexamethasone Seems to have superior OS (*)

Note: efficacy is reported based on the 2007 update.

Preceding treatment

Targeted therapy

Supportive medications

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

35-day cycle for 3 cycles

References

  1. APEX: Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM, Anderson KC. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007 Jan;21(1):151-7. Epub 2006 Nov 9. link to original article PubMed
    2. Update: Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San Miguel J, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007 Nov 15;110(10):3557-60. Epub 2007 Aug 9. link to original article contains verified protocol PubMed

Melphalan, then auto HSCT

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cook et al. 2014 (NCRI Myeloma X Relapse) 2008-2012 Phase III (E-esc) Cyclophosphamide Seems to have superior OS (*)

Efficacy reported is based on the 2016 update.

Preceding treatment

Chemotherapy

Stem cells re-infused on day 0

References

  1. NCRI Myeloma X Relapse: Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. Epub 2014 Jun 16. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Dosage error in article text. link to original article PubMed NCT00747877
    1. Update: Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. link to original article contains protocol PubMed
    2. Subgroup analysis: Cook G, Royle KL, O'Connor S, Cairns DA, Ashcroft AJ, Williams CD, Hockaday A, Cavenagh JD, Snowden JA, Ademokun D, Tholouli E, Andrews VE, Jenner M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Drayson MT, Brown JM, Morris TCM; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long-term follow-up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Br J Haematol. 2019 May;185(3):450-467. Epub 2019 Feb 6. link to original article link to PMC article PubMed

Maintenance after second-line therapy

Bortezomib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Orlowski et al. 2015 2006-2009 Randomized Phase II (C) Bortezomib & Siltuximab Did not meet primary endpoint of PFS

Preceding treatment

Targeted therapy

35-day cycles

References

  1. Orlowski RZ, Gercheva L, Williams C, Sutherland H, Robak T, Masszi T, Goranova-Marinova V, Dimopoulos MA, Cavenagh JD, Špička I, Maiolino A, Suvorov A, Bladé J, Samoylova O, Puchalski TA, Reddy M, Bandekar R, van de Velde H, Xie H, Rossi JF. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol. 2015 Jan;90(1):42-9. contains verified protocol link to PMC article PubMed

Bortezomib & Cyclophosphamide

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Regimen

Study Evidence
de Waal et al. 2015 Phase II

Preceding treatment

Targeted therapy

Chemotherapy

Supportive medications

  • Pneumococccal and anti-fungal prophylaxis "according to local protocols"
  • Valacyclovir (Valtrex) (dose not specified) for herpes prophylaxis

14-day cycle for up to 26 cycles (1 year)

References

  1. de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. link to original article contains verified protocol PubMed

Daratumumab monotherapy

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Regimen

Study Evidence
Palumbo et al. 2016 (CASTOR) Non-randomized portion of RCT

Preceding treatment

Targeted therapy

28-day cycles

References

  1. CASTOR: Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed
    1. Update: Spencer A, Lentzsch S, Weisel K, Avet-Loiseau H, Mark TM, Spicka I, Masszi T, Lauri B, Levin MD, Bosi A, Hungria V, Cavo M, Lee JJ, Nooka AK, Quach H, Lee C, Barreto W, Corradini P, Min CK, Scott EC, Chanan-Khan AA, Horvath N, Capra M, Beksac M, Ovilla R, Jo JC, Shin HJ, Sonneveld P, Soong D, Casneuf T, Chiu C, Amin H, Qi M, Thiyagarajah P, Sasser AK, Schecter JM, Mateos MV. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018 Dec;103(12):2079-87. Epub 2018 Sep 20. link to original article PubMed

KPD

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KPD: Kyprolis (Carfilzomib), Pomalidomide, Dexamethasone
CPD: Carfilzomib, Pomalidomide, Dexamethasone

Regimen

Study Evidence
Shah et al. 2015 (PO-MM-PI-0034) Phase I (*)

Note, although this is described as a Phase I trial, an additional 20 patients were enrolled at the MTD, which is the dose reported here.

Preceding treatment

Targeted therapy

Supportive medications

28-day cycles

References

  1. PO-MM-PI-0034: Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. Epub 2015 Sep 17. link to original article contains verified protocol link to PMC article PubMed

Pomalidomide monotherapy

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Regimen

Study Evidence Efficacy
Paludo et al. 2017 (MC1082) Phase I/II ORR: 86%

Preceding treatment

Targeted therapy

Supportive medications

28-day cycles

References

  1. MC1082: Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1198-1204. Epub 2017 Jul 6. link to original article contains verified protocol PubMed

Pomalidomide & Prednisone

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Regimen

Study Evidence Efficacy
Larocca et al. 2013 Phase I/II ORR: 51%

Details are for the phase II portion of the published phase I/II trial.

Preceding treatment

Targeted therapy

Supportive medications

Continued indefinitely

References

  1. Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A. Pomalidomide, cyclophosphamide and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013 Oct 17;122(16):2799-806. Epub 2013 Aug 16. link to original article contains verified protocol PubMed

RVD

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

Regimen

Study Evidence
Richardson et al. 2014 (DFCI 06-147) Phase II

Preceding treatment

Targeted therapy

Supportive medications

21-day cycles

References

  1. DFCI 06-147: Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial IM, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9. Epub 2014 Jan 15. link to original article contains verified protocol link to PMC article PubMed


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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