Multiple myeloma - historical

From HemOnc.org - A Hematology Oncology Wiki
Jump to: navigation, search

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? Please go to the main multiple myeloma regimen page to find other regimens.

41 regimens on this page
68 variants on this page

Contents


First-line therapy

ABCM

back to top

ABCM: Adriamycin (Doxorubicin), BCNU (Carmustine), Cyclophosphamide, Melphalan

Regimen

Study Evidence Comparator Comparative Efficacy
MacLennan et al. 1992 (MRC Myeloma V) Phase III (E) M7 Superior OS
Child et al. 2003 (MRC Myeloma VII) Phase III (C) C-VAMP Seems to have inferior OS

Chemotherapy

References

  1. MRC Myeloma V: MacLennan IC, Chapman C, Dunn J, Kelly K; The Medical Research Council Working Party for Leukaemia in Adults. Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis. Lancet. 1992 Jan 25;339(8787):200-5. link to original article PubMed
  2. MRC Myeloma VII: Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. link to original article PubMed

mCOP/MP

back to top

mCOP/MP: modified Cyclophosphamide, Oncovin (Vincristine), Prednisolone alternating with Melphalan & Prednisolone

Regimen

Study Evidence Comparator Comparative Efficacy
Takenaka et al. 2004 (JCOG 9301) Phase III (C) MCNU-COP/MP Seems not superior

Chemotherapy, COP portion

Chemotherapy, MP portion

References

  1. JCOG 9301: Takenaka T, Itoh K, Suzuki T, Utsunomiya A, Matsuda S, Chou T, Sai T, Sano M, Konda S, Ohno T, Mikuni C, Deura K, Yamada T, Mizorogi F, Nagoshi H, Tomonaga M, Hotta T, Kawano K, Tsushita K, Hirano M, Shimoyama M; Lymphoma Study Group of the Japan Clinical Oncology Group. Phase III study of ranimustine, cyclophosphamide, vincristine, melphalan, and prednisolone (MCNU-COP/MP) versus modified COP/MP in multiple myeloma: a Japan clinical oncology group study, JCOG 9301. Int J Hematol. 2004 Feb;79(2):165-73. link to original article PubMed

C-VAMP

back to top

C-VAMP: Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), MethylPrednisolone

Regimen

Study Evidence Comparator Comparative Efficacy
Raje et al. 1997 Non-randomized
Child et al. 2003 (MRC Myeloma VII) Phase III (E) ABCM Seems to have superior OS

A minimum of 3 cycles were given before stem cell harvest.

Chemotherapy

21-day cycles, given until maximal response was achieved

Subsequent treatment

References

  1. Raje N, Powles R, Kulkarni S, Milan S, Middleton G, Singhal S, Mehta J, Millar B, Viner C, Raymond J, Treleaven J, Cunningham D, Gore M. A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma. Br J Haematol. 1997 Apr;97(1):153-60. link to original article PubMed
  2. MRC Myeloma VII: Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. link to original article contains verified protocol PubMed

Cyclophosphamide monotherapy

back to top

Regimen

Study Evidence
Korst et al. 1964 Non-randomized portion of RCT

Chemotherapy

References

  1. Korst DR, Clifford GO, Fowler WM, Louis J, Will J, Wilson HE. Multiple myeloma II: analysis of cyclophosphamide therapy in 165 patients. JAMA. 1964 Sep 7;189:758-62. link to original article PubMed

Dexamethasone monotherapy

back to top

Variant #1, 35-day cycles

Study Evidence
Alexanian et al. 1986 Non-randomized
Alexanian et al. 1992 Non-randomized

Chemotherapy

35-day cycle for 3 cycles (Alexanian et al. 1992) or until maximal response (Alexanian et al. 1986)

Subsequent treatment

Variant #2, indefinite with 35-day induction cycles

Study Evidence Comparator Comparative Efficacy
Zonder et al. 2010 (SWOG S0232) Phase III (C) Len-Dex Inferior PFS

This regimen was intended for transplantation-ineligible or -denying patients who had to have symptomatic disease with a measurable M-protein, be at least 18 years old, and have a performance status less than 3 (unless resulting from myeloma). Note that the first 3 cycles, termed "induction" in the protocol, were 35-day cycles. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
    • Cycle 4 onwards: 40 mg PO once per day on days 1 to 4

Supportive medications

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

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

Variant #3, indefinite with 28-day induction cycles

Study Evidence Comparator Comparative Efficacy
Rajkumar et al. 2008 Phase III (C) TD Inferior TTP

This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

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

28-day cycles

Variant #4, indefinite with alternating dexamethasone intensity

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Rajkumar et al. 2005 (ECOG E1A00) Phase III (C) TD Seems to have inferior RR Superior toxicity

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

Chemotherapy

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

28-day cycles

Variant #5, 12 cycles total

Study Evidence Comparator Comparative Efficacy
Facon et al. 2005 (IFM 95-01) Phase III (E) 1. DEX-IFN Seems not superior
2. MP
3. M-DEX
Inferior PFS

This regimen was intended for patients aged between 65 and 75 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria. Some stage I patients were allowed; see text for details.

Chemotherapy

  • Dexamethasone (Decadron) as follows:
    • Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
    • Cycles 3 to 12: 40 mg PO once per day on days 1 to 4

42-day cycle for 12 cycles

References

  1. Alexanian R, Barlogie B, Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Med. 1986 Jul;105(1):8-11. link to original article contains verified protocol PubMed
  2. Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B. Primary dexamethasone treatment of multiple myeloma. Blood. 1992 Aug 15;80(4):887-90. link to original article contains verified protocol PubMed
  3. Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, Voillat L, Dorvaux V, Hulin C, Lepeu G, Harousseau JL, Eschard JP, Ferrant A, Blanc M, Maloisel F, Orfeuvre H, Rossi JF, Azaïs I, Monconduit M, Collet P, Anglaret B, Yakoub-Agha I, Wetterwald M, Eghbali H, Vekemans MC, Maisonneuve H, Troncy J, Grosbois B, Doyen C, Thyss A, Jaubert J, Casassus P, Thielemans B, Bataille R; Intergroupe Francophone du Myélome (IFM) group. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006 Feb 15;107(4):1292-8. Epub 2005 Sep 20. link to original paper contains protocol PubMed
  4. ECOG E1A00: Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern Cooperative Oncology Group. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006 Jan 20;24(3):431-6. Epub 2005 Dec 19. link to original article contains protocol PubMed
  5. Rajkumar SV, Rosiñol L, Hussein M, Catalano J, Jedrzejczak W, Lucy L, Olesnyckyj M, Yu Z, Knight R, Zeldis JB, Bladé J. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 2008 May 1;26(13):2171-7. Epub 2008 Mar 24. link to original article contains verified protocol link to PMC article PubMed
  6. Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood. 2010 Dec 23;116(26):5838-41. Epub 2010 Sep 27. link to original article link to PMC article contains verified protocol PubMed

DEX-IFN

back to top

DEXamethasone, InterFeroN alfa-2b

Regimen

Study Evidence Comparator Comparative Efficacy
Facon et al. 2005 (IFM 95-01) Phase III (E) 1. Dexamethasone Seems not superior
2. MP
3. M-DEX
Inferior PFS

This regimen was intended for patients aged between 65 and 75 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria. Some stage I patients were allowed; see text for details.

Chemotherapy

  • Dexamethasone (Decadron) as follows:
    • Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
    • Cycles 3 to 12: 40 mg PO once per day on days 1 to 4
  • Interferon alfa-2b (Intron-A) 3,000,000 units SC 3 times per week; start with dexamethasone and stop on on day 42 of the last cycle of dexamethasone

42-day cycle for 12 cycles

References

  1. Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, Voillat L, Dorvaux V, Hulin C, Lepeu G, Harousseau JL, Eschard JP, Ferrant A, Blanc M, Maloisel F, Orfeuvre H, Rossi JF, Azaïs I, Monconduit M, Collet P, Anglaret B, Yakoub-Agha I, Wetterwald M, Eghbali H, Vekemans MC, Maisonneuve H, Troncy J, Grosbois B, Doyen C, Thyss A, Jaubert J, Casassus P, Thielemans B, Bataille R; Intergroupe Francophone du Myélome (IFM) group. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006 Feb 15;107(4):1292-8. Epub 2005 Sep 20. link to original paper contains protocol PubMed

EDAP

back to top

EDAP: Etoposide, Dexamethasone, Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study Evidence
Barlogie et al. 1997 (Total Therapy 1) Non-randomized

Given as a component of Total Therapy.

Chemotherapy

References

  1. Total Therapy 1: Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93. link to original article PubMed
    1. Update: Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. link to original article contains verified protocol PubMed
    2. Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed

Melphalan monotherapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Bergsagel et al. 1965 Non-randomized
Hoogstraten et al. 1967 Non-randomized portion of RCT
Rivers & Patno 1969 Phase III (E) Cyclophosphamide Seems not superior
Hoogstraten et al. 1969a Non-randomized

Chemotherapy

References

  1. Bergsagel DE, Migliore PJ, Griffith KM. Myeloma proteins and the clinical response to melphalan therapy. Science. 1965 Apr 16;148(3668):376-7. link to original article PubMed
  2. Hoogstraten B, Sheehe PR, Cuttner J, Cooper T, Kyle RA, Oberfield RA, Townsend SR, Harley JB, Hayes DM, Costa G, Holland JF. Melphalan in multiple myeloma. Blood. 1967 Jul;30(1):74-83. link to original article PubMed
  3. Rivers SL, Patno ME. Cyclophosphamide vs melphalan in treatment of plasma cell myeloma. JAMA. 1969 Feb 17;207(7):1328-34. link to original article PubMed
  4. Hoogstraten B, Costa J, Cuttner J, Forcier J, Leone LA, Harley JB, Glidewell OJ. Intermittent melphalan therapy in multiple myeloma. JAMA. 1969 Jul 14;209(2):251-3. link to original article PubMed

M-DEX

back to top

M-DEX: Melphalan & DEXamethasone
MD: Melphalan & Dexamethasone

Variant #1, 0.25/40

Study Evidence Comparator Comparative Efficacy
Facon et al. 2005 (IFM 95-01) Phase III (E) 1. Dexamethasone
2. DEX-IFN
Superior PFS
3. MP Seems not superior

This regimen was intended for patients aged between 65 and 75 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria. Some stage I patients were allowed; see text for details.

Chemotherapy

  • Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
    • Cycles 3 to 12: 40 mg PO once per day on days 1 to 4

42-day cycle for 12 cycles

Variant #2, 9/20

Study Evidence Comparator Comparative Efficacy
Hernández et al. 2004 Phase III (E) MP Seems not superior

Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Chemotherapy

28-day cycles

References

  1. Hernández JM, García-Sanz R, Golvano E, Bladé J, Fernandez-Calvo J, Trujillo J, Soler JA, Gardella S, Carbonell F, Mateo G, San Miguel JF. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. Br J Haematol. 2004 Oct;127(2):159-64. link to original article contains verified protocol PubMed
  2. IFM 95-01: Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, Voillat L, Dorvaux V, Hulin C, Lepeu G, Harousseau JL, Eschard JP, Ferrant A, Blanc M, Maloisel F, Orfeuvre H, Rossi JF, Azaïs I, Monconduit M, Collet P, Anglaret B, Yakoub-Agha I, Wetterwald M, Eghbali H, Vekemans MC, Maisonneuve H, Troncy J, Grosbois B, Doyen C, Thyss A, Jaubert J, Casassus P, Thielemans B, Bataille R; Intergroupe Francophone du Myélome (IFM) group. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006 Feb 15;107(4):1292-8. Epub 2005 Sep 20. link to original paper contains verified protocol PubMed

MP

back to top

MP: Melphalan & Predniso(lo)ne

Variant #1, melphalan 0.15 mg/kg

Note: Though this regimen is listed in several online references, no primary reference for this exact regimen could be found. Specifically, some references cite the Facon et al. 2006 paper for this regimen, but this regimen is not in that paper. Many additional variations of MP can be found in the Myeloma Trialists' Collaborative Group 1998 Journal of Clinical Oncology paper referenced below.

Chemotherapy

42-day cycles

Variant #2, melphalan 0.18 mg/kg

Study Evidence Comparator Comparative Efficacy
Palumbo et al. 2012 (MM-015) Phase III (C) 1. MPR Seems not superior
2. MPR-R Inferior PFS

This regimen was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were not candidates for transplantation (greater than or equal to 65 years of age).

Chemotherapy

Supportive medications

  • Thromboprophylaxis: Aspirin 75 to 100 mg PO once per day

28-day cycle for 9 cycles

Variant #3, melphalan 0.2 mg/kg

Study Evidence Comparator Comparative Efficacy
Hulin et al. 2009 (IFM 01/01) Phase III (C) MPT Seems to have inferior OS

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

Chemotherapy

42-day cycle for 12 cycles

Variant #4, melphalan 0.25 mg/kg x 4 d/cycle, prednisone 2 mg/kg

Study Evidence Comparator Comparative Efficacy
Alexanian et al. 1969 (SWG01) Non-randomized
Alexanian et al. 1972 Phase III (C) MPP Seems not superior
Facon et al. 2005 (IFM 95-01) Phase III (C) 1. Dexamethasone
2. DEX-IFN
Superior PFS
3. M-DEX Seems not superior
Facon et al. 2007 (IFM 99-06) Phase III (C) 1. MPT Inferior OS
2. VAD, then MEL100 Seems not superior

In IFM 95-01 this regimen was intended for patients aged between 65 and 75 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria. Some stage I patients were allowed; see text for details. In IFM 99-06 this regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 75 years. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

42-day cycle for 12 cycles (IFM 95-01 & IFM 99-06) or indefinitely (SWG01)

Variant #5, melphalan 0.25 mg/kg x 4 d/cycle, flat dose prednisone

Study Evidence Comparator Comparative Efficacy
Keldsen et al. 1993 Phase III (C) NOP Seems to have superior OS
Hjorth et al. 1996 Phase III (C) MP & IFN alfa-2b Seems not superior
Waage et al. 2010 (NMSG12) Phase III (C) MPT Seems not superior

In NMSG12, this regimen was intended for patients with previously untreated symptomatic MM, who were not eligible for high-dose treatment with autologous stem cell support.

Chemotherapy

42-day cycles

Treatment was continued until plateau phase.

Variant #6, melphalan 0.25 mg/kg x 5 d/cycle

Study Evidence Comparator Comparative Efficacy
Wijermans et al. 2010 (HOVON 49) Phase III (C) MP-T Might have inferior OS

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

Chemotherapy

Supportive medications

28-day cycle for 8 cycles

Variant #7, melphalan 4 mg/m2

Study Evidence Comparator Comparative Efficacy
Palumbo et al. 2006 Phase III (C) MPT Seems to have inferior PFS

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

Chemotherapy

28-day cycle for 6 cycles

Variant #8, melphalan 7 mg/m2

Study Evidence Comparator Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX) Phase III (C) CTDa Not reported

This is a nonintensive treatment pathway, as determined by performance status, informed discussion, and patient preference. Note that this regimen uses prednisolone, not prednisone.

Chemotherapy

Supportive medications

28-day cycle for 6 to 9 cycles

Subsequent treatment

Variant #9, melphalan 9 mg/m2, limited duration

Study Evidence Comparator Comparative Efficacy
San Miguel et al. 2008 (VISTA) Phase III (C) VMP Inferior OS
Beksac et al. 2010 (TMSG-2005-001) Phase III (C) MPT Seems to have inferior ORR

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

Chemotherapy

42-day cycle for 8 (VISTA) or 9 cycles (TMSG-2005-001)

Variant #10, melphalan 9 mg/m2, indefinite

Study Evidence Comparator Comparative Efficacy
Bergsagel et al. 1979 Phase III (C) 1. B/C/M Seems not superior
2. BCM Seems not superior
Hernández et al. 2004 Phase III (C) MD Seems not superior

Chemotherapy

  • Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
  • Prednisone (Sterapred) as follows:
    • Bergsagel et al. 1979: 100 mg PO once per day on days 1 to 4
    • Hernández et al. 2004: 60 mg/m2 PO once per day on days 1 to 4

28-day cycles

Variant #11, melphalan 15 mg/m2

Study Evidence Comparator Comparative Efficacy
Pönisch et al. 2006 Phase III (C) BP Inferior TTF

Chemotherapy

28-day cycles

References

  1. SWG01: Alexanian R, Haut A, Khan AU, Lane M, McKelvey EM, Migliore PJ, Stuckey WJ Jr, Wilson HE. Treatment for multiple myeloma: combination chemotherapy with different melphalan dose regimens. JAMA. 1969 Jun 2;208(9):1680-5. link to original article contains verified protocol PubMed
  2. Alexanian R, Bonnet J, Gehan E, Haut A, Hewlett J, Lane M, Monto R, Wilson H. Combination chemotherapy for multiple myeloma. Cancer. 1972 Aug;30(2):382-9. link to original article PubMed
  3. Bergsagel DE, Bailey AJ, Langley GR, MacDonald RN, White DF, Miller AB. The chemotherapy on plasma-cell myeloma and the incidence of acute leukemia. N Engl J Med. 1979 Oct 4;301(14):743-8. link to original article PubMed
  4. Keldsen N, Bjerrum OW, Dahl IM, Drivsholm A, Ellegaard J, Gadeberg O, Gimsing P, Grønvold T, Hansen MM, Hippe E, Lamvik J, Ly B, Skarbøvik A, Talstad I, Thorling K, Wesenberg K, Wisløff F; Nordic Myeloma Study Group (NMSG). Multiple myeloma treated with mitoxantrone in combination with vincristine and prednisolone (NOP regimen) versus melphalan and prednisolone: a phase III study. Eur J Haematol. 1993 Aug;51(2):80-5. link to original article contains protocol PubMed
  5. Hjorth M, Westin J, Dahl IMS, Gimsing P, Hippe E, Holmberg E, Lamvik J, Nielsen JL, Lofvenberg E, Palva IP, Rodjer S, Talstad I, Turesson I, Wisloff F, Zador G; The Nordic Myeloma Study Group. Interferon-alpha 2b added to melphalan-prednisone for initial and maintenance therapy in multiple myeloma: a randomized, controlled trial. Ann Intern Med. 1996 Jan 15;124(2):212-22. link to original article PubMed
  6. Review: Myeloma Trialists' Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol. 1998 Dec;16(12):3832-42. link to original article contains protocol PubMed
  7. Hernández JM, García-Sanz R, Golvano E, Bladé J, Fernandez-Calvo J, Trujillo J, Soler JA, Gardella S, Carbonell F, Mateo G, San Miguel JF. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. Br J Haematol. 2004 Oct;127(2):159-64. link to original article contains verified protocol PubMed
  8. IFM 95-01: Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, Voillat L, Dorvaux V, Hulin C, Lepeu G, Harousseau JL, Eschard JP, Ferrant A, Blanc M, Maloisel F, Orfeuvre H, Rossi JF, Azaïs I, Monconduit M, Collet P, Anglaret B, Yakoub-Agha I, Wetterwald M, Eghbali H, Vekemans MC, Maisonneuve H, Troncy J, Grosbois B, Doyen C, Thyss A, Jaubert J, Casassus P, Thielemans B, Bataille R; Intergroupe Francophone du Myélome (IFM) group. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006 Feb 15;107(4):1292-8. Epub 2005 Sep 20. link to original paper contains verified protocol PubMed
  9. Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network (GIMEMA). Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31. link to original article contains protocol PubMed
    1. Update: Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14. Epub 2008 May 27. link to original article contains protocol PubMed
  10. Pönisch W, Mitrou PS, Merkle K, Herold M, Assmann M, Wilhelm G, Dachselt K, Richter P, Schirmer V, Schulze A, Subert R, Harksel B, Grobe N, Stelzer E, Schulze M, Bittrich A, Freund M, Pasold R, Friedrich T, Helbig W, Niederwieser D; East German Study Group of Hematology and Oncology (OSHO). Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone--a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO). J Cancer Res Clin Oncol. 2006 Apr;132(4):205-12. Epub 2006 Jan 10. link to original article contains verified protocol PubMed
  11. IFM 99-06: Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, Doyen C, Kolb B, Anglaret B, Grosbois B, Yakoub-Agha I, Mathiot C, Avet-Loiseau H; Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007 Oct 6;370(9594):1209-18. link to original article contains protocol PubMed content property of HemOnc.org
  12. VISTA: San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17. link to original article contains verified protocol PubMed
    1. Update: Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010 May 1;28(13):2259-66. Epub 2010 Apr 5. link to original article contains protocol PubMed
    2. Update: San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van de Velde H, Richardson PG. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-55. Epub 2012 Dec 10. link to original article PubMed
  13. IFM 01/01: Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C, Dib M, Guillerm G, Salles B, Eschard JP, Lenain P, Casassus P, Azaïs I, Decaux O, Garderet L, Mathiot C, Fontan J, Lafon I, Virion JM, Moreau P. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009 Aug 1;27(22):3664-70. Epub 2009 May 18. link to original article contains verified protocol PubMed
  14. NMSG12: Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, Carlson K, Dahl IM, Forsberg K, Gulbrandsen N, Haukås E, Hjertner O, Hjorth M, Karlsson T, Knudsen LM, Nielsen JL, Linder O, Mellqvist UH, Nesthus I, Rolke J, Strandberg M, Sørbø JH, Wisløff F, Juliusson G, Turesson I; Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010 Sep 2;116(9):1405-12. Epub 2010 May 6. link to original article contains verified protocol PubMed
  15. HOVON 49: Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010 Jul 1;28(19):3160-6. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
  16. MRC Myeloma IX: Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. link to original article link to PMC article PubMed
    1. Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article contains verified protocol link to PMC article PubMed
    2. Update: Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article contains verified protocol PubMed
    3. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. link to original article contains verified protocol link to PMC article PubMed
    4. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed
  17. TMSG-2005-001: Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N, Sucak G, Kaygusuz I, Karakus S, Kaya E, Ali R, Gulbas Z, Ozet G, Goker H, Undar L. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011 Jan;86(1):16-22. Epub 2010 Nov 22. link to original article contains protocol PubMed
  18. Meta-analysis: Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksaç M, Bringhen S, Mary JY, Gimsing P, Termorshuizen F, Haznedar R, Caravita T, Moreau P, Turesson I, Musto P, Benboubker L, Schaafsma M, Sonneveld P, Facon T; Nordic Myeloma Study Group; Italian Multiple Myeloma Network; Turkish Myeloma Study Group; Hemato-Oncologie voor Volwassenen Nederland; Intergroupe Francophone du Myélome; European Myeloma Network. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011 Aug 4;118(5):1239-47. Epub 2011 Jun 13. link to original article PubMed
  19. MM-015: Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. link to original article contains verified protocol PubMed

RD

back to top

RD: Revlimid (Lenalidomide) & high-dose Dexamethasone

Regimen

Study Evidence Comparator Comparative Efficacy
Rajkumar et al. 2009 (ECOG E4A03) Phase III (C) Rd Inferior OS

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

Chemotherapy

Supportive medications

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

28-day cycle for 4 cycles (see below)

Subsequent treatment

References

  1. ECOG E4A03: Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010 Jan;11(1):29-37. Epub 2009 Oct 21. Erratum in: Lancet Oncol. 2010 Jan;11(1):14. link to original article contains verified protocol link to PMC article PubMed
    1. Subgroup analysis: Jacobus SJ, Kumar S, Uno H, Van Wier SA, Ahmann GJ, Henderson KJ, Callander NS, Williams ME, Siegel DS, Greipp PR, Rajkumar SV, Fonseca R. Impact of high-risk classification by FISH: an eastern cooperative oncology group (ECOG) study E4A03. Br J Haematol. 2011 Nov;155(3):340-8. Epub 2011 Sep 9. link to original article link to PMC article PubMed

VAD

back to top

VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone
VAd: Vincristine, Adriamycin (Doxorubicin), low-dose dexamethasone

Variant #1, 0.4/9/40 x 3 (bolus doxorubicin & vincristine, dex 12 days/cycle)

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

This regimen was intended for patients 18 to 65 years of age with newly diagnosed MM, Durie-Salmon stage II to III, WHO performance status 0 to 2, or WHO 3 when caused by MM. Observed efficacy is for induction PAD, then transplant, then maintenance bortezomib compared with induction VAD, then transplant, then maintenance thalidomide. Stem cells collected 4 to 6 weeks after induction therapy.

Chemotherapy

Supportive medications

  • One of the following bisphosphonates recommended:
  • "Prophylactic antibiotics" (no further specifics) during induction therapy
  • Erythropoietin and pain medications at physician discretion
  • One of the following for Herpes zoster prophylaxis throughout bortezomib induction:
    • Acyclovir (Zovirax) 800 mg PO per day (did not specify whether taken once per day or as a divided twice per day dose)
    • Valacyclovir (Valtrex) 1000 mg PO per day (did not specify whether taken once per day or as a divided twice per day dose)

28-day cycle for 3 cycles

Subsequent treatment

Variant #2, 0.4/9/40 x 4 (CI doxorubicin, bolus vincristine, dex 12 days/cycle in cycles 1 & 2)

Study Evidence Comparator Comparative Efficacy
Harousseau et al. 2010 (IFM 2005-01) Phase III (C) VD Might have inferior PFS

This regimen was intended for patients age less than or equal to 65 years with untreated symptomatic MM with measurable paraprotein in serum (greater than 1.0 g/dL) or urine (greater than 0.2 g/24 h).

Chemotherapy

  • Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg)
  • Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
    • Cycle 3 onwards: 40 mg PO once per day on days 1 to 4

Supportive medications

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

28-day cycle for 4 cycles

Subsequent treatment

Variant #3, 0.4/9/40 (CI doxorubicin & vincristine, dex 4 days/cycle)

Study Evidence Comparator Comparative Efficacy
Cook et al. 2004 (WOS MM1) Phase III (C) Z-Dex Might have superior ORR
Rifkin et al. 2006 Phase III (C) DVd Non-inferior ORR
Attal et al. 2006 (IFM 99-02) Non-randomized portion of RCT

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

Chemotherapy

28-day cycles

Subsequent treatment

Variant #4, 0.4/9/40 (CI doxorubicin & vincristine, dex 8 days/cycle)

Study Evidence Comparator Comparative Efficacy
Friedenberg et al. 2006 (ECOG E1A95) Phase III (C) VAD & Valspodar Might have superior OS

Chemotherapy

28-day cycles

Variant #5, 0.4/9/40 (bolus doxorubicin & vincristine, dex 12 days/cycle in cycles 1-3)

Study Evidence Comparator Comparative Efficacy
Dimopoulos et al. 2003 Phase III (C) VAD doxil Seems not superior

This regimen was intended for all patients with previously untreated multiple myeloma who were considered candidates for systemic treatment.

Chemotherapy

Supportive medications

28-day cycle for 4 cycles

Variant #6, 0.4/9/40 (CI doxorubicin & vincristine, dex 12 days/cycle)

Study Evidence
Barlogie et al. 2006 (SWOG S9321) Non-randomized portion of RCT

Chemotherapy

Supportive medications

35-day cycles (see below)

Subsequent treatment

Variant #7, 0.4/9/40 (Bolus doxorubicin, CI vincristine, dex 12 days per odd cycle)

Study Evidence
Segeren et al. 1999 Phase II

Chemotherapy

Supportive medications

28-day cycles

Variant #8, 0.4/9/40 (CI doxorubicin & vincristine, dex 4 days per odd cycle)

Study Evidence
Samson et al. 1989 Non-randomized
Cavo et al. 2007 (Bologna 96) Non-randomized portion of RCT

Note: In Samson et al. 1989, the odd cycles were 21 days in length. In Bologna 96, this regimen was intended for patients with a confirmed diagnosis of symptomatic or progressive MM, an upper age limit of 60 years, and previously untreated.

Chemotherapy

  • Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg)
  • Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 & 3: 40 mg PO once per day on days 1 to 4
    • Cycles 2 & 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20

28-day cycle for 4 cycles (Bologna 96) or indefinitely (Samson et al. 1989)

Subsequent treatment

Variant #9, 2/50/40

Study Evidence
Corso et al. 2004 Phase II

Chemotherapy

Two cycles; time intervals were not specified.

Subsequent treatment

References

  1. Samson D, Gaminara E, Newland A, Van de Pette J, Kearney J, McCarthy D, Joyner M, Aston L, Mitchell T, Hamon M, Barrett AJ, Evans M. Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma. Lancet. 1989 Oct 14;2(8668):882-5. link to original article contains verified protocol PubMed
  2. Segeren CM, Sonneveld P, van der Holt B, Baars JW, Biesma DH, Cornellissen JJ, Croockewit AJ, Dekker AW, Fibbe WE, Löwenberg B, van Marwijk Kooy M, van Oers MH, Richel DJ, Schouten HC, Vellenga E, Verhoef GE, Wijermans PW, Wittebol S, Lokhorst HM. Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol. 1999 Apr;105(1):127-30. link to original article contains verified protocol PubMed
  3. Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A, Katodritou I, Kokkini G, Terpos E, Vyniou N, Tzilianos M, Chatzivassili A, Kyrtsonis MC, Panayiotidis P, Maniatis A; Greek Myeloma Study Group. Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol. 2003 Jul;14(7):1039-44. link to original article contains protocol PubMed
  4. Corso A, Barbarano L, Zappasodi P, Cairoli R, Alessandrino EP, Mangiacavalli S, Ferrari D, Fava S, Fiumanò M, Frigerio G, Isa L, Luraschi A, Klersy C, De Paoli A, Vergani C, Banfi L, Perego D, Ucci G, Pinotti G, Savarè M, Uziel L, Vismara A, Morra E, Lazzarino M. The VAD-DCEP sequence is an effective pre-transplant therapy in untreated multiple myeloma. Haematologica. 2004 Sep;89(9):1124-7. link to original article contains verified protocol PubMed
  5. WOS MM1: Cook G, Clark RE, Morris TC, Robertson M, Lucie NP, Anderson S, Paul J, Franklin IM. A randomized study (WOS MM1) comparing the oral regime Z-Dex (idarubicin and dexamethasone) with vincristine, adriamycin and dexamethasone as induction therapy for newly diagnosed patients with multiple myeloma. Br J Haematol. 2004 Sep;126(6):792-8. link to original article PubMed
  6. Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006 May 1;107(9):3474-80. Epub 2006 Jan 5. link to original article PubMed
    1. Update: Moreau P, Garban F, Attal M, Michallet M, Marit G, Hulin C, Benboubker L, Doyen C, Mohty M, Yakoub-Agha I, Leyvraz S, Casassus P, Avet-Loiseau H, Garderet L, Mathiot C, Harousseau JL; IFM Group. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Nov 1;112(9):3914-5. link to original article PubMed
    2. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
  7. ECOG E1A95: Friedenberg WR, Rue M, Blood EA, Dalton WS, Shustik C, Larson RA, Sonneveld P, Greipp PR. Phase III study of PSC-833 (valspodar) in combination with vincristine, doxorubicin, and dexamethasone (valspodar/VAD) versus VAD alone in patients with recurring or refractory multiple myeloma (E1A95): a trial of the Eastern Cooperative Oncology Group. Cancer. 2006 Feb 15;106(4):830-8. link to original article contains verified protocol PubMed
  8. Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a phase III multicenter randomized trial. Cancer. 2006 Feb 15;106(4):848-58. link to original article contains verified protocol PubMed
  9. IFM 99-02: Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. link to original article contains verified protocol PubMed
    1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
  10. Bologna 96: Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. link to original article contains verified protocol PubMed
    1. Sub-group analysis: Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D, de Vivo A, Testoni N, Nicci C, Terragna C, Grafone T, Perrone G, Ceccolini M, Tura S, Baccarani M; Bologna 2002 study. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005 Jul 1;106(1):35-9. Epub 2005 Mar 10. link to original article contains protocol PubMed
  11. SWOG S9321: Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, McCoy J, Moore DF Jr, Dakhil SR, Lanier KS, Chapman RA, Cromer JN, Salmon SE, Durie B, Crowley JC. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006 Feb 20;24(6):929-36. Epub 2006 Jan 23. Erratum in: J Clin Oncol. 2006 Jun 10;24(17):2687. Moore, Dennis F Jr [added]. link to original article refers to protocol in Barlogie et al. 1984 PubMed
    1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
  12. HOVON-50: Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article contains verified protocol PubMed
    1. Update: van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. link to original article PubMed
  13. IFM 2005-01: Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010 Oct 20;28(30):4621-9. Epub 2010 Sep 7. link to original article contains protocol PubMed
  14. HOVON-65/GMMG-HD4: Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. link to original article PubMed
    2. Update: Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. link to original article PubMed

VAMP

back to top

VAMP: Vincristine, Adriamycin (Doxorubicin), MethylPrednisolone

Regimen

Study Evidence Comparator Comparative Efficacy
Gore et al. 1989 Phase II
Raje et al. 1997 Non-randomized
Fermand et al. 1998 Phase III (E) VMCP Seems to have superior EFS
Fermand et al. 2005 Phase III (E) VMCP Might have superior EFS

Note: this is to be distinguished from the VAMP protocols used in AML and Hodgkin lymphoma.

Chemotherapy

Subsequent treatment

  • Raje et al. 1997: HDT with autograft (details not specified in abstract)
  • Fermand et al. 1998: Lomustine, melphalan, TBI with auto HSCT
  • Fermand et al. 2005: MEL200 with auto HSCT or melphalan & busulfan with auto HSCT

References

  1. Gore ME, Selby PJ, Viner C, Clark PI, Meldrum M, Millar B, Bell J, Maitland JA, Milan S, Judson IR, Tillyer C, Malpas JS, McElwain TJ. Intensive treatment of multiple myeloma and criteria for complete remission. Lancet. 1989 Oct 14;2(8668):879-82. link to original article PubMed
  2. Raje N, Powles R, Kulkarni S, Milan S, Middleton G, Singhal S, Mehta J, Millar B, Viner C, Raymond J, Treleaven J, Cunningham D, Gore M. A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma. Br J Haematol. 1997 Apr;97(1):153-60. link to original article PubMed
  3. Fermand JP, Ravaud P, Chevret S, Divine M, Leblond V, Belanger C, Macro M, Pertuiset E, Dreyfus F, Mariette X, Boccacio C, Brouet JC. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998 Nov 1;92(9):3131-6. link to original article PubMed
  4. Fermand JP, Katsahian S, Divine M, Leblond V, Dreyfus F, Macro M, Arnulf B, Royer B, Mariette X, Pertuiset E, Belanger C, Janvier M, Chevret S, Brouet JC, Ravaud P; Group Myelome-Autogreffe. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005 Dec 20;23(36):9227-33. Epub 2005 Nov 7. link to original article PubMed

VBMC

back to top

VBMC: Vincristine, BiCNU (Carmustine), Melphalan, Cyclophosphamide

Regimen

Study Evidence Comparator Comparative Efficacy
Child et al. 2003 (MRC Myeloma VII) Phase III (C) Melphalan & Methylprednisolone, then auto HSCT Seems to have inferior OS

Chemotherapy

Subsequent treatment

References

  1. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. link to original article PubMed

VBMCP

back to top

VBMCP: Vincristine, BiCNU (Carmustine), Melphalan, Cyclophosphamide, Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy
Oken et al. 1997 (ECOG E2479) Phase III (E) MP Superior ORR
Oken et al. 1999 (ECOG E9486) Phase III (C) VBMCP/HiCy Seems not superior
VBMCP/IFN Seems to have inferior TTP
Barlogie et al. 2006 (SWOG S9321) Phase III (C) Melphalan & TBI, then auto HSCT Seems not superior
Kyle et al. 2009 (ECOG E5A93) Phase III (C) VBMCP/HiCy & IFN Seems not superior

Chemotherapy

References

  1. ECOG E2479: Oken MM, Harrington DP, Abramson N, Kyle RA, Knospe W, Glick JH. Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer. 1997 Apr 15;79(8):1561-7. link to original article PubMed
  2. ECOG E9486: Oken MM, Leong T, Lenhard RE Jr, Greipp PR, Kay NE, Van Ness B, Keimowitz RM, Kyle RA. The addition of interferon or high dose cyclophosphamide to standard chemotherapy in the treatment of patients with multiple myeloma: phase III Eastern Cooperative Oncology Group Clinical Trial EST 9486. Cancer. 1999 Sep 15;86(6):957-68. link to original article PubMed
  3. SWOG S9321: Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, McCoy J, Moore DF Jr, Dakhil SR, Lanier KS, Chapman RA, Cromer JN, Salmon SE, Durie B, Crowley JC. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006 Feb 20;24(6):929-36. Epub 2006 Jan 23. Erratum in: J Clin Oncol. 2006 Jun 10;24(17):2687. Moore, Dennis F Jr [added]. link to original article PubMed
    1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
  4. ECOG E5A93: Kyle RA, Jacobus S, Friedenberg WR, Slabber CF, Rajkumar SV, Greipp PR. The treatment of multiple myeloma using vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alternating with high-dose cyclophosphamide and alpha(2)beta interferon versus VBMCP: results of a phase III Eastern Cooperative Oncology Group Study E5A93. Cancer. 2009 May 15;115(10):2155-64. link to original article link to PMC article PubMed

VBMCP/VBAD

back to top

VBMCP/VBAD: Vincristine, BiCNU (Carmustine), Melphalan, Cyclophosphamide, Prednisone alternating with Vincristine, BiCNU (Carmustine), Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study Evidence
Bladé et al. 2005 Non-randomized portion of RCT
Rosiñol et al. 2008 (PETHEMA MM 2000) Non-randomized portion of RCT

Chemotherapy, VBMCP portion

Chemotherapy, VBAD portion

Subsequent treatment

  • Bladé et al. 2005, with response after 4 cycles: VBMCP/VBAD x 8 (12 cycles total) versus HDT with MEL200 with auto HSCT or MEL140 & TBI with auto HSCT
  • PETHEMA MM 2000: Bu/Mel with tandem auto HSCT versus Bu/Mel with auto HSCT, then RIC allo HSCT

References

  1. Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, García-Laraña J, Mateos MV, Palomera L, Fernández-Calvo J, Martí JM, Giraldo P, Carbonell F, Callís M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA). High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005 Dec 1;106(12):3755-9. Epub 2005 Aug 16. link to original article PubMed
  2. PETHEMA MM 2000: Rosiñol L, Pérez-Simón JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ, González JD, Díaz-Mediavilla J, Hernández B, García-Frade J, Carrera D, León A, Hernández M, Abellán PF, Bergua JM, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas y Grupo Español de Mieloma (PETHEMA/GEM). A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood. 2008 Nov 1;112(9):3591-3. Epub 2008 Jul 8. link to original article does not contain protocol PubMed

VCP

back to top

VCP: Vincristine, Cyclophosphamide, Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy
Durie et al. 1986 (SWOG S7927/S7928) Phase III (C) VMCP/VBAP Seems to have inferior OS

Chemotherapy

References

  1. SWOG S7927/S7928: Durie BG, Dixon DO, Carter S, Stephens R, Rivkin S, Bonnet J, Salmon SE, Dabich L, Files JC, Costanzi JJ. Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol. 1986 Aug;4(8):1227-37. link to original article PubMed

VMCP

back to top

VMCP: Vincristine, Melphalan, Cyclophosphamide, Prednisone
VCMP: Vincristine, Cyclophosphamide, Melphalan, Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy
Alexanian et al. 1977 (SWOG S7305) Phase III (E) Alkylator-prednisone combinations Superior OS
Fermand et al. 2005 Phase III (C) VAMP, then auto HSCT Might have inferior EFS

Chemotherapy

1-month cycles

References

  1. SWOG S7305: Alexanian R, Salmon S, Bonnet J, Gehan E, Haut A, Weick J. Combination therapy for multiple myeloma. Cancer. 1977 Dec;40(6):2765-71. link to original article PubMed
  2. Fermand JP, Katsahian S, Divine M, Leblond V, Dreyfus F, Macro M, Arnulf B, Royer B, Mariette X, Pertuiset E, Belanger C, Janvier M, Chevret S, Brouet JC, Ravaud P; Group Myelome-Autogreffe. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005 Dec 20;23(36):9227-33. Epub 2005 Nov 7. link to original articlecontains verified protocol PubMed

VMCP/VBAP

back to top

VMCP/VBAP: Vincristine, Melphalan, Cyclophosphamide, Prednisone alternating with Vincristine, BiCNU (Carmustine), Adriamycin (Doxorubicin), Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy
Durie et al. 1986 (SWOG S7927/S7928) Phase III (E) VCP Seems to have superior OS
Salmon et al. 1990 (SWOG S8229/S8230) Non-randomized portion of RCT
Attal et al. 1996 (IFM90) Phase III (E) VMCP/VBAP alone Seems to have superior OS

Chemotherapy, VMCP portion

21-day cycle for 2 to 3 cycles, given in an alternating fashion with VBAP

Chemotherapy, VBAP portion

21-day cycle for 2 to 3 cycles, given in an alternating fashion with VMCP

VMCP and VBAP are given in an alternating fashion x a total of 4 to 6 cycles

Subsequent treatment

References

  1. SWOG S7927/S7928: Durie BG, Dixon DO, Carter S, Stephens R, Rivkin S, Bonnet J, Salmon SE, Dabich L, Files JC, Costanzi JJ. Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol. 1986 Aug;4(8):1227-37. link to original article PubMed
  2. SWOG S8229/S8230: Salmon SE, Tesh D, Crowley J, Saeed S, Finley P, Milder MS, Hutchins LF, Coltman CA Jr, Bonnet JD, Cheson B, Knost JA, Samhouri A, Beckord J, Stock-Novack D. Chemotherapy is superior to sequential hemibody irradiation for remission consolidation in multiple myeloma: a Southwest Oncology Group study. J Clin Oncol. 1990 Sep;8(9):1575-84. link to original article PubMed
  3. IFM90: Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R; Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996 Jul 11;335(2):91-7. link to original article contains verified protocol PubMed

VMCP/VCAP

back to top

VMCP/VCAP: Vincristine, Melphalan, Cyclophosphamide, Prednisone alternating with Vincristine, Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy
Salmon et al. 1983 (SWOG S7704) Phase III (E) MP Superior OS

Chemotherapy, VMCP portion

Chemotherapy, VCAP portion

References

  1. SWOG S7704: Salmon SE, Haut A, Bonnet JD, Amare M, Weick JK, Durie BG, Dixon DO. Alternating combination chemotherapy and levamisole improves survival in multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol. 1983 Aug;1(8):453-61. link to original article PubMed

Consolidation after first-line therapy

Melphalan monotherapy

back to top

Regimen

Study Evidence
McElwain & Powles 1983 Pilot Study
Segeren et al. 2003 (HOVON 24) Non-randomized portion of RCT

Note that this is highly obsolete but included for historical interest. Stem cell rescue was NOT used.

Preceding treatment

  • HOVON 24: VAD x 3 to 4

Chemotherapy

Subsequent treatment

References

  1. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983 Oct 8;2(8354):822-4. link to original article PubMed
  2. HOVON 24: Segeren CM, Sonneveld P, van der Holt B, Vellenga E, Croockewit AJ, Verhoef GE, Cornelissen JJ, Schaafsma MR, van Oers MH, Wijermans PW, Fibbe WE, Wittebol S, Schouten HC, van Marwijk Kooy M, Biesma DH, Baars JW, Slater R, Steijaert MM, Buijt I, Lokhorst HM; Dutch-Belgian Hemato-Oncology Cooperative Study Group. Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood. 2003 Mar 15;101(6):2144-51. Epub 2002 Nov 27. link to original article PubMed
    1. Update: Sonneveld P, van der Holt B, Segeren CM, Vellenga E, Croockewit AJ, Verhoe GE, Cornelissen JJ, Schaafsma MR, van Oers MH, Wijermans PW, Westveer PH, Lokhorst HM; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term follow-up of the Dutch Cooperative Group HOVON 24 trial. Haematologica. 2007 Jul;92(7):928-35. link to original article PubMed

Melphalan, then auto HSCT, then Melphalan & Busulfan, then auto HSCT

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Cavo et al. 2007 (Bologna 96) Phase III (E) Melphalan, then auto HSCT Superior EFS

Chemotherapy, first transplant

Stem cells re-infused on day 0

Chemotherapy, second transplant

Stem cells re-infused on day 0

References

  1. Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. link to original article contains verified protocol PubMed

MEL200, then auto HSCT, then MEL220 & Dexamethasone, then auto HSCT

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Moreau et al. 2005 (IFM 99-04) Phase III (C) MEL200, then MEL220 + Dex + B-E8 Seems not superior

This regimen was meant for patients who did not have an HLA-identical sibling donor.

Preceding treatment

Chemotherapy, first transplant

Stem cells re-infused on day 0

Chemotherapy, second transplant

Stem cells re-infused on day 0

No further treatment.

References

  1. Moreau P, Hullin C, Garban F, Yakoub-Agha I, Benboubker L, Attal M, Marit G, Fuzibet JG, Doyen C, Voillat L, Berthou C, Ketterer N, Casassus P, Monconduit M, Michallet M, Najman A, Sotto JJ, Bataille R, Harousseau JL; Intergroupe Francophone du Myélome group. Tandem autologous stem cell transplantation in high-risk de novo multiple myeloma: final results of the prospective and randomized IFM 99-04 protocol. Blood. 2006 Jan 1;107(1):397-403. Epub 2005 Sep 13. link to original article contains verified protocol PubMed
    1. Update: Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006 May 1;107(9):3474-80. Epub 2006 Jan 5. link to original article contains verified protocol PubMed
    2. Update: Moreau P, Garban F, Attal M, Michallet M, Marit G, Hulin C, Benboubker L, Doyen C, Mohty M, Yakoub-Agha I, Leyvraz S, Casassus P, Avet-Loiseau H, Garderet L, Mathiot C, Harousseau JL; IFM Group. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Nov 1;112(9):3914-5. link to original article PubMed
    3. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed

Melphalan, then auto HSCT, then Melphalan & TBI, then auto HSCT

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Barlogie et al. 1997 (Total Therapy 1) Non-randomized
Attal et al. 2003 (IFM94) Phase III (E) MEL140-TBI & auto HSCT Superior OS

In Total Therapy, this regimen was intended for patients not achieving at least PR after the first transplant.

Preceding treatment

  • IFM 94: VAD x 3 to 4

Chemotherapy, first transplant

Stem cells re-infused on day 0

Chemoradiotherapy, second transplant

  • Melphalan (Alkeran) 140 mg/m2 IV once on day -4
  • Total body irradiation (TBI) as follows:
    • Total Therapy: dose of 850 to 1020 cGy in 5 to 6 fractions delivered on days -3 to -1
    • IFM94: 2 Gy fractions once per day x 4 = total dose of 8 Gy, without lung shielding

Stem cells re-infused on day 0

Subsequent treatment

References

  1. Total Therapy 1: Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93. link to original article PubMed
    1. Update: Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. link to original article contains verified protocol PubMed
    2. Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
  2. IFM94: Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M, Hulin C, Caillot D, Bouabdallah R, Voillat L, Sotto JJ, Grosbois B, Bataille R; InterGroupe Francophone du Myélome. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003 Dec 25;349(26):2495-502. Erratum in: N Engl J Med. 2004 Jun17;350(25):2628. link to original article contains verified protocol PubMed
    1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed

Melphalan, then auto HSCT, then RIC allo HSCT

back to top

Variant #1, Bu/Flu/ATG RIC-allo

Study Evidence
Garban et al. 2006 (IFM99-03) Non-randomized

This regimen was meant for patients who had an HLA-identical sibling donor, and is here for historical interest.

Preceding treatment

Chemotherapy, first transplant

Stem cells re-infused on day 0, followed in two months by:

Chemotherapy, second transplant

Chemotherapy

Immunosuppressive therapy

GVHD prophylaxis

  • Cyclosporine A (type not specified) with starting dose on day -1 of 3 mg/kg/day, doses adjusted to "serum levels", tapered on day +60 to off by day +100 (if no GVHD)
  • Methotrexate (MTX) 10 mg/m2 (route not specified) once per day on days +1, +3, +6


Variant #2, TBI RIC-allo

Study Evidence
Bruno et al. 2007 Non-randomized

This regimen was meant for patients who had an HLA-identical sibling donor, and is here for historical interest.

Preceding treatment

Chemotherapy, first transplant

Stem cells re-infused on day 0, followed by:

Radiotherapy, second transplant

References

  1. IFM99-03: Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006 May 1;107(9):3474-80. Epub 2006 Jan 5. link to original article contains verified protocol PubMed
    1. Update: Moreau P, Garban F, Attal M, Michallet M, Marit G, Hulin C, Benboubker L, Doyen C, Mohty M, Yakoub-Agha I, Leyvraz S, Casassus P, Avet-Loiseau H, Garderet L, Mathiot C, Harousseau JL; IFM Group. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Nov 1;112(9):3914-5. link to original article PubMed
    2. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
  2. Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, Giaccone L, Sorasio R, Omedè P, Baldi I, Bringhen S, Massaia M, Aglietta M, Levis A, Gallamini A, Fanin R, Palumbo A, Storb R, Ciccone G, Boccadoro M. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007 Mar 15;356(11):1110-20. link to original article contains partial protocol PubMed

Melphalan & Methylprednisolone, then auto HSCT

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Child et al. 2003 (MRC Myeloma VII) Phase III (E) VBMC Seems to have superior OS

Preceding treatment

Chemotherapy

Subsequent treatment

References

  1. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. link to original article PubMed

Melphalan & TBI, then auto HSCT

back to top

Variant #1, MEL140 & TBI 8 Gy

Study Evidence Comparator Comparative Efficacy
Attal et al. 1996 (IFM90) Phase III (E) VMCP/VBAP x 18 Seems to have superior OS
Moreau et al. 2002 (IFM 9502) Phase III (C) High-dose melphalan & autologous transplant Might have inferior OS
Attal et al. 2003 (IFM94) Phase III (C) Melphalan, then auto HSCT, then Melphalan & TBI, then auto HSCT Inferior OS
Barlogie et al. 2006 (SWOG S9321) Phase III (E) VBMCP To be completed

Preceding treatment

  • IFM90: VMCP alternating with VBAP for 4 to 6 cycles
  • IFM 9502 and SWOG S9321: VAD x 3
  • IFM 94: VAD x 3 to 4

Chemoradiotherapy

  • Melphalan (Alkeran) 140 mg/m2 IV (day not specified)
  • Total-body irradiation in 2 Gy fractions once per day x 4 = total dose of 8 Gy, without lung shielding

One course; relative date of stem cell re-infusion not specified

Subsequent treatment

Variant #2, MEL140 & TBI 12 Gy

Study Evidence Comparator Comparative Efficacy
Bladé et al. 2005 Phase III (E) 1. MEL200 with auto HSCT
2. VBMCP/VBAD
Seems not superior

Note: it is not clear from the manuscript what the primary endpoint was. While this regimen had inferior CR, there was no difference in PFS or OS.

Preceding treatment

Chemoradiotherapy

  • Melphalan (Alkeran) 140 mg/m2 IV once on day -2
  • Total-body irradiation in 3 Gy fractions once per day on days -6 to -3 = total dose of 12 Gy

Re-infusion of stem cells on day 0

Subsequent treatment

References

  1. IFM90: Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R; Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996 Jul 11;335(2):91-7. link to original article contains verified protocol PubMed
    1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
  2. IFM 9502: Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, Doyen C, Jaubert J, Fuzibet JG, François S, Benboubker L, Monconduit M, Voillat L, Macro M, Berthou C, Dorvaux V, Pignon B, Rio B, Matthes T, Casassus P, Caillot D, Najman N, Grosbois B, Bataille R, Harousseau JL; Intergroupe Francophone du Myélome. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood. 2002 Feb 1;99(3):731-5. link to original article PubMed
  3. IFM94: Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M, Hulin C, Caillot D, Bouabdallah R, Voillat L, Sotto JJ, Grosbois B, Bataille R; InterGroupe Francophone du Myélome. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003 Dec 25;349(26):2495-502. Erratum in: N Engl J Med. 2004 Jun17;350(25):2628. link to original article PubMed
    1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
  4. Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, García-Laraña J, Mateos MV, Palomera L, Fernández-Calvo J, Martí JM, Giraldo P, Carbonell F, Callís M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA). High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005 Dec 1;106(12):3755-9. Epub 2005 Aug 16. link to original article contains verified protocol PubMed
  5. SWOG S9321: Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, McCoy J, Moore DF Jr, Dakhil SR, Lanier KS, Chapman RA, Cromer JN, Salmon SE, Durie B, Crowley JC. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006 Feb 20;24(6):929-36. Epub 2006 Jan 23. Erratum in: J Clin Oncol. 2006 Jun 10;24(17):2687. Moore, Dennis F Jr [added]. link to original article refers to protocol in Barlogie et al. 1984 PubMed
    1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed

Maintenance after first-line therapy

Dexamethasone monotherapy

back to top

Variant #1, 1 year

Study Evidence Comparator Comparative Efficacy
Maiolino et al. 2012 Phase III (C) Thal-Dex Inferior PFS

Preceding treatment

Chemotherapy

28-day cycle for 12 months or until disease progression

Variant #2, indefinite

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

Preceding treatment

  • TD versus VTD consolidation

Chemotherapy

Supportive medications

28-day cycles until progression, relapse, or undue toxicity

References

  1. GIMEMA MM-BO2005: Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. link to original article contains protocol PubMed
    1. Update: Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. link to original article contains verified protocol PubMed
  2. Maiolino A, Hungria VT, Garnica M, Oliveira-Duarte G, Oliveira LC, Mercante DR, Miranda EC, Quero AA, Peres AL, Barros JC, Tanaka P, Magalhães RP, Rego EM, Lorand-Metze I, Lima CS, Renault IZ, Braggio E, Chiattone C, Nucci M, de Souza CA; Brazilian Multiple Myeloma Study Group (BMMSG/GEMOH). Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012 Oct;87(10):948-52. Epub 2012 Jun 23. link to original article contains verified protocol PubMed

Interferon alfa monotherapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Mandelli et al. 1990 Phase III (E) Observation Might have superior OS
Browman et al. 1995 Phase III (E) Observation Seems to have superior OS
Child et al. 2003 (MRC Myeloma VII) Non-randomized portion of RCT
Schaar et al. 2005 (HOVON-16) Phase III (E) Observation Superior PFS
Lokhorst et al. 2009 (HOVON-50) Phase III (C) See link See link
Ludwig et al. 2010 Phase III (C) Interferon alfa & Thalidomide Inferior PFS
Rosiñol et al. 2012 (GEM05/MENOS65) Phase III (C) 1. Thalidomide Not reported
2. VT Seems to have inferior PFS (*)

Note: Reported efficacy for GEM05/MENOS65 is based on the 2017 update.

Preceding treatment

Immunotherapy

References

  1. Mandelli F, Avvisati G, Amadori S, Boccadoro M, Gernone A, Lauta VM, Marmont F, Petrucci MT, Tribalto M, Vegna ML, Dammacco F, Pileri A. Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med. 1990 May 17;322(20):1430-4. link to original article PubMed
  2. Browman GP, Bergsagel D, Sicheri D, O'Reilly S, Wilson KS, Rubin S, Belch A, Shustik C, Barr R, Walker I, James K, Zee B, Johnston D. Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1995 Sep;13(9):2354-60. link to original article PubMed
  3. IFM90: Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R; Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996 Jul 11;335(2):91-7. link to original article PubMed
    1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
  4. Meta-analysis: Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol. 2000 Nov;11(11):1427-36. link to original article PubMed
  5. MRC Myeloma VII: Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. link to original article PubMed
  6. HOVON-16: Schaar CG, Kluin-Nelemans HC, Te Marvelde C, le Cessie S, Breed WP, Fibbe WE, van Deijk WA, Fickers MM, Roozendaal KJ, Wijermans PW; Dutch-Belgian Hemato-Oncology Cooperative Group HOVON. Interferon-alpha as maintenance therapy in patients with multiple myeloma. Ann Oncol. 2005 Apr;16(4):634-9. Epub 2005 Mar 1. link to original article PubMed
  7. HOVON-50: Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article contains verified protocol PubMed
    1. Update: van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. link to original article PubMed
  8. Ludwig H, Adam Z, Tóthová E, Hajek R, Labar B, Egyed M, Spicka I, Gisslinger H, Drach J, Kuhn I, Hinke A, Zojer N. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica. 2010 Sep;95(9):1548-54. Epub 2010 Apr 23. link to original article PubMed
  9. GEM05/MENOS65: Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. link to original article contains verified protocol PubMed
    1. Update: Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. link to original article contains verified protocol PubMed

Interferon alfa & Dexamethasone

back to top

Regimen

Study Evidence
Bladé et al. 2005 Non-randomized portion of RCT

Preceding treatment

Chemoimmunotherapy

References

  1. Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, García-Laraña J, Mateos MV, Palomera L, Fernández-Calvo J, Martí JM, Giraldo P, Carbonell F, Callís M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA). High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005 Dec 1;106(12):3755-9. Epub 2005 Aug 16. link to original article PubMed

Interferon alfa & Prednisone

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Salmon et al. 1998 (SWOG 9028) Phase III (E) Interferon alfa Superior PFS

Chemoimmunotherapy

References

  1. SWOG 9028: Salmon SE, Crowley JJ, Balcerzak SP, Roach RW, Taylor SA, Rivkin SE, Samlowski W. Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol. 1998 Mar;16(3):890-6. link to original article PubMed

Interferon alfa & Thalidomide

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Ludwig et al. 2010 Phase III (E) Interferon alfa Superior PFS

Chemoimmunotherapy

References

  1. Ludwig H, Adam Z, Tóthová E, Hajek R, Labar B, Egyed M, Spicka I, Gisslinger H, Drach J, Kuhn I, Hinke A, Zojer N. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica. 2010 Sep;95(9):1548-54. Epub 2010 Apr 23. link to original article PubMed

Observation

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Alexanian et al. 1975 Phase III (C) 1. MP
2. Carmustine & Prednisone
Seems not superior
Belch et al. 1988 Phase III (C) MP Inferior FFS
Salmon et al. 1994 (SWOG S8624) Phase III (C) IFN alfa Seems not superior
Attal et al. 2006 (IFM 99-02) Phase III (C) Thalidomide Inferior OS
Morgan et al. 2010 (MRC Myeloma IX) Phase III (C) Thalidomide Inferior PFS
Stewart et al. 2013 (NCIC CTG Myeloma 10) Phase III (C) Thalidomide & Prednisone Inferior PFS
Mellqvist et al. 2013 (NMSG 15/05) Phase III (C) Bortezomib Might have inferior PFS
Palumbo et al. 2014 (MPRvsMEL200) Phase III (C) Lenalidomide Inferior PFS

No further treatment; used as a comparator arm.

Preceding treatment

References

  1. Alexanian R, Balcerzak SP, Haut A, Hewlett J, Gehan E. Remission maintenance therapy for multiple myeloma. Arch Intern Med. 1975 Jan;135(1):147-52. link to original article PubMed
  2. Belch A, Shelley W, Bergsagel D, Wilson K, Klimo P, White D, Willan A. A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer. 1988 Jan;57(1):94-9. link to original article PubMed
  3. SWOG S8624: Salmon SE, Crowley JJ, Grogan TM, Finley P, Pugh RP, Barlogie B. Combination chemotherapy, glucocorticoids, and interferon alfa in the treatment of multiple myeloma: a Southwest Oncology Group study. J Clin Oncol. 1994 Nov;12(11):2405-14. link to original article PubMed
  4. IFM 99-02: Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. link to original article PubMed
    1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
  5. MRC Myeloma IX: Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. link to original article link to PMC article PubMed
    1. Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article contains verified protocol link to PMC article PubMed
    2. Update: Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article contains verified protocol PubMed
    3. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. link to original article contains verified protocol link to PMC article PubMed
    4. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed
  6. BMT CTN 0102: Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG; Blood Marrow Transplant Clinical Trials Network (BMT CTN). Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203. Epub 2011 Sep 29. link to PMC article PubMed
  7. NCIC CTG Myeloma 10: Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, Reiman T, Roy J, Shustik C, Kovacs MJ, Rubinger M, Cantin G, Song K, Tompkins KA, Marcellus DC, Lacy MQ, Sussman J, Reece D, Brundage M, Harnett EL, Shepherd L, Chapman JA, Meyer RM. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013 Feb 28;121(9):1517-23. Epub 2013 Jan 7. link to original article link to PMC article PubMed
  8. NMSG 15/05: Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, Steingrimsdottir H, Abildgaard N, Ahlberg L, Blimark C, Dahl IM, Forsberg K, Gedde-Dahl T, Gregersen H, Gruber A, Guldbrandsen N, Haukås E, Carlson K, Kvam AK, Nahi H, Lindås R, Andersen NF, Turesson I, Waage A, Westin J; Nordic Myeloma Study Group. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013 Jun 6;121(23):4647-54. Epub 2013 Apr 24. link to original article link to PMC article PubMed
  9. MPRvsMEL200: Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article PubMed

Placebo

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Attal et al. 2012 (IFM 2005-02) Phase III (C) Lenalidomide Inferior PFS
Palumbo et al. 2012 (MM-015) Phase III (E) Lenalidomide Inferior PFS
McCarthy et al. 2012 (CALGB 100104) Phase III (C) Lenalidomide Seems to have inferior OS
Dimopoulos et al. 2018 (TOURMALINE-MM3) Phase III (C) Ixazomib Inferior PFS

No active antineoplastic treatment.

References

  1. IFM 2005-02: Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, Stoppa AM, Hulin C, Benboubker L, Garderet L, Decaux O, Leyvraz S, Vekemans MC, Voillat L, Michallet M, Pegourie B, Dumontet C, Roussel M, Leleu X, Mathiot C, Payen C, Avet-Loiseau H, Harousseau JL; IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1782-91. link to original article PubMed
    1. Update: Abstract: Michel Attal, MD, Valerie Cances Lauwers, Gerald Marit, Denis Caillot, Thierry Facon, MD, Cyrille Hulin, Philippe Moreau, MD, Claire Mathiot, Murielle Roussel, Catherine Payen, H. Avet-Loiseau and Jean Luc Harousseau. Maintenance Treatment with Lenalidomide After Transplantation for MYELOMA : Final Analysis of the IFM 2005-02. ASH 2010 Abstract 310. link to abstract
  2. MM-015: Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. link to original article contains verified protocol PubMed
  3. CALGB 100104: McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Seiler M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1770-81. link to original article link to supplementary appendix link to PMC article PubMed
    1. Update: Holstein SA, Jung SH, Richardson PG, Hofmeister CC, Hurd DD, Hassoun H, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, van Besien K, Gentile TG, Isola L, Maziarz RT, Bashey A, Landau H, Martin T, Qazilbash MH, Rodriguez C, McClune B, Schlossman RL, Smith SE, Hars V, Owzar K, Jiang C, Boyd M, Schultz C, Wilson M, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Linker C, Anderson KC, McCarthy PL. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol. 2017 Sep;4(9):e431-e442. Epub 2017 Aug 17. link to original article PubMed
  4. TOURMALINE-MM3: Dimopoulos MA, Gay F, Schjesvold F, Beksac M, Hajek R, Weisel KC, Goldschmidt H, Maisnar V, Moreau P, Min CK, Pluta A, Chng WJ, Kaiser M, Zweegman S, Mateos MV, Spencer A, Iida S, Morgan G, Suryanarayan K, Teng Z, Skacel T, Palumbo A, Dash AB, Gupta N, Labotka R, Rajkumar SV; TOURMALINE-MM3 study group. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2018 Dec 10. [Epub ahead of print] link to original article contains protocol PubMed

Prednisolone monotherapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Spencer et al. 2009 (ALLG MM6) Phase III (C) Thalidomide & Prednisolone Inferior OS

Preceding treatment

Chemotherapy

Continued indefinitely

References

  1. ALLG MM6: Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009 Apr 10;27(11):1788-93. Epub 2009 Mar 9. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Ho PJ, Brown RD, Spencer A, Jeffels M, Daniher D, Gibson J, Joshua DE. Thalidomide consolidation improves progression-free survival in myeloma with normal but not up-regulated expression of fibroblast growth factor receptor 3: analysis from the Australasian Leukaemia and Lymphoma Group MM6 clinical trial. Leuk Lymphoma. 2012 Sep;53(9):1728-34. Epub 2012 Mar 13. link to original article PubMed

Prednisone monotherapy

back to top

Variant #1, high-dose

Study Evidence Comparator Comparative Efficacy
Berenson et al. 2002 (SWOG 9210) Phase III (E) Low-dose prednisone Seems to have superior OS

Preceding treatment

Chemotherapy

Continued indefinitely

Variant #2, low-dose

Study Evidence Comparator Comparative Efficacy
Berenson et al. 2002 (SWOG 9210) Phase III (E) Low-dose prednisone Seems to have inferior OS

Preceding treatment

Chemotherapy

Continued indefinitely

References

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

Relapsed or refractory

Carmustine & Doxorubicin

back to top

Regimen

Study Evidence
Alberts et al. 1976 Non-randomized, <20 pts

Chemotherapy

References

  1. Alberts DS, Durie BG, Salmon SE. Doxorubicin/BCNU chemotherapy for multiple myeloma in relapse. Lancet. 1976 May 1;1(7966):926-8. link to original article PubMed

Dexamethasone monotherapy

back to top

Variant #1

Study Evidence Comparator Comparative Efficacy
Chanan-Khan et al. 2009 Phase III (C) Oblimersen & Dexamethasone Seems not superior
San Miguel et al. 2013 (MM-003) Phase III (C) PD Inferior OS (*)

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

Chemotherapy

28-day cycles

Variant #2

Study Evidence Comparator Comparative Efficacy
Weber et al. 2007 (MM-009) Phase III (C) RD Seems to have inferior OS (*)
Dimopoulos et al. 2007 (MM-010) Phase III (C) RD Seems to have inferior OS
Kropff et al. 2011 (OPTIMUM) Phase III (C) 1. Thalidomide 100 mg/d
2. Thalidomide 200 mg/d
3. Thalidomide 400 mg/d
Seems not superior

Note: efficacy of MM-009 is based on the 2009 pooled update.

Chemotherapy

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

28-day cycles for up to 12 cycles (OPTIMUM) or indefinitely

Variant #3, limited duration

Study Evidence Comparator Comparative Efficacy
Richardson et al. 2005 (APEX) Phase III (C) Bortezomib Seems to have inferior OS (*)

Note: efficacy reported is based on the 2007 update.

Chemotherapy

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

35-day cycle for 4 cycles, then 28-day cycle for 4 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. 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, Miguel JS, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007 Nov 15;110(10):3557-60. Epub 2007 Aug 9. link to original article 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. Chanan-Khan AA, Niesvizky R, Hohl RJ, Zimmerman TM, Christiansen NP, Schiller GJ, Callander N, Lister J, Oken M, Jagannath S. Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma. 2009 Apr;50(4):559-65. link to original article PubMed
  5. OPTIMUM: Kropff M, Baylon HG, Hillengass J, Robak T, Hajek R, Liebisch P, Goranov S, Hulin C, Bladé J, Caravita T, Avet-Loiseau H, Moehler TM, Pattou C, Lucy L, Kueenburg E, Glasmacher A, Zerbib R, Facon T. Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial. Haematologica. 2012 May;97(5):784-91. Epub 2011 Dec 1. link to original article link to PMC article contains verified protocol PubMed
  6. MM-003: San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-66. Epub 2013 Sep 3. link to original article contains verified protocol PubMed
    1. Update: Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Spencer A, Knop S, Bahlis NJ, Renner C, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel JF. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015 Oct;100(10):1327-33. Epub 2015 Aug 6. link to original article link to PMC article PubMed

EDAP

back to top

EDAP: Etoposide, Dexamethasone, Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study Evidence
Barlogie et al. 1989 Non-randomized

Chemotherapy

References

  1. Barlogie B, Velasquez WS, Alexanian R, Cabanillas F. Etoposide, dexamethasone, cytarabine, and cisplatin in vincristine, doxorubicin, and dexamethasone-refractory myeloma. J Clin Oncol. 1989 Oct;7(10):1514-7. link to original article PubMed

Placebo

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Holland et al. 1966 Randomized (C) Urethane Seems not superior

No active antineoplastic treatment.

References

  1. Holland JR, Hosley H, Scharlau C, Carbone PP, Frei E 3rd, Brindley CO, Hall TC, Shnider BI, Gold GL, Lasagna L, Owens AH Jr, Miller SP. A controlled trial of urethane treatment in multiple myeloma. Blood. 1966 Mar;27(3):328-42. link to original article PubMed

Pomalidomide, Dexamethasone, Pembrolizumab

back to top

Regimen

Study Evidence Efficacy
Badros et al. 2017 Phase II ORR: 60%

This is of historical interest only, at this time. While the phase II had a high degree of efficacy (thus meeting our inclusion criteria), subsequent phase III trials were halted by the FDA for excess deaths in this arm; see "Note added in proof" in the paper for more details.

Chemoimmunotherapy

References

  1. Badros A, Hyjek E, Ma N, Lesokhin A, Dogan A, Rapoport AP, Kocoglu M, Lederer E, Philip S, Milliron T, Dell C, Goloubeva O, Singh Z. Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1189-1197. Epub 2017 May 1. link to original article PubMed

Tisagenlecleucel monotherapy

back to top

Regimen

Study Evidence
Garfall et al. 2015 Pilot

Note: this regimen is of historic interest in this context. It is not FDA approved for this indication.

Immunotherapy

References

  1. Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, Zheng Z, Vogl DT, Cohen AD, Weiss BM, Dengel K, Kerr ND, Bagg A, Levine BL, June CH, Stadtmauer EA. Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma. N Engl J Med. 2015 Sep 10;373(11):1040-7. link to original article link to PMC article PubMed

VAD

back to top

VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone
VAd: Vincristine, Adriamycin (Doxorubicin), low-dose dexamethasone

Regimen

Study Evidence Comparator Comparative Efficacy
Barlogie et al. 1984 Phase II
Dalton et al. 1995 (SWOG S8900) Phase III (C) VAD/v Seems not superior

Chemotherapy

Supportive medications

35-day cycles (see below)

Subsequent treatment

  • Treatment was given "until a maximum reduction in myeloma protein had occurred" and patients received four additional cycles of therapy beyond their best response

References

  1. Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med. 1984 May 24;310(21):1353-6. link to original article contains verified protocol PubMed
  2. SWOG S8900: Dalton WS, Crowley JJ, Salmon SS, Grogan TM, Laufman LR, Weiss GR, Bonnet JD. A phase III randomized study of oral verapamil as a chemosensitizer to reverse drug resistance in patients with refractory myeloma: a Southwest Oncology Group study. Cancer. 1995 Feb 1;75(3):815-20. link to original article PubMed

VAD & Cyclosporine

back to top

VAD & Cyclosporine: Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Cyclosporine

Regimen

Study Evidence Comparator Comparative Efficacy
Sonneveld et al. 1992 Non-randomized
Sonneveld et al. 2001 (EORTC 06914) Phase II/III (E) VAD Seems not superior

Chemotherapy

References

  1. Sonneveld P, Durie BG, Lokhorst HM, Marie JP, Solbu G, Suciu S, Zittoun R, Löwenberg B, Nooter K; The Leukaemia Group of the EORTC and the HOVON. Modulation of multidrug-resistant multiple myeloma by cyclosporin. Lancet. 1992 Aug 1;340(8814):255-9. link to original article PubMed
  2. EORTC 06914: Sonneveld P, Suciu S, Weijermans P, Beksac M, Neuwirtova R, Solbu G, Lokhorst H, van der Lelie J, Dohner H, Gerhartz H, Segeren CM, Willemze R, Lowenberg B; European Organization for Research and Treatment of Cancer (EORTC); Leukaemia Cooperative Group (LCG); Dutch Haemato-Oncology Cooperative Study Group (HOVON). Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol. 2001 Dec;115(4):895-902. link to original article PubMed