Difference between revisions of "Multiple myeloma"

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===References===
 
===References===
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# de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Sep 11. [Epub ahead of print] [http://onlinelibrary.wiley.com/doi/10.1111/bjh.13653/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/26358087 PubMed]
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# de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. [http://onlinelibrary.wiley.com/doi/10.1111/bjh.13653/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/26358087 PubMed]
  
 
==Car-Pom-d {{#subobject:bfa533|Regimen=1}}==
 
==Car-Pom-d {{#subobject:bfa533|Regimen=1}}==

Revision as of 19:51, 11 April 2016

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Untreated (including transplant ineligible), randomized data

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

CPR

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CPR: Cyclophosphamide, Prednisone, Revlimid (Lenalidomide)

Regimen

Study Evidence Comparator
Magarotto et al. 2016 (EMN01) Phase III MPR
Rd

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

Supportive medications:

28-day cycle x 9 cycles

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

References

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

CTD

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

Regimen #1, CTD

Study Evidence Comparator
Morgan et al. 2011 (MRC Myeloma IX) Phase III CVAD

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

Supportive medications:

21-day cycle x up to 6 cycles until maximum response

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

Regimen #2, CTDa

Study Evidence Comparator
Morgan et al. 2011 (MRC Myeloma IX) Phase III MP

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

Supportive medications:

28-day cycle x 6 to 9 cycles

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

References

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

CVAD

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

Regimen

Study Evidence Comparator
Morgan et al. 2011 (MRC Myeloma IX) Phase III CTD

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

Supportive medications:

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

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

References

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

Dexamethasone (Decadron)

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Regimen #1

Study Evidence Comparator Efficacy
Rajkumar et al. 2008 Phase III TD Inferior TTP

This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h.

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

28-day cycles

Regimen #2

Study Evidence Comparator Efficacy Toxicity
Rajkumar et al. 2005 Phase III TD Seems to have inferior RR Superior toxicity

This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h.

  • 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

Regimen #3

Study Evidence Comparator Efficacy
Facon et al. 2005 (IFM 95-01) Phase III DEX-IFN Seems not superior
MP
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.

  • 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

6-week cycle x 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
  2. 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
  3. 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 PubMed
  4. Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood. 2010 Dec 23;116(26):5838-41. Epub 2010 Sep 27. link to original article PubMed

DEX-IFN

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DEXamethasone, InterFeroN alfa-2b

Regimen

Study Evidence Comparator Efficacy
Facon et al. 2005 (IFM 95-01) Phase III Dexamethasone Seems not superior
MP
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.

  • 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 million units SC 3 times per week; start with dexamethasone and stop on on day 42 of the last cycle of dexamethasone

6-week cycle x 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

DVD, VAD doxil

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

Regimen #1, "DVd"

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

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

4-week cycles, given until maximal response, progression of disease, or unacceptable toxicity

Regimen #2

Study Evidence Comparator
Dimopoulos et al. 2003 Phase III VAD
Zervas et al. 2007 Phase III TVAD-Doxil

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

Supportive medications (which were in the cited Segeren et al. 1999 VAD protocol reference):

4-week cycle x 4 cycles

References

  1. 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
  2. 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
  3. Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol. 2007 Aug;18(8):1369-75. link to original article contains verified protocol PubMed

M-DEX

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M-DEX: Melphalan, DEXamethasone

Regimen

Study Evidence Comparator Efficacy
Facon et al. 2005 (IFM 95-01) Phase III Dexamethasone
DEX-IFN
 Superior PFS
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.

  • 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

6-week cycle x 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 verified protocol PubMed

MP

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MP: Melphalan, Prednisone/rednisolone

Regimen #1

Study Evidence Comparator Efficacy
Palumbo et al. 2012 (MM-015) Phase III MPR
MPR-R 		Inferior PFS

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

Supportive medications:

  • Aspirin 75 to 100 mg PO once per day as thromboprophylaxis

28-day cycle x 9 cycles

Regimen #2

Study Evidence Comparator
Morgan et al. 2011 (MRC Myeloma IX) Phase III CTDa

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

Supportive medications:

28-day cycle x 6 to 9 cycles

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

Regimen #3

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

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

Supportive medications:

28-day cycle x 8 cycles

Regimen #4

Study Evidence Comparator
Hulin et al. 2009 (IFM 01/01) Phase III MPT

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.

6-week cycle x 12 cycles

Regimen #5

Study Evidence Comparator Efficacy
San Miguel et al. 2008 (VISTA) Phase III VMP Inferior OS

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

6-week cycle x 9 cycles

Regimen #6

Study Evidence Comparator Efficacy
Facon et al. 2005 (IFM 95-01) Phase III Dexamethasone
DEX-IFN
 Superior PFS
M-DEX Seems not superior
Facon et al. 2007 (IFM 99-06) Phase III MPT Inferior OS
VAD -> 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.

6-week cycle x 12 cycles

Regimen #7

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

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

28-day cycle x 6 cycles

Regimen #8

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.

6-week cycles

References

  1. 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 PubMed
  2. Kyle RA. Monoclonal gammopathy and multiple myeloma in the elderly. Baillieres Clin Haematol. 1987 Jun;1(2):533-57. PubMed
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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 PubMed
  10. 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
  11. 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 PubMed
  12. 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 PMC article contains verified protocol PubMed
    1. 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 PubMed
    2. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-Term Follow-Up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed
  13. 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
  14. 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

MPR

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MPR: Melphalan, Prednisone, Revlimid (Lenalidomide)
MPR-R: Melphalan, Prednisone, Revlimid (Lenalidomide) followed by Revlimid (Lenalidomide) maintenance
MPL: Melphalan, Prednisone, Lenalidomide

Regimen #1

Study Evidence Comparator
Magarotto et al. 2016 (EMN01) Phase III CPR
Rd

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

Supportive medications:

28-day cycle x 9 cycles

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

Regimen #2, "MPR-R"

Study Evidence Comparator Efficacy
Palumbo et al. 2007 Phase II
Palumbo et al. 2012 (MM-015) Phase III MP
MPR 		Superior PFS
Zweegman et al. 2016 (HOVON87/NMSG18) Phase III MPT-T

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

Supportive medications (varies depending on reference):

28-day cycle x 9 cycles

Followed by lenalidomide maintenance.

Regimen #3, "mPR-R"

Study Evidence Comparator
Stewart et al. 2015 (ECOG E1A06) Phase III MPT-T

This regimen was intended for patients who were ≥65 years or were <65 years and were not candidates for autologous stem cell transplantation or had declined transplant.

Supportive medications:

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

28-day cycle x 12 cycles

Followed by lenalidomide maintenance.

Regimen #4

Study Evidence Comparator Efficacy
Palumbo et al. 2012 (MM-015) Phase III MP Seems to have superior PFS
MPR-R Inferior PFS

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

Supportive medications:

  • Aspirin 75 to 100 mg PO once per day as thromboprophylaxis

28-day cycle x 9 cycles

References

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

MPT

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MPT: Melphalan, Prednisone, Thalidomide

Regimen #1, "MPT-T"

Study Evidence Comparator
Zweegman et al. 2016 (HOVON87/NMSG18) Phase III MPR-R

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

Supportive medications:

28-day cycle x 9 cycles

Treatment followed by thalidomide maintenance.

Regimen #2, "MPT-T"

Study Evidence Comparator
Stewart et al. 2015 (ECOG E1A06) Phase III mPR-R

This regimen was intended for patients who were ≥65 years or were <65 years and were not candidates for autologous stem cell transplantation or had declined transplant.

Supportive medications:

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

28-day cycle x 12 cycles

Treatment followed by thalidomide maintenance.

Regimen #3

Study Evidence Comparator Efficacy
Benboubker et al. 2014 (FIRST) Phase III LD
LD18 		Seems to have inferior OS

This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were ≥65 years of age or were <65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose.

  • Melphalan (Alkeran) starting dose as follows:
    • Age ≤75 AND ANC ≥1500 AND Platelets ≥100,000: 0.25 mg/kg PO once per day on days 1 to 4
    • Age >75 AND ANC ≥1500 AND Platelets ≥100,000: 0.2 mg/kg PO once per day on days 1 to 4
    • Age ≤75 AND ANC <1500 but ≥1000 OR Platelets <100,000 but ≥50,000: 0.125 mg/kg PO once per day on days 1 to 4
    • Age >75 AND ANC <1500 but ≥1000 OR Platelets <100,000 but ≥50,000: 0.1 mg/kg PO once per day on days 1 to 4
  • Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
  • Thalidomide (Thalomid) starting dose as follows:
    • Age ≤75: 200 mg PO once per day
    • Age >75: 100 mg PO once per day

42-day cycle x 12 cycles

Regimen #4, "MP-T"

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

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

Supportive medications:

28-day cycle x 8 cycles

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

Regimen #5

Study Evidence Comparator
Hulin et al. 2009 (IFM 01/01) Phase III MP

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.

42-day cycle x 12 cycles

Regimen #6

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

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

42-day cycle x 12 cycles

Regimen #7

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

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

Supportive medications:

28-day cycle x 6 cycles

Patients then proceeded to maintenance thalidomide.

References

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

PAD

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

Regimen #1, "PAd"

Study Evidence Comparator
Mai et al. 2015 (MM5) Phase III VCD

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

Supportive medications:

28-day cycle x 3 cycles

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

Regimen #2

Study Evidence Comparator Efficacy
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4) Phase III VAD Seems to have superior OS

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 -> transplant -> maintenance bortezomib compared with induction VAD -> transplant -> maintenance thalidomide.

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

  • One of the following bisphosphonates recommended:
  • "Prophylactic antibiotics" (no further specifics) during induction therapy
  • Erythropoietin and pain medications at physician discretion
  • One of the following for Herpes zoster prophylaxis throughout bortezomib induction:
    • Acyclovir (Zovirax) 800 mg 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 x 3 cycles

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

References

  1. 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
  2. Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article contains verified protocol PubMed

RD, RevDex, Rd, Len-Dex

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RD: Revlimid (Lenalidomide), Dexamethasone
RevDex: Revlimid (Lenalidomide), Dexamethasone
Rd: Revlimid (Lenalidomide), low dose dexamethasone
Len-Dex: Lenalidomide, Dexamethasone

Regimen #1, "Rd"

Study Evidence Comparator
Magarotto et al. 2016 (EMN01) Phase III CPR
MPR

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

Supportive medications:

28-day cycle x 9 cycles

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

Regimen #2, "LD"

Study Evidence Comparator Efficacy
Benboubker et al. 2014 (FIRST) Phase III LD18
MPT 		Seems to have superior OS

This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were ≥65 years of age or were <65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. This was superior to LD18, below. See supplemental appendix for dose adjustments from the starting dose.

  • Lenalidomide (Revlimid) starting dose as follows:
    • Normal renal function: 25 mg PO once per day on days 1 to 21
    • Moderate renal impairment (CrCl 30-50 ml/min): 10 mg PO once per day on days 1 to 21
    • Severe renal impairment (CrCl <30 ml/min): 15 mg PO once every other day on days 1 to 21
  • Dexamethasone (Decadron) starting dose as follows:
    • Age ≤75: 40 mg PO once per day on days 1, 8, 15, 22
    • Age >75: 20 mg PO once per day on days 1, 8, 15, 22

28-day cycle given until disease progression

Regimen #3, "LD18"

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

This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were ≥65 years of age or were <65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. This was inferior to LD, above. See supplemental appendix for dose adjustments from the starting dose.

  • Lenalidomide (Revlimid) starting dose as follows:
    • Normal renal function: 25 mg PO once per day on days 1 to 21
    • Moderate renal impairment (CrCl 30-50 ml/min): 10 mg PO once per day on days 1 to 21
    • Severe renal impairment (CrCl <30 ml/min): 15 mg PO once every other day on days 1 to 21
  • Dexamethasone (Decadron) starting dose as follows:
    • Age ≤75: 40 mg PO once per day on days 1, 8, 15, 22
    • Age >75: 20 mg PO once per day on days 1, 8, 15, 22

28-day cycle x 18 cycles

Regimen #4, "Rd"

Study Evidence Comparator
Rajkumar et al. 2010 (ECOG E4A03) Phase III RD
Gay et al. 2010 Retrospective
Gay et al. 2015 Non-randomized

In ECOG E4A03 this is the low-dose dexamethasone arm, and was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h. Gay et al. 2015 was intended for transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger.

Supportive medications (as described in Rajkumar et al. 2010):

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

28-day cycle x 4 cycles (see below)

Responding patients in ECOG E4A03 could choose after 4 cycles to proceed to high-dose melphalan with autologous stem cell transplant or to continue Rd until progression of disease or intolerable toxicity; nonresponders were transitioned to Thal-Dex (details not described). Patients in Gay et al. 2015 were randomized after 4 cycles to tandem high-dose melphalan with autologous stem cell transplant versus CRD consolidation.

Regimen #5, "RD"

Study Evidence Comparator
Rajkumar et al. 2010 (ECOG E4A03) Phase III Rd

This is the high-dose dexamethasone arm, and was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h.

Supportive medications:

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

28-day cycle x 4 cycles (see below)

Responding patients could choose after 4 cycles to proceed to high-dose melphalan with autologous stem cell transplant or to continue RD until progression of disease or intolerable toxicity; nonresponders were transitioned to Thal-Dex (details not described).

References

  1. 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. link to PMC article contains verified protocol PubMed
  2. Retrospective: Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. link to original article contains verified protocol PubMed
  3. 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 PubMed
  4. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. link to original article link to supplemental appendix contains verified protocol PubMed
  5. Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article contains protocol PubMed
  6. Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed

RVD, VDR, VRD

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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone

Regimen

Study Evidence Comparator
Kumar et al. 2012 (EVOLUTION) Randomized Phase II VDC
VDC-mod
VDCR

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

21-day cycle x 8 cycles

Treatment followed by bortezomib consolidation.

References

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

RVDC, VDCR

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

Regimen

Study Evidence Comparator
Kumar et al. 2012 (EVOLUTION) Randomized Phase II, >20 in this arm VDC
VDC-mod
VDR

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

Supportive medications:

21-day cycle x 8 cycles

Treatment followed by bortezomib consolidation.

References

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

TAD

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TAD: Thalidomide, Adriamycin (Doxorubicin), Dexamethasone

Regimen

To be completed

References

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

TD

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TD: Thalidomide, Dexamethasone

Regimen #1

Study Evidence Comparator
Rosiñol et al. 2012 (PETHEMA GEM05MENOS65) Phase III VTD
VBMCP/VBAD/B

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

Supportive medications:

28-day cycle x 6 cycles

Regimen #2

Study Evidence Comparator
Cavo et al. 2010 (GIMEMA MM-BO2005) Phase III VTD

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

Induction therapy

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

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

First stem cell transplant

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

Thalidomide & dexamethasone therapy

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

Second stem cell transplant

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

Thalidomide & dexamethasone consolidation

35-day cycle x 2 cycles

Treatment followed by dexamethasone maintenance.

Supportive medications:

Regimen #3

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

This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h.

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

28-day cycles

Regimen #4

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

In Rajkumar et al. 2006 his regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h.

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

28-day cycles

Regimen #5

Study Evidence
Cavo et al. 2004 (Bologna 2002) Phase II
  • Thalidomide (Thalomid) as follows:
    • Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to end of month
    • Cycles 2 to 4: 200 mg PO once per day on days 1 to end of month
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
    • Cycles 2 & 4: 40 mg PO once per day on days 1 to 4

Monthly cycle x 4 cycles

Responders proceeded to autologous stem cell transplant.

References

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

VAD

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VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone
VAd: Vincristine, Adriamycin (Doxorubicin), low-dose dexamethasone
Note: VAD is given as a bolus or a continuous infusion regimen; see variants for details.

Regimen #1

Study Evidence Comparator Efficacy
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4) Phase III PAD Seems to have inferior OS

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 -> transplant -> maintenance bortezomib compared with induction VAD -> transplant -> maintenance thalidomide.

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

  • One of the following bisphosphonates recommended:
  • "Prophylactic antibiotics" (no further specifics) during induction therapy
  • Erythropoietin and pain medications at physician discretion
  • One of the following for Herpes zoster prophylaxis throughout bortezomib induction:
    • Acyclovir (Zovirax) 800 mg 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 x 3 cycles

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

Regimen #2

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

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

  • Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1.6 mg)
  • Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 36 mg/m2)
  • 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:

28-day cycle x 4 cycles

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

Regimen #3, "VAd"

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

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

28-day cycles

Regimen #4, VAD bolus

Study Evidence Comparator
Dimopoulos et al. 2003 Phase III VAD Doxil

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

Supportive medications (which were in the cited Segeren et al. 1999 reference):

4-week cycle x 4 cycles

References

  1. 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
  2. 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
  3. 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
  4. 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

VAD-P

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

Regimen

Study Evidence Comparator
Berenson et al. 2002 (SWOG 9210) Phase III VAD-P/Q
  • Vincristine (Oncovin) 0.4 mg/day (total dose per cycle: 1.6 mg) IV continuous infusion over 4 days on days 1 to 4
  • Doxorubicin (Adriamycin) 9 mg/m2/day (total dose per cycle: 36 mg/m2) IV continuous infusion over 4 days on days 1 to 4
    • Poor-risk patients received 6.75 mg/m2/day (total dose 27 mg/m2) in cycle 1, with increase to full dose starting cycle 2 if no undue toxicity
  • Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
  • Prednisone (Sterapred) 50 mg PO once per day on days 9, 11, 13, 15, 17, 19

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

Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were then started on prednisone maintenance therapy.

References

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

VAD-P/Q

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

Regimen

Study Evidence Comparator
Berenson et al. 2002 (SWOG 9210) Phase III VAD-P
  • Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 4 days on days 2 to 5 (total dose per cycle: 1.6 mg)
  • Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 4 days on days 2 to 5 (total dose per cycle: 36 mg/m2)
    • Poor-risk patients received 6.75 mg/m2/day (total dose 27 mg/m2) in cycle 1, with increase to full dose starting cycle 2 if no undue toxicity
  • Dexamethasone (Decadron) 40 mg PO once per day on days 2 to 5
  • Prednisone (Sterapred) 50 mg PO once per day on days 10, 12, 14, 16, 18, 20
  • Quinine (Qualaquin) 400 mg PO TID on days 1 to 6

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

Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were then started on prednisone maintenance.

References

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

VD

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VD: Velcade (Bortezomib), Dexamethasone

Regimen #1

Study Evidence Comparator
Niesvizky et al. 2015 (UPFRONT) Phase III VMP
VTD

This regimen was meant for transplant ineligible patients.

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

21-day cycle x 8 cycles

Treatment followed by bortezomib maintenance.

Regimen #2

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

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

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

21-day cycle x 4 cycles

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

Regimen #3

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

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

Supportive medications:

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

21-day cycle x 4 cycles

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

References

  1. Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010 Oct 20;28(30):4621-9. Epub 2010 Sep 7. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, Marit G, Benboubker L, Voillat L, Mathiot C, Kolb B, Macro M, Campion L, Wetterwald M, Stoppa AM, Hulin C, Facon T, Attal M, Minvielle S, Harousseau JL. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010 Oct 20;28(30):4630-4. Epub 2010 Jul 19. link to original article PubMed
  2. Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. link to original article contains verified protocol PubMed
  3. Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed

VDC, VDC-mod

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

Regimen #1, "VCD"

Study Evidence Comparator
Mai et al. 2015 (MM5) Phase III PAd

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

Supportive medications:

21-day cycle x 3 cycles

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

Regimen #2, "VDC"

Study Evidence Comparator
Kumar et al. 2012 (EVOLUTION) Randomized Phase II VDC-mod
VDR
VDCR

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

Supportive medications:

21-day cycle x 8 cycles

Treatment followed by bortezomib consolidation.

Regimen #3, "VDC-mod"

Study Evidence Comparator
Kumar et al. 2012 (EVOLUTION) Randomized Phase II, <20 in this arm VDC
VDR
VDCR

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

Supportive medications:

21-day cycle x 8 cycles

Treatment followed by bortezomib consolidation.

References

  1. Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. link to original article contains verified protocol PubMed
  2. Meta-Analysis: Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. link to original article PubMed
  3. Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article contains verified protocol PubMed

VMP

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VMP: Velcade (Bortezomib), Melphalan, Prednisone

Regimen #1

Study Evidence Comparator
Niesvizky et al. 2015 (UPFRONT) Phase III VD
VTD

This regimen was meant for transplant ineligible patients.

21-day cycle x 8 cycles

Treatment followed by bortezomib maintenance.

Regimen #2

Study Evidence Comparator Efficacy
San Miguel et al. 2008 (VISTA) Phase III MP Superior OS
Palumbo et al. 2010 Phase III VMPT-VT Seems to have inferior OS

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

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

Supportive medication:

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

42-day cycle x 9 cycles

Regimen #3

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

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

Supportive medications:

42-day cycle x 1 cycle, then

Supportive medications:

35-day cycle x 5 cycles

Treatment followed by bortezomib & prednisone maintenance versus VT maintenance.

Regimen #4, weekly bortezomib

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

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

35-day cycle x 9 cycles

References

  1. Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Díaz-Mediavilla J, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, de Arriba F, Alegre A, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006 Oct 1;108(7):2165-72. Epub 2006 Jun 13. link to original article PubMed
    1. Update: Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Garcia-Sanchez P, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, Alegre A, de Arriba F, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica. 2008 Apr;93(4):560-5. Epub 2008 Mar 5. link to original article PubMed
  2. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17. link to original article contains protocol PubMed
    1. Update: Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010 May 1;28(13):2259-66. Epub 2010 Apr 5. link to original article contains protocol PubMed
    2. Update: San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van de Velde H, Richardson PG. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-55. Epub 2012 Dec 10. link to original article PubMed
  3. Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. link to original article contains verified protocol PubMed
    1. Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article PubMed
    2. Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. link to original article contains verified protocol PubMed
  4. Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. link to original article contains verified protocol PubMed
    1. Post-hoc analysis: Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. link to original article contains verified protocol PubMed
    2. Subset analysis: Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. link to original article PubMed
    3. Update: Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. link to original article contains verified protocol PubMed
  5. Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed

VMP -> Rd

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

Regimen

Study Evidence Comparator
Mateos et al. 2015 (PETHEMA GEM05) Phase III VMP/Rd

This regimen was intended for patients aged ≥65 years with newly diagnosed, untreated, symptomatic, measurable MM.

VMP

42-day cycle x 1 cycle, then:

28-day cycle x 8 cycles, followed by:

Rd

28-day cycle x 9 cycles

Supportive medications:

References

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

VMP/Rd

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

Regimen

Study Evidence Comparator
Mateos et al. 2015 (PETHEMA GEM05) Phase III VMP -> Rd

This regimen was intended for patients aged ≥65 years with newly diagnosed, untreated, symptomatic, measurable MM.

VMP

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

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

Rd

28-day cycle alternating with VMP x 9 cycles

Supportive medications:

References

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

VMPT

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

Regimen #1

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

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

42-day cycle x 9 cycles

Treatment followed by VT maintenance therapy.

Regimen #2

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

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

35-day cycle x 9 cycles

Treatment followed by VT maintenance therapy.

References

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

VTD

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

Regimen #1

Study Evidence Comparator
Niesvizky et al. 2015 (UPFRONT) Phase III VD
VMP

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

21-day cycle x 8 cycles

Treatment followed by bortezomib maintenance.

Regimen #2

Study Evidence Comparator
Cavo et al. 2010 (GIMEMA MM-BO2005) Phase III TD

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

Induction therapy

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

First stem cell transplant

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

Thalidomide & Dexamethasone therapy

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

Second stem cell transplant

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

Bortezomib, thalidomide, dexamethasone therapy

35-day cycle x 2 cycles

Patients then proceed to dexamethasone maintenance therapy.

Supportive medications:

Regimen #3, "vTD"

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

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

21-day cycle x 4 cycles

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

Regimen #4

Study Evidence Comparator
Ludwig et al. 2013 Randomized Phase II VTDC

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

21-day cycle x 4 cycles

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

Regimen #5

Study Evidence Comparator
Rosiñol et al. 2012 (PETHEMA GEM05MENOS65) Phase III TD
VBMCP/VBAD/B

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

Supportive Medications:

28-day cycle x 6 cycles

References

  1. 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. Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. link to original article contains verified protocol PubMed
  3. Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. link to original article contains verified protocol PubMed
  4. Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Ricci D, Cakana A, Enny C, Feng H, van de Velde H, Harousseau JL. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol. 2013 Jan 10;31(2):247-55. Epub 2012 Oct 22. link to original article contains verified protocol PubMed
    1. Update: Ludwig H, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Chaturvedi S, Ataman O, Enny C, Feng H, van de Velde H, Viterbo L. Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up. Br J Haematol. 2015 Nov;171(3):344-54. Epub 2015 Jul 7. link to original article PubMed
  5. Meta-Analysis: Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. link to original article PubMed
  6. Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed

VTP

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VTP: Velcade (Bortezomib), Thalidomide, Prednisone

Regimen

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

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

Supportive medications:

42-day cycle x 1 cycle, then

Supportive medications:

35-day cycles x 5 cycles

Treatment followed by bortezomib & prednisone maintenance versus VT maintenance.

References

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

Untreated (including transplant ineligible), non-randomized or retrospective data

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

BDD

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BDD: Bortezomib, Doxorubicin, Dexamethasone

Regimen

Study Evidence
Ludwig et al. 2010 Phase II

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

  • Bortezomib (Velcade) 1.0 mg/m2 (route not specified) once per day on days 1, 4, 8, 11
    • Patients without grade 3 or 4 toxicity during the first two cycles could have bortezomib dose increased to 1.3 mg/m2 (route not specified) once per day on days 1, 4, 8, 11
  • Doxorubicin (Adriamycin) 9 mg/m2 IV once per day on days 1 & 4
    • Patients without grade 3 or 4 toxicity during the first two cycles could have number of doxorubicin doses increased to 9 mg/m2 IV once per day on days 1, 4, 8, 11
  • Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1, 4, 8, 11

21-day cycles x up to 8 cycles

References

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

BiRD

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BiRD: Biaxin, Revlimid (Lenalidomide), Dexamethasone

Phase II Retrospective improved PFS Retrospective increased toxicity

Regimen

Study Evidence
Niesvizky et al. 2007 Phase II
  • Clarithromycin (Biaxin) as follows:
    • Cycle 1: 500 mg PO BID on days 2 to 28
    • Cycle 2 onwards: 500 mg PO BID on days 1 to 28
  • Lenalidomide (Revlimid) as follows:
    • Cycle 1: 25 mg PO once per day on days 3 to 21
    • Cycle 2 onwards: 25 mg PO once per day on days 1 to 21
  • Dexamethasone (Decadron) as follows:
    • Cycle 1: 40 mg PO once per day on days 1, 2, 3, 8, 15, 22
    • Cycle 2 onwards: 40 mg PO once per day on days 1, 8, 15, 22

Supportive medications:

28-day cycles

References

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

CAD

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CAD: Cyclophosphamide, Adriamycin (Doxorubicin), Dexamethasone

Regimen

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

To be completed

References

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

CCyd

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CCyd: Carfilzomib, Cyclophosphamide, dexamethasone

Regimen

Study Evidence
Bringhen et al. 2014 Phase II

28-day cycles x 9 cycles

Followed by maintenance carfilzomib.

References

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

CMP

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CMP: Carfilzomib, Melphalan, Prednisone

Regimen

Study Evidence
Moreau et al. 2015 Phase I/II

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

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

42-day cycle x 9 cycles

References

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

CRd

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

Regimen

Study Evidence
Jakubowiak et al. 2012 Phase II

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

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

28-day cycle x 8 cycles

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

References

  1. Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. link to original article contains verified protocol PubMed
  2. Abstract: Korde, Neha; Zingone, Adriana; Kwok, Mary; Manasanch, Elisabet E.; Costello, Rene; Zuchlinski, Diamond; Mulquin, Marcia; Maric, Irina; Calvo, Katherine R; Braylan, Raul C.; Yuan, Constance; Tembhare, Prashant Ramesh; Stetler-Stevenson, Maryalice; Arthur, Diane C; Raffeld, Mark; Xi, Liqiang; Choyke, Peter; Kurdziel, Karen; Lindenberg, Liza; Steinberg, Seth M.; Roschewski, Mark; Landgren, Ola. Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (MM) Patients ASH Annual Meeting Abstracts 2012 120: 732 link to abstract

CyBorD

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CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone

Regimen #1, once per week bortezomib

Study Evidence
Reeder et al. 2010 Phase II

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

28-day cycles x 4 cycles

Regimen #2

Study Evidence
Reeder et al. 2009 Phase II

Supportive medications:

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

28-day cycles x 4 to 12 cycles

References

  1. Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, Noble B, Pirooz NA, Spong JE, Piza JG, Zepeda VH, Mikhael JR, Leis JF, Bergsagel PL, Fonseca R, Stewart AK. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009 Jul;23(7):1337-41. Epub 2009 Feb 19. link to original article contains protocol PubMed
  2. Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K, Hentz J, Pirooz NA, Piza JG, Tiedemann R, Mikhael JR, Bergsagel PL, Leis JF, Fonseca R, Stewart AK. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010 Apr 22;115(16):3416-7. link to original letter contains verified protocol PubMed

CYKLONE

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

Regimen

Study Evidence
Mikhael et al. 2015 Phase II

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

Supportive medications:

28-day cycle x 4 to 12 cycles

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

References

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

DVd

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DVd: Doxil (Liposomal Doxorubicin), Vincristine, reduced-dose dexamethasone

Regimen

Study Evidence
Hussein et al. 2002 Phase II

Supportive medications:

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

4-week cycle x 6 to 8 cycles

References

  1. Hussein MA, Wood L, Hsi E, Srkalovic G, Karam M, Elson P, Bukowski RM. A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients. Cancer. 2002 Nov 15;95(10):2160-8. link to original article contains protocol PubMed

Ixazomib, Lenalidomide, Dexamethasone

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Regimen

Study Evidence
Kumar et al 2014 Phase I/II

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

28-day cycle x up to 12 cycles

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

References

  1. Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A11, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. link to original article PubMed

KTd

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KTd: Kyprolis (Carfilzomib), Thalidomide, dexamethasone

Regimen

Study Evidence
Sonneveld et al. 2014 Phase II

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

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

28-day cycle x 4 cycles

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

References

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

PAD

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PAD: PS-341 (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study Evidence
Oakervee et al. 2005 Phase II

21-day cycle x 4 cycles

References

  1. Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005 Jun;129(6):755-62. link to original article contains protocol PubMed

RD, RevDex, Rd, Len-Dex

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RD: Revlimid (Lenalidomide), Dexamethasone
RevDex: Revlimid (Lenalidomide), Dexamethasone
Rd: Revlimid (Lenalidomide), low dose dexamethasone
Len-Dex: Lenalidomide, Dexamethasone

Regimen

Study Evidence
Rajkumar et al. 2005 Phase II

Supportive medications:

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

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

References

  1. Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005 Dec 15;106(13):4050-3. Epub 2005 Aug 23. link to original article contains protocol PubMed

RP

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RP-MPR-RP: Revlimid (Lenalidomide), Prednisone, followed by Melphalan, Prednisone, Revlimid (Lenalidomide), followed by Revlimid (Lenalidomide), Prednisone

Regimen, "RP-MPR-RP"

Study Evidence
Falco et al. 2012 Phase II

Supportive medications:

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

28-day cycle x 4 cycles

Treatment is followed by MPR consolidation.

References

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

RVD, VDR, VRD

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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone

Regimen #1

Study Evidence
Roussel et al. 2014 Phase II

Supportive medications:

21-day cycle x 3 cycles

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

Regimen #2

Study Evidence
Richardson et al. 2010 Phase II

Supportive medications:

21-day cycle x 4 to 8 cycles

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

References

  1. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12. link to original article contains protocol PubMed
  2. Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed

Total Therapy

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Regimen

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

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

Induction therapy, VTD-PACE

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

  • Bortezomib (Velcade) 1.0 mg/m2 SC once per day on days 1, 4, 8, 11
  • Thalidomide (Thalomid) 200 mg PO once per day on days 4 to 7
  • Dexamethasone (Decadron) 40 mg PO once per day on days 4 to 7
  • Cisplatin (Platinol) 10 mg/m2/day (total dose per cycle: 40 mg/m2) IV continuous infusion over 4 days on days 4 to 7
  • Doxorubicin (Adriamycin) 10 mg/m2/day (total dose per cycle: 40 mg/m2) IV continuous infusion over 4 days on days 4 to 7
  • Cyclophosphamide (Cytoxan) 400 mg/m2/day (total dose per cycle: 1600 mg/m2) IV continuous infusion over 4 days on days 4 to 7
  • Etoposide (Vepesid) 40 mg/m2/day (total dose per cycle: 160 mg/m2) IV continuous infusion over 4 days on days 4 to 7
  • Peripheral blood stem cells (PBSC) are usually collected during cycle 1--cycle 2 PBSC collection is done if needed--with a median CD34 count of 29 x 106/kg. 87% of collections yielded at least 20 x 106/kg.

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

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

21-day cycles, given between induction cycles and transplant

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

Supportive medications, as described in Barlogie et al. 2006, which Barlogie et al. 2007 refers to. Note: Barlogie et al. 2007 lists an incorrect title for the reference. See below for the the correct full reference.

  • Filgrastim (Neupogen) "was administered to support induction and consolidation chemotherapy regimens"
  • "Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed
  • Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide

Autologous stem cell transplant

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

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

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

Consolidation therapy, VTD-PACE

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

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

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

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

21-day cycles, given between consolidation cycles and maintenance

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

Supportive medications, as described in Barlogie et al. 2006, which Barlogie et al. 2007 refers to. Note: Barlogie et al. 2007 lists an incorrect title for the reference. See below for the the correct full reference.

  • Filgrastim (Neupogen) "was administered to support induction and consolidation chemotherapy regimens"
  • "Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed
  • Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide

Maintenance therapy, year 1 - VTD

VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

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

28-day cycles x 1 year, then proceed to maintenance therapy years 2 to 3

Maintenance therapy, years 2 & 3 - TD

TD: Thalidomide, Dexamethasone

28-day cycles x 2 years

References

  1. Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, Fassas A, Zangari M, Hollmig K, Pineda-Roman M, Lee C, Talamo G, Thertulien R, Kiwan E, Krishna S, Fox M, Crowley J. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006 Mar 9;354(10):1021-30. link to original article supportive medication details PubMed
    1. Update: Zangari M, van Rhee F, Anaissie E, Pineda-Roman M, Haessler J, Crowley J, Barlogie B. Eight-year median survival in multiple myeloma after total therapy 2: roles of thalidomide and consolidation chemotherapy in the context of total therapy 1. Br J Haematol. 2008 May;141(4):433-44. Epub 2008 Mar 26. link to original article link to PMC article PubMed
    2. Update: Barlogie B, Pineda-Roman M, van Rhee F, Haessler J, Anaissie E, Hollmig K, Alsayed Y, Waheed S, Petty N, Epstein J, Shaughnessy JD Jr, Tricot G, Zangari M, Zeldis J, Barer S, Crowley J. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008 Oct 15;112(8):3115-21. Epub 2008 May 20. link to original article PubMed
  2. Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007 Jul;138(2):176-85. link to original article contains verified protocol PubMed

VAD

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VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen #1

Study Evidence
Barlogie et al. 1984 Phase II

Supportive medications:

Cycle duration not specified; treatment was given "until a maximum reduction in myeloma protein had occurred." Patients received four additional cycles of therapy beyond their best response.

Regimen #2

Study Evidence
Segeren et al. 1999 Phase II

Supportive medications:

4-week cycles

Regimen #3

Study Evidence
Cavo et al. 2007 (Bologna 96) Non-randomized

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.

  • Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1.6 mg)
  • Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 36 mg/m2)
  • 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 x 4 cycles

Responders were randomized to single autologous stem cell transplant versus tandem autologous stem cell transplant.

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. 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. 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

VAD-DCEP

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VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone
DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol (Cisplatin)

Regimen

Study Evidence
Corso et al. 2004 Phase II

VAD portion

Two cycles; time intervals were not specified.

DCEP portion

Stem cells were mobilized and collected after each course of therapy.

Supportive medications:

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

Two courses; time intervals were not specified.

Followed by high dose melphalan with autologous stem cell transplant.

References

  1. 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

VD

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VD: Velcade (Bortezomib), Dexamethasone

Regimen #2

Study Evidence
Girnius et al. 2014 Phase II

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

References

  1. Girnius SK, Lee S, Kambhampati S, Rose MG, Mohiuddin A, Houranieh A, Zimelman A, Grady T, Mehta P, Behler C, Hayes TG, Efebera YA, Prabhala RH, Han A, Yellapragada SV, Klein CE, Roodman GD, Lichtenstein A, Munshi NC. A Phase II trial of weekly bortezomib and dexamethasone in veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell transplantation. Br J Haematol. 2015 Apr;169(1):36-43. Epub 2015 Jan 8. Epub 2014 Sep 18. link to original article contains verified protocol PubMed

VDD; PAD

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

Regimen #1

Study Evidence
Jakubowiak et al. 2009 Phase II

Supportive medications:

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

21-day cycles x 6 cycles

Regimen #2

Study Evidence
Palumbo et al. 2010 Phase II

Induction therapy

21-day cycles x 4 cycles, then proceed to stem cell mobilization & reinfusion

Stem cell mobilization & reinfusion

Paper did not describe the full details

Consolidation

28-day cycles x 4 cycles, then proceed to maintenance therapy

Maintenance

28-day cycles, given until relapsed disease

Supportive medications:

References

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

VMP

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VMP: Velcade (Bortezomib), Melphalan, Prednisone

Regimen, short-course bortezomib

Study Evidence
Gasparetto et al. 2010 Phase II

Supportive medications:

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

References

  1. Gasparetto C, Gockerman JP, Diehl LF, de Castro CM, Moore JO, Long GD, Horwitz ME, Keogh G, Chute JP, Sullivan KM, Neuwirth R, Davis PH, Sutton LM, Anderson RD, Chao NJ, Rizzieri D. "Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma. Biol Blood Marrow Transplant. 2010 Jan;16(1):70-7. Epub 2009 Sep 3. link to SD article contains verified protocol PubMed

VTD

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VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

Regimen #1, SC Bortezomib

Study Evidence
Lok et al. 2014 Non-randomized

Induction therapy

21-day cycle x 4 cycles, proceed to stem cell transplant:

Stem cell transplant

Proceed with consolidation (timing not specified):

Consolidation

21-day cycle x 2 cycles

Regimen #2

Study Evidence
Kaufman et al. 2010 Retrospective

Supportive medications:

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

21-day cycle x 3 to 4 cycles

References

  1. Retrospective: Kaufman JL, Nooka A, Vrana M, Gleason C, Heffner LT, Lonial S. Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma: a retrospective study. Cancer. 2010 Jul 1;116(13):3143-51. link to original article contains protocol PubMed
  2. Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous Bortezomib incorporated into the Bortezomib-Thalidomide-Dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. link to original article contains verified protocol PubMed

VTD-PACE

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

Regimen

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

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

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

References

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

Consolidation after upfront therapy

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

DCEP

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

Regimen

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

Treatment preceded by VD x 4 verus VAD x 4.

28-day cycle x 2 cycles

All patients then proceeded to receive autologous stem cell transplant.

References

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

KTd

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KTd: Kyprolis (Carfilzomib), Thalidomide, dexamethasone

Regimen

Study Evidence
Sonneveld et al. 2014 Phase II

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

28-day cycle x 4 cycles

References

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

Melphalan (Alkeran)

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Regimen

Study Evidence
McElwain, Powles 1983 Pilot Study

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

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

Melphalan -> autologous stem cell transplant

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Note that this is incomplete and will be filled in over time.

Regimen

Study Evidence Comparator Efficacy
Moreau et al. 2002 (IFM 9502) Phase III Melphalan & TBI -> autologous transplant Might have superior OS
Morgan et al. 2011 (MRC Myeloma IX) Non-randomized
Moreau et al. 2011 (IFM2007-02) Non-randomized
Sonneveld et al. 2012 (HOVON-65) Non-randomized
Roussel et al. 2014 Phase II
Palumbo et al. 2014 (RV-MM-PI-209) Phase III MPR consolidation Seems to have superior OS
Sonneveld et al. 2014 Phase II
Mai et al. 2015 (MM5) Non-randomized

Treatment preceded by varying induction regimens:

Preparative regimen

Stem cells re-infused on day 0

Treatment followed by varying consolidation and/or maintenance regimens:

References

  1. Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, Doyen C, Jaubert J, Fuzibet JG, François S, Benboubker L, Monconduit M, Voillat L, Macro M, Berthou C, Dorvaux V, Pignon B, Rio B, Matthes T, Casassus P, Caillot D, Najman N, Grosbois B, Bataille R, Harousseau JL; Intergroupe Francophone du Myélome. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood. 2002 Feb 1;99(3):731-5. link to original article PubMed
  2. 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
  3. 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
  4. 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 PubMed
  5. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
  6. 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 PMCl article contains verified protocol PubMed
    1. 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
  7. Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. link to original article contains verified protocol PubMed
  8. 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
  9. Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
  10. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article contains verified protocol PubMed
  11. Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. link to original article contains verified protocol PubMed
  12. Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article contains verified protocol PubMed

MPR

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RP-MPR-RP: Revlimid (Lenalidomide), Prednisone, followed by Melphalan, Prednisone, Revlimid (Lenalidomide), followed by Revlimid (Lenalidomide), Prednisone

Regimen, "RP-MPR-RP"

Study Evidence
Falco et al. 2012 Phase II

Treatment is preceded by RP induction x 4.

Supportive medications:

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

28-day cycle x 6 cycles

Treatment is followed by RP maintenance.

References

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

Tandem melphalan -> autologous stem cell transplant

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To be completed

Regimen

Study Evidence Comparator
Gay et al. 2015 Phase III CRD consolidation

Treatment preceded by varying induction regimens:

Preparative regimen

Stem cells re-infused on day 0

Repeated twice

Treatment followed by varying consolidation and/or maintenance regimens:

References

  1. Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. link to original article PubMed
  2. 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
  3. Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. link to original article contains verified protocol PubMed
  4. 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
  5. 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 PubMed
  6. Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article contains protocol PubMed

VTD

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VTD: Velcade (bortezomib), Thalidomide, Dexamethasone

Regimen #1

Study Evidence
Cavo et al. 2010 Non-randomized

Treatment preceded by VTD induction therapy and tandem autologous stem cell transplant. VTD consolidation is to begin 3 months after the second transplant.

Supportive medications:

35-day cycle x 2 cycles

Treatment followed by dexamethasone maintenance.

Regimen #2

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

Patients had at least a very good partial response (VGPR) after autologous stem cell transplantation.

35-day cycle x 4 cycles

References

  1. Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L, Crippa C, De Rosa L, Pregno P, Grasso M, Liberati AM, Caravita T, Pisani F, Guglielmelli T, Callea V, Musto P, Cangialosi C, Passera R, Boccadoro M, Palumbo A. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010 Apr 20;28(12):2077-84. Epub 2010 Mar 22. link to original article contains verified protocol PubMed
    1. Update: Ferrero S, Ladetto M, Drandi D, Cavallo F, Genuardi E, Urbano M, Caltagirone S, Grasso M, Rossini F, Guglielmelli T, Cangialosi C, Liberati AM, Callea V, Carovita T, Crippa C, De Rosa L, Pisani F, Falcone AP, Pregno P, Oliva S, Terragna C, Musto P, Passera R, Boccadoro M, Palumbo A. Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival. Leukemia. 2015 Mar;29(3):689-95. Epub 2014 Jul 16. link to original article PubMed
  2. 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

Maintenance therapy

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

Bortezomib (Velcade)

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Regimen #1

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

Treatment preceded by VD x 8 versus VMP x 8 versus VTD x 8. All patients received the same maintenance program:

35-day cycle x 5 cycles

Regimen #2

Study Evidence Comparator Efficacy
Mellqvist et al. 2013 Phase III Observation Might have superior PFS

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

21-day cycle x 2 cycles, then:

Supportive medications:

28-day cycle x 4 cycles

Regimen #3

Study Evidence Comparator Efficacy
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4) Phase III Thalidomide Seems to have superior OS

Observed efficacy is for induction PAD -> transplant -> maintenance bortezomib compared with induction VAD -> transplant -> maintenance thalidomide. Treatment started 4 weeks after single autologous stem cell transplant (HOVON-65) or tandem autologous stem cell transplant (GMMG-HD4).

14-day cycle x 2 years

Regimen #4

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

Treatment preceded by VDC versus VDC-mod versus VDR versus VDCR.

Supportive medications:

42-day cycles x 4 cycles

References

  1. Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. link to original article contains verified protocol PubMed
  2. 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
  3. Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, Steingrimsdottir H, Abildgaard N, Ahlberg L, Blimark C, Dahl IM, Forsberg K, Gedde-Dahl T, Gregersen H, Gruber A, Guldbrandsen N, Haukås E, Carlson K, Kvam AK, Nahi H, Lindås R, Andersen NF, Turesson I, Waage A, Westin J; Nordic Myeloma Study Group. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013 Jun 6;121(23):4647-54. Epub 2013 Apr 24. link to original article contains verified protocol PubMed
  4. Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed

Bortezomib & Prednisone

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Regimen

Study Evidence Comparator
Mateos et al. 2010 (GEM2005) Phase III VT

Treatment preceded by VMP x 6 versus VTP x 6.

Supportive medications:

3-month cycle x up to 3 years

References

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

Carfilzomib (Kyprolis)

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Regimen

Study Evidence
Bringhen et al. 2014 Phase II

Treatment preceded by CCyd x 9.

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

References

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

CRd

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

Regimen

Study Evidence
Jakubowiak et al. 2012 Phase II

This is the MTD dosing in this phase I/II trial. Treatment preceded by CRd x 8 cycles.

28-day cycle x 16 cycles

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

References

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

Dexamethasone (Decadron)

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Regimen

Study Evidence
Cavo et al. 2010 Non-randomized

Treatment preceded by TD consolidation versus VTD consolidation.

Supportive medications:

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

References

  1. 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 PubMed

Interferon alfa

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Regimen

Study Evidence Comparator
Ludwig et al. 2010 Phase III Interferon alfa & Thalidomide

This is of historical interest but is no longer commonly used.

References

  1. 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
  2. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996 Jul 11;335(2):91-7. link to original article contains verified protocol PubMed
  3. 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

Interferon alfa & Thalidomide

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Regimen

Study Evidence Comparator
Ludwig et al. 2010 Phase III Interferon alfa

This is of historical interest but is no longer commonly used.

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

Ixazomib (Ninlaro)

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Regimen

Study Evidence
Kumar et al 2014 Phase I/II

Treatment preceded by ixazomib, lenalidomide, dexamethasone x 12 cycles.

28-day cycles until progression

References

  1. Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A11, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. link to original article PubMed

Lenalidomide (Revlimid)

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Regimen #1

Study Evidence Comparator Efficacy
Palumbo et al. 2007 Phase II
Palumbo et al. 2012 (MM-015) Phase III Placebo Superior PFS
Palumbo et al. 2014 (RV-MM-PI-209) Phase III Observation Superior PFS
Stewart et al. 2015 (ECOG E1A06) Non-randomized
Gay et al. 2015 Phase III Lenalidomide & Prednisone
Magarotto et al. 2016 (EMN01) Phase III Lenalidomide & Prednisone
Zweegman et al. 2016 (HOVON87/NMSG18) Phase III Thalidomide

Treatment in Palumbo et al. 2007 and MM-015 was preceded by MPR x 9. Treatment in RV-MM-PI-209 was preceded by high-dose melphalan with autologous stem cell transplant versus MPR consolidation. Treatment in ECOG E1A06 was preceded by mPR x 12. Treatment in Gay et al. 2015 preceded by tandem high-dose melphalan with autologous stem cell transplant versus CRD consolidation. Treatment in EMN01 preceded by CPR x 9 versus MPR x 9 versus Rd x 9. Treatment in HOVON87/NMSG18 preceded by MPR x 9.

Supportive medications (varies depending on reference):

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

28-day cycles, given until progression or intolerable toxicity

Regimen #2

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

Consolidation

28-day cycle x 2 cycles, then

Maintenance

Supportive medications:

  • "Thromboprophylaxis was not used"

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

Regimen #3

Study Evidence Comparator
McCarthy et al. 2012 (CALGB 100104) Phase III Placebo

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

  • Lenalidomide (Revlimid) 20 mg PO once per day; after 3 months, dose may be increased to 30 mg PO once per day if the patient's ANC remains at least 1000/uL and platelet count is at least 75,000/uL
    • Dose adjustments can be found in the paper's supplementary appendix

Supportive medications:

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

Given until progression of disease or unacceptable toxicity

Regimen #4

Study Evidence
Palumbo et al. 2010 Phase II

See First-line regimens: VDD; PAD: Palumbo et al. 2010 for details about the induction therapy portion of this regimen.

Consolidation

28-day cycle x 4 cycles, then proceed to maintenance therapy

Maintenance

28-day cycles, given until relapsed disease

Supportive medications:

Regimen #5, limited duration

Study Evidence
Roussel et al. 2014 Phase II

Treatment preceded by RVD x 2.

12-month course

Regimen #6

Study Evidence
Jakubowiak et al. 2012 Phase II

Treatment preceded by CRd x 24.

28-day cycles until progression

References

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

Lenalidomide & Prednisone

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Regimen #1

Study Evidence Comparator
Magarotto et al. 2016 (EMN01) Phase III Lenalidomide

Treatment preceded by CPR x 9 versus MPR x 9 versus Rd x 9.

Supportive medications:

28-day cycles

Regimen #2

Study Evidence Comparator
Gay et al. 2015 Phase III Lenalidomide

Treatment preceded by tandem high-dose melphalan with autologous stem cell transplant versus CRD consolidation.

28-day cycles

Regimen #3, "RP-MPR-RP"

Study Evidence
Falco et al. 2012 Phase II

Treatment is preceded by MPR consolidation x 6.

Supportive medications:

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

28-day cycles, to continue until relapse, progression, or intolerable side effects

References

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

Observation

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Regimen

Study Evidence Comparator Efficacy
Attal et al. 2012 (IFM 2005-02) Phase III Lenalidomide
McCarthy et al. 2012 (CALGB 100104) Phase III Lenalidomide
Stewart et al. 2013 (NCICCTG Myeloma 10 Trial) Phase III Thalidomide & Prednisone
Mellqvist et al. 2013 Phase III Bortezomib Might have inferior PFS
Palumbo et al. 2014 (RV-MM-PI-209) Phase III Lenalidomide

No treatment or placebo; used as a comparator arm.

References

  1. 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
  2. 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 PubMed
  3. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, Stoppa AM, Hulin C, Benboubker L, Garderet L, Decaux O, Leyvraz S, Vekemans MC, Voillat L, Michallet M, Pegourie B, Dumontet C, Roussel M, Leleu X, Mathiot C, Payen C, Avet-Loiseau H, Harousseau JL; IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1782-91. link to original article contains verified protocol PubMed
    1. Abstract: Update: Michel Attal, MD, Valerie Cances Lauwers, Gerald Marit, Denis Caillot, Thierry Facon, MD, Cyrille Hulin, Philippe Moreau, MD, Claire Mathiot, Murielle Roussel, Catherine Payen, H. Avet-Loiseau and Jean Luc Harousseau. Maintenance Treatment with Lenalidomide After Transplantation for MYELOMA : Final Analysis of the IFM 2005-02. ASH 2010 Abstract 310. link to abstract
  4. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Seiler M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1770-81. link to original article link to supplementary appendix contains verified protocol PubMed
  5. Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, Reiman T, Roy J, Shustik C, Kovacs MJ, Rubinger M, Cantin G, Song K, Tompkins KA, Marcellus DC, Lacy MQ, Sussman J, Reece D, Brundage M, Harnett EL, Shepherd L, Chapman JA, Meyer RM. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013 Feb 28;121(9):1517-23. Epub 2013 Jan 7. link to original article contains verified protocol PubMed
  6. Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, Steingrimsdottir H, Abildgaard N, Ahlberg L, Blimark C, Dahl IM, Forsberg K, Gedde-Dahl T, Gregersen H, Gruber A, Guldbrandsen N, Haukås E, Carlson K, Kvam AK, Nahi H, Lindås R, Andersen NF, Turesson I, Waage A, Westin J; Nordic Myeloma Study Group. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013 Jun 6;121(23):4647-54. Epub 2013 Apr 24. link to original article contains verified protocol PubMed
  7. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article contains verified protocol PubMed

Prednisone

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Regimen #1

Study Evidence Comparator
Berenson et al. 2002 (SWOG 9210) Phase III Low-dose prednisone

Treatment preceded by VAD-P or VAD-P/Q.

Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were then started on maintenance therapy:

Given until disease progression

Regimen #2

Study Evidence Comparator
Berenson et al. 2002 (SWOG 9210) Phase III High-dose prednisone

Treatment preceded by VAD-P or VAD-P/Q.

Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were then started on maintenance therapy:

Given until disease progression

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
  2. 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 PubMed

RVD

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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone

Regimen #1

Study Evidence
Roussel et al. 2014 Phase II

Treatment preceded by autologous stem cell transplant. Two months after hematologic recovery, patients without progressive disease received:

Supportive medications:

21-day cycle x 2 cycles

Patients then proceeded to receive lenalidomide maintenance.

Regimen #2

Study Evidence
Richardson et al. 2010 Phase II

Treatment preceded by RVD x 4 to 8 cycles.

Supportive medications:

21-day cycles until progression or intolerance

References

  1. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12. link to original article contains protocol PubMed
  2. Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014 Mar;28(3):690-3. Epub 2013 Nov 13. link to original article PubMed
  3. Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed

Thalidomide (Thalomid)

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Regimen #1

Study Evidence Comparator Efficacy
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4) Phase III Bortezomib Seems to have inferior OS

Observed efficacy is for induction PAD -> transplant -> maintenance bortezomib compared with induction VAD -> transplant -> maintenance thalidomide. Treatment preceded by single autologous stem cell transplant (HOVON-65) or tandem autologous stem cell transplant (GMMG-HD4).

2 years, starting 4 weeks after autologous stem cell transplant

Regimen #2

Study Evidence Comparator
Palumbo et al. 2006 Non-randomized
Stewart et al. 2015 (ECOG E1A06) Non-randomized
Zweegman et al. 2016 (HOVON87/NMSG18) Phase III Lenalidomide

Treatment in Palumbo et al. 2006 preceded by MPT x 6. Treatment in ECOG E1A06 preceded by MPT x 12. Treatment in HOVON87/NMSG18 preceded by MPT x 9.

Supportive medications:

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

Continued until evidence of relapse or refractory disease

Regimen #3

Study Evidence
Wijermans et al. 2010 (HOVON 49) Non-randomized

Treatment preceded by MPT x 8.

Supportive medications:

Continued until progression

References

  1. Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network, GIMEMA. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31. link to original article contains protocol PubMed
    1. Update: Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14. Epub 2008 May 27. link to original article contains protocol PubMed
  2. Sahebi F, Spielberger R, Kogut NM, Fung H, Falk PM, Parker P, Krishnan A, Rodriguez R, Nakamura R, Nademanee A, Popplewell L, Frankel P, Ruel C, Tin R, Ilieva P, Forman SJ, Somlo G. Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma. Bone Marrow Transplant. 2006 May;37(9):825-9. link to original article PubMed
  3. Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. link to original article PubMed
  4. **RETRACTED** Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB, Omri HE, Elloumi M, Belaaj H, Jeddi R, Aissaouï L, Ksouri H, Hassen AB, Msadek F, Saad A, Hsaïri M, Boukef K, Amouri A, Louzir H, Dellagi K, Abdeladhim AB; Tunisian Multiple Myeloma Study Group. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood. 2008 Feb 15;111(4):1805-10. Epub 2007 Sep 17. link to original article contains verified protocol PubMed **RETRACTED**
  5. Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010 Jul 1;28(19):3160-6. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
  6. 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 PubMed
  7. 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
  8. Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article contains verified protocol link to PMC article PubMed
  9. Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article contains verified protocol PubMed

Thalidomide & Dexamethasone

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Regimen

Study Evidence Comparator
Maiolino et al. 2012 Phase III Dexamethasone

Treatment preceded by high-dose melphalan & autologous stem cell transplant.

12 months or until disease progression

References

  1. Maiolino A, Hungria VT, Garnica M, Oliveira-Duarte G, Oliveira LC, Mercante DR, Miranda EC, Quero AA, Peres AL, Barros JC, Tanaka P, Magalhães RP, Rego EM, Lorand-Metze I, Lima CS, Renault IZ, Braggio E, Chiattone C, Nucci M, de Souza CA; Brazilian Multiple Myeloma Study Group (BMMSG/GEMOH). Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012 Oct;87(10):948-52. Epub 2012 Jun 23. link to original article contains verified protocol PubMed

Thalidomide & Prednisone

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Regimen

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

Treatment preceded by autologous stem cell transplant.

Supportive Medications:

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

Four years or until disease progression

References

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

VT

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VT: Velcade (Bortezomib), Thalidomide

Regimen #1

Study Evidence Comparator
Mateos et al. 2010 (GEM2005) Phase III Bortezomib & Prednisone

Treatment preceded by VMP x 6 versus VTP x 6.

Supportive medications:

3-month cycle x up to 3 years

Regimen #2

Study Evidence
Palumbo et al. 2010 Non-randomized

Treatment preceded by VMPT x 9.

14-day cycles x 2 years or until disease progression or relapse

References

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

Relapsed/refractory

BBD

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BBD: Bendamustine, Bortezomib, Dexamethasone

Regimen

Study Evidence
Ludwig et al. 2013 Phase II

28-day cycle up to 8 cycles

References

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

BD, Bort-Dex

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BD: Bortezomib, Dexamethasone
Bort-Dex: Bortezomib, Dexamethasone

Regimen #1

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

Phase 1

21-day cycle x 8 cycles

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

Phase 2

6-week cycle x 4 cycles

Regimen #2

Study Evidence Comparator Efficacy
Hjorth et al. 2012 Phase III Thal-Dex Equivalent PFS
Dimopoulos et al. 2013 Phase II

Supportive medications:

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

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

Regimen #3

Study Evidence
Fukushima et al. 2011 Phase II

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

References

  1. Subgroup Analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains protocol PubMed
  2. Fukushima T, Nakamura T, Iwao H, Nakajima A, Miki M, Sato T, Sakai T, Sawaki T, Fujita Y, Tanaka M, Masaki Y, Nakajima H, Motoo Y, Umehara H. Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events. Anticancer Res. 2011 Jun;31(6):2297-302. link to original article contains verified protocol PubMed
  3. Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group (NMSG). Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. Epub 2012 Mar 30. link to original article contains verified protocol PubMed
  4. Dimopoulos MA, Beksac M, Benboubker L, Roddie H, Allietta N, Broer E, Couturier C, Mazier MA, Angermund R, Facon T. Phase 2 study of bortezomib-dexamethasone alone or with added cyclophosphamide or lenalidomide for sub-optimal response as second-line treatment for patients with multiple myeloma. Haematologica. 2013 Aug;98(8):1264-72. Epub 2013 May 28. link to original article contains verified protocol PubMed
  5. San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. link to original article PubMed

Bortezomib, Dexamethasone, Panobinostat

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Regimen

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

Phase 1

21-day cycle x 8 cycles

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

Phase 2

6-week cycles

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

References

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

BLD

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BLD: Bendamustine, Lenalidomide, Dexamethasone

Regimen

Study Evidence
Lentzsch et al. 2012 Phase I/II

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

Supportive medications:

28-day cycle x up to 8 cycles

References

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

Bortezomib (Velcade)

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Regimen #1

Study Evidence Comparator
Jagannath et al. 2004 (CREST) Randomized Phase II Low-dose Bortezomib +/- Dexamethasone
Moreau et al. 2011 (MMY-3021) Phase III Subcutaneous Bortezomib +/- Dexamethasone

Moreau et al. 2011 allowed for up to 10 cycles of treatment.

  • Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11
  • Patients with suboptimal response after cycle 4 (less than complete response (CR), without disease progression) could also receive, in addition to bortezomib: Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle x 8 cycles

Regimen #2

Study Evidence Comparator
Richardson et al. 2005 (APEX) Phase III High-dose dexamethasone

21-day cycle x 8 cycles, then

35-day cycle x 3 cycles

Supportive medications:

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

Regimen #3, Subcutaneous Bortezomib +/- Dexamethasone

Study Evidence Comparator
Moreau et al. 2011 (MMY-3021) Phase III Intravenous Bortezomib +/- Dexamethasone
  • Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
    • Subcutaneous injections are 2.5 mg/mL (3.5 mg bortezomib reconstituted in 1.4 mL NS)
    • SC injections are in the thighs or abdomen, with injection sites rotated between proximal/distal right/left thigh and upper/lower right/left abdominal quadrants
  • Patients with suboptimal response after cycle 4 (less than complete response (CR), without disease progression) could also receive, in addition to bortezomib: Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

Supportive medications:

21-day cycle x 8 to 10 cycles

Regimen #4

Study Evidence Comparator
Orlowski et al. 2007 Phase III Bortezomib & Doxorubicin liposomal
Dimopoulos et al. 2013 (VANTAGE 088) Phase III Bortezomib & Vorinostat

21-day cycles until progression or intolerance

Regimen #5

Study Evidence Comparator
Jagannath et al. 2004 (CREST) Randomized Phase II Bortezomib +/- Dexamethasone
  • Bortezomib (Velcade) 1 mg/m2 IV bolus once per day on days 1, 4, 8, 11
  • Patients with suboptimal response after cycle 4 (less than complete response (CR), without disease progression) could also receive, in addition to bortezomib: Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle x 8 cycles

Regimen #6

Study Evidence
Richardson et al. 2003 (SUMMIT) Phase II

21-day cycle x 8 cycles

References

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

Bortezomib, Cyclophosphamide, Dexamethasone

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Regimen #1

Study Evidence
de Waal et al. 2015 Phase II

Treatment intended for bortezomib-naive patients.

  • Bortezomib (Velcade) as follows:
    • Cycles 1 to 3: 1.3 mg/m2 IV/SC once per day on days 1, 4, 8, 11
    • Cycles 4 to 6: 1.6 mg/m2 IV/SC once per day on days 1, 8, 15, 22
  • Cyclophosphamide (Cytoxan) 50 mg PO once per day (continuous)
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 3: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
    • Cycles 4 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

Supportive medications:

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

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

Patients with PR/CR after 6 cycles proceeded to bortezomib & cyclophosphamide maintenance.

Regimen #2

Study Evidence
Kropff et al. 2007 Phase II

Treatment intended for bortezomib-naive patients.

  • Bortezomib (Velcade) as follows:
    • Cycles 1 to 3: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
    • Cycles 4 to 6: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
  • Cyclophosphamide (Cytoxan) 50 mg PO once per day (continuous)
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 3: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
    • Cycles 4 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

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

References

  1. Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, Dechow T, Kröger N, Salwender H, Metzner B, Sezer O, Engelhardt M, Wolf HH, Einsele H, Volpert S, Heinecke A, Berdel WE, Kienast J; Deutsche Studiengruppe Multiples Myelom,. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007 Aug;138(3):330-7. link to original article contains verified protocol PubMed
  2. de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. link to original article contains verified protocol PubMed

Bortezomib & Doxorubicin liposomal

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Regimen

Study Evidence Comparator
Orlowski et al. 2007 Phase III Bortezomib

Supportive medications:

21-day cycle x up to 8 cycles

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

References

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

Bortezomib & Vorinostat

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Regimen

Study Evidence Comparator
Dimopoulos et al. 2013 (VANTAGE 088) Phase III Bortezomib

21-day cycles

References

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

BTD

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BTD: Bendamustine, Thalidomide, Dexamethasone

Regimen

Study Evidence Comparator
Schey et al. 2015 (MUKone) Randomized Phase II BTD with higher-dose benadmustine

This study involved two doses of bendamustine but the higher dose was too toxic. Dosage listed is the lower dose.

Supportive medications:

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

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

References

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

Carfilzomib (Kyprolis)

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Regimen #1 "20/56 dosing"

Study Evidence
Lendvai et al. 2014 Phase II
  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV over 30 minutes once per day on days 1 & 2, then 56 mg/m2 IV over 30 minutes once per day on days 8, 9, 15, 16
    • Cycle 2 onwards: 56 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16

Supportive medications:

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

Regimen #2 "20/27 dosing"

Study Evidence
Vij et al. 2012 (PX-171-004) Phase II
Siegel et al. 2012 (PX-171-003-A1) Phase II
  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 (body surface area capped at 2.2 m2) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
    • Cycle 2 onwards: 27 mg/m2 (body surface area capped at 2.2 m2) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
    • Note: Neither Vij et al. 2012 nor Siegel et al. 2012 specify that carfilzomib is capped at a body surface area of 2.2 m2, but the Carfilzomib (Kyprolis) package insert specifies that: "The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%."

Supportive medications:

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

Dose Adjustments:

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

28-day cycle x up to 12 cycles, given until progression of disease or unacceptable toxicity

Regimen #3

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

As described in the abstract, this variant does not include dose escalation or BSA capping.

28-day cycle x up to 12 cycles

Regimen #4 "15/20/27 dosing for renal impairment"

Study Evidence
Badros et al. 2013 (PX-171-005) Phase II
  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 15 mg/m2 IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
    • Cycle 2: 20 mg/m2 IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
    • Cycle 3 onwards: 27 mg/m2 IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16

Supportive medications:

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

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

Patients with less than PR after 2 cycles or less than CR after 4 cycles were allowed to receive Dexamethasone (Decadron) 20 mg prior to each dose of carfilzomib.

References

  1. Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012 Jun 14;119(24):5661-70. Epub 2012 May 3. link to original article contains verified protocol PubMed
  2. Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T, Somlo G, Bahlis N, Lonial S, Kunkel LA, Wong A, Orlowski RZ, Siegel DS. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8. link to original article contains protocol PubMed
  3. Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012 Oct 4;120(14):2817-25. Epub 2012 Jul 25. link to original article contains verified protocol PubMed Pivotal trial for accelerated FDA approval
    1. Subset analysis: Jakubowiak AJ, Siegel DS, Martin T, Wang M, Vij R, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Harrison BL, Wong AF, Orlowski RZ, Jagannath S. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leukemia. 2013 Dec;27(12):2351-6. Epub 2013 May 14. link to original article PubMed
  4. Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, Lee S, Wong AF, Niesvizky R. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013 Aug;27(8):1707-14. Epub 2013 Jan 31. link to PMC article contains verified protocol PubMed
  5. Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, Tsakos I, Redling K, Koehne G, Chung DJ, Schaffer WL, Giralt SA. A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma. Blood. 2014 Aug 7;124(6):899-906. Epub 2014 Jun 24. link to original article contains verified protocol PubMed

Carfilzomib & Panobinostat

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Regimen

Study Evidence
Berdeja et al. 2015 Phase II
  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV once on days 1 & 2, then 45 mg/m2 IV over 30 minutes on days 8, 9, 15, 16
    • Cycle 2 onwards: 45 mg/m2 IV once on days 1, 2, 8, 9, 15, 16
  • Panobinostat (Farydak) 30 mg PO once per day on days 1, 3, 5, 15, 17, 19

28-day cycles until progression or intolerance

References

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

Car-Pom-d

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Car-Pom-d: Carfilzomib, Pomalidomide, (low-dose) dexamethasone

Regimen

Study Evidence
Shah et al. 2015 Phase II

'This is the MTD reported for the phase I portion of the trial.

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

Supportive medications:

28-day cycles x 6 cycles or until disease progression, or unacceptable toxicity

Treatment followed by maintenance Car-Pom-d.

References

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

CPR

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CPR: Cyclophosphamide, Prednisone, Revlimid (Lenalidomide)

Regimen

Study Evidence
Reece et al. 2014 Phase I/II

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

28-day cycles

References

  1. Reece DE, Masih-Khan E, Atenafu EG, Jimenez-Zepeda VH, Anglin P, Chen C, Kukreti V, Mikhael JR, Trudel S. Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma. Br J Haematol. 2015 Jan;168(1):46-54. Epub 2014 Aug 22. link to original article contains protocol PubMed

CRd; KRd

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

Regimen #1

Study Evidence Comparator Efficacy
Stewart et al. 2014 (ASPIRE) Phase III Rd Superior PFS
  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV over 10 minutes once per day on days 1 & 2, then 27 mg/m2 IV over 10 minutes once per day on days 8, 9, 15, 16
    • Cycles 2 to 12: 27 mg/m2 IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
    • Cycles 13 to 18: 27 mg/m2 IV over 10 minutes once per day on days 1, 2, 15, 16
  • Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
  • Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

Supportive medications:

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

Regimen #2

Study Evidence
Wang et al. 2013 Phase II
  • Carfilzomib (Kyprolis) as follows:
    • Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 27 mg/m2 IV once per day on days 8, 9, 15, 16
    • Cycles 2 to 12: 27 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
    • Cycles 13 to 18: 27 mg/m2 IV once per day on days 1, 2, 15, 16
  • Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
  • Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

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

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

References

  1. Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E, Huang M, Orlowski RZ, Niesvizky R. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013 Oct 31;122(18):3122-8. Epub 2013 Sep 6. link to original article contains verified protocol PubMed
  2. Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; the ASPIRE Investigators. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article contains verified protocol PubMed

CTD

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CTD: Cyclophosphamide, Thalidomide, Dexamethasone

Regimen

Study Evidence
Dimopoulos et al. 2004 Phase II
  • Cyclophosphamide (Cytoxan) 150 mg/m2 PO every 12 hours (before meals) on days 1 to 5
  • Thalidomide (Thalomid) as follows:
    • Cycles 1 to 3: 400 mg PO every evening on days 1 to 5 and 14 to 18
    • Cycle 4 onwards: 400 mg PO every evening on days 1 to 5
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 3: 20 mg PO every morning after breakfast on days 1 to 5 and 14 to 18
    • Cycle 4 onwards: 20 mg PO every morning after breakfast on days 1 to 5

28-day cycles

References

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

Daratumumab (Darzalex)

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Regimen

Study Evidence
Lokhorst et al. 2015 Phase I/II
Lonial et al. 2016 (SIRIUS) Phase II

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

  • Daratumumab (Darzalex) as follows:
    • Weeks 1 to 8: 16 mg/kg IV once per week
    • Weeks 9 to 24: 16 mg/kg IV once every 2 weeks
    • Weeks 25 and on: 16 mg/kg IV once every 4 weeks
    • Per the package insert, daratumumab infusion should complete within 15 hours. In Lokhorst et al. 2015, daratumumab was given over 8 hours.

Given until progression of disease or unacceptable toxicity

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

  • Prior to all daratumumab infusions:
    • Methylprednisolone (Solumedrol) 100 mg IV prior to every dose of daratumumab. Per the package insert, after the second dose of daratumumab, methylprednisolone may be reduced to 60 mg IV. Per Lokhorst et al. 2015, after the fourth dose of daratumumab, methylprednisolone "could be reduced to 50 mg."
    • Acetaminophen (Tylenol) (paracetamol) 1000 mg (package insert: 650 to 1000 mg) PO 1 to 2 hours prior to daratumumab
    • Antihistamine: clemastine 1 mg IV, Cetirizine (Zyrtec) 10 mg PO, Diphenhydramine (Benadryl) 25 to 50 mg PO/IV, or equivalent 1 to 2 hours prior to daratumumab
  • Post-treatment medications:
    • Methylprednisolone (Solumedrol) 20 to 25 mg (package insert: 20 mg) PO or equivalent one and two days after every daratumumab infusion
    • Package insert: "For patients with a history of obstructive pulmonary disorder, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids."
  • Package insert: "Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting DARZALEX and continue for 3 months following treatment"

References

  1. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. link to original article contains verified protocol link to supplementary appendix link to study protocol PubMed
  2. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Bladé J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Jan 6. [Epub ahead of print] link to original article contains protocol PubMed

Daratumumab, Lenalidomide, Dexamethasone

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Regimen

Study Evidence
Plesner et al. 2014 Phase I/II

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

28-day cycle x up to 24 months

References

  1. Abstract: Torben Plesner, MD, Hendrik-Tobias Arkenau, MD, Henk M. Lokhorst, MD PhD, Peter Gimsing, MD, PhD, Jakub Krejcik, MD, Charlotte Lemech, MD, Monique C. Minnema, MD PhD, Ulrik Lassen, MD PhD, Jacob P. Laubach, MD, Tahamtan Ahmadi, MD, PhD, Howard Yeh, MD, Mary E Guckert, MSN, RN, Huaibao Feng, Nikolai Constantin Brun, MD PhD, Steen Lisby, Linda Basse, MD DMSc, Antonio Palumbo, MD. Safety and Efficacy of Daratumumab with Lenalidomide and Dexamethasone in Relapsed or Relapsed, Refractory Multiple Myeloma. ASH 2014 Abstract 84. link to abstract.

DCEP

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

Regimen #1

Study Evidence
Lazzarino et al. 2001 Phase II

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

Supportive medications:

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

One course

Regimen #2

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

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

Supportive medications:

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

28-day cycles

References

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

Dexamethasone (Decadron)

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Regimen #1

Study Evidence Comparator Efficacy
San Miguel et al. 2013 (MM-003) Phase III PD Inferior PFS

28-day cycles until disease progression or unacceptable toxicity

Regimen #2

Study Evidence Comparator Efficacy
Weber et al. 2007 (MM-009) Phase III RD Seems to have inferior OS
Dimopoulos et al. 2007 (MM-010) Phase III RD Seems to have inferior OS
  • Dexamethasone (Decadron) as follows:
    • Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
    • Cycle 5 onwards: 40 mg PO once per day on days 1 to 4

28-day cycles until progression or intolerable side effects

Regimen #3, "LoDEX"

Study Evidence Comparator Efficacy
Richardson et al. 2014 Randomized phase II, >20 patients POM+LoDEX (PD) Seems to have inferior PFS

Supportive medications:

  • Aspirin 81 to 100 mg per day unless contraindicated

28-day cycles until disease progression or unacceptable toxicity

References

  1. 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
  2. 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
  3. 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
  4. Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article contains verified protocol PubMed

DTPACE

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

Regimen

Study Evidence
Lee et al. 2003 Prospective

To be completed

References

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

Elotuzumab, Lenalidomide, Dexamethasone

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Regimen

Study Evidence Comparator
Lonial et al. 2015 (ELOQUENT-2) Phase III Lenalidomide & Dexamethasone
  • Elotuzumab (Empliciti) as follows:
    • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15, 22
    • Cycle 3 onwards: 10 mg/kg IV once per day on days 1 & 15
  • Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
  • Dexamethasone (Decadron) 40 mg PO once per week on weeks without elotuzumab; 28 mg PO and 8 mg IV on days when Elotuzumab (Empliciti) is administered
    • According to the elotuzumab package insert, the 28 mg PO dose should be given between 3 and 24 hours before elotuzumab; the 8 mg IV dose should be given 45 to 90 minutes before elotuzumab.

Supportive medications:

  • Mandatory premedications 30 to 90 minutes prior to elotuzumab:
  • "Thromboembolic prophylaxis (e.g., aspirin, low-molecular-weight heparin, or vitamin K antagonists) was administered according to institutional guidelines or at the discretion of the investigator."

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

References

  1. Phase I: Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK, Jagannath S. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012 Jun 1;30(16):1953-9. link to original article contains verified protocol PubMed
  2. Abstract: Richardson, Paul G., Jagannath, Sundar, Moreau, Philippe, Jakubowiak, Andrzej, Raab, Marc S, Facon, Thierry, Vij, Ravi, White, Darrell J., Reece, Donna, Benboubker, Lotfi, Zonder, Jeffrey A., Deng, Wei, Kroog, Glenn, Singhal, Anil K, Lonial, Sagar. A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidomide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R MM): Updated Results. ASH Annual Meeting Abstracts 2012 120: 202
    1. Abstract: Update: Paul G. Richardson, Sundar Jagannath, MD, Philippe Moreau, MD, Andrzej Jakubowiak, MD, PhD, Marc S Raab, MD, PhD, Thierry Facon, MD, Ravi Vij, MBBS, MD, Darrell White, MD, Donna E. Reece, MD, Lotfi Benboubker, MD, PhD, Jeffrey Zonder, MD, L. Claire Tsao, PhD, Kenneth C. Anderson, MD, Eric Bleickardt, MD, Anil K Singhal, MD and Sagar Lonial, MD. Final Results for the 1703 Phase 1b/2 Study of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. ASH 2014 Abstract 302 link to abstract
  3. Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. link to original article contains verified protocol PubMed

Hyper-CVAD

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

Regimen

Study Evidence
Dimopoulos et al. 1996 Phase II

To be completed

References

  1. Dimopoulos MA, Weber D, Kantarjian H, Delasalle KB, Alexanian R. HyperCVAD for VAD-resistant multiple myeloma. Am J Hematol. 1996 Jun;52(2):77-81. link to original article PubMed

Ixazomib, Lenalidomide, Dexamethasone

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Regimen

Study Evidence Comparator
TOURMALINE-MM1 Phase III Lenalidomide & Dexamethasone

Unpublished; the regimen is being listed in this section because ixazomib was FDA-approved for patients with relapsed/refractory disease and because of anticipated upcoming data from TOURMALINE-MM1. The listed dose of ixazomib is the FDA-approved dose and the one used in the phase III trial.

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

References

  1. Ixazomib (Ninlaro) package insert
  2. A Phase 3 Study Comparing Oral Ixazomib Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma (TOURMALINE-MM1)

Lenalidomide (Revlimid)

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Regimen

Study Evidence Comparator
Richardson et al. 2006 Randomized Phase II Lenalidomide 15 mg PO BID

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

28-day cycles; patients with SD or progression after 2 cycles were escalated to RD.

References

  1. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. link to original article link to PMC article contains verified protocol PubMed

PCP

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PCP: Pomalidomide, Cyclophosphamide, Prednisone

Regimen

Study Evidence
Larocca et al. 2013 Phase I/II

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

Supportive medications:

28-day cycle x 6 cycles

Treatment followed by pomalidomide & prednisone maintenance.

References

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

PD

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PD: Pomalidomide, Dexamethasone

Regimen #1

Study Evidence Comparator Efficacy
San Miguel et al. 2013 (MM-003) Phase III Dexamethasone Superior PFS
Leleu et al. 2013 (IFM 2009-02) Randomized phase II, >20 patients Pom-Dex (28/28) Seems not superior
Richardson et al. 2014 Randomized phase II, >20 patients LoDEX (Dexamethasone) Seems to have superior PFS
Leleu et al. 2015 (IFM 2010-02) Phase II

Supportive medications:

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

28-day cycles until disease progression or unacceptable toxicity

Regimen #2

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

Supportive medications:

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

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

Regimen #3

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

Supportive medications:

28-day cycles given until disease progression or unacceptable toxicity

References

  1. Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Kyle RA, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009 Oct 20;27(30):5008-14. Epub 2009 Aug 31. link to original article contains verified protocol PubMed
  2. Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV, Buadi F. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010 Nov;24(11):1934-9. Epub 2010 Sep 9. link to original article contains verified protocol PubMed
  3. Lacy MQ, Allred JB, Gertz MA, Hayman SR, Short KD, Buadi F, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Stewart AK, Laumann K, Mandrekar SJ, Reeder C, Rajkumar SV, Mikhael JR. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011 Sep 15;118(11):2970-5. Epub 2011 Jun 20. link to original article contains verified protocol PubMed
  4. Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, Mathiot C, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B, Stoppa AM, Hennache B, Bréchignac S, Meuleman N, Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L, Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, Fermand JP, Avet-Loiseau H, Facon T. Pomalidomide plus low dose dexamethasone is active and well tolerated in bortezomib and lenalidomide refractory multiple myeloma: IFM 2009-02. 2013 Mar 14;121(11):1968-1975. Epub 2013 Jan 14. link to original article contains verified protocol PubMed
  5. 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
  6. Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article contains verified protocol PubMed
  7. Leleu X, Karlin L, Macro M, Hulin C, Garderet L, Roussel M, Arnulf B, Pegourie B, Kolb B, Stoppa AM, Brechiniac S, Marit G, Thielemans B, Onraed B, Mathiot C, Banos A, Lacotte L, Tiab M, Dib M, Fuzibet JG, Petillon MO, Rodon P, Wetterwald M, Royer B, Legros L, Benboubker L, Decaux O, Escoffre-Barbe M, Caillot D, Fermand JP, Moreau P, Attal M, Avet-Loiseau H, Facon T; Intergroupe Francophone du Myélome (IFM). Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015 Feb 26;125(9):1411-7. Epub 2015 Jan 9. link to original article contains verified protocol PubMed

RD; Rd

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RD: Revlimid (Lenalidomide), Dexamethasone
Rd: Revlimid (Lenalidomide), (low-dose) dexamethasone

Regimen #1

Study Evidence Comparator Efficacy
Stewart et al. 2014 (ASPIRE) Phase III CRd Inferior PFS

Supportive medications:

28-day cycles until progression or intolerable side effects

Regimen #2

Study Evidence Comparator Efficacy
Weber et al. 2007 (MM-009) Phase III Dexamethasone Seems to have superior OS
Dimopoulos et al. 2007 (MM-010) Phase III Dexamethasone Seems to have superior OS

28-day cycles until progression or intolerable side effects

Regimen #3

Study Evidence Comparator
Richardson et al. 2006 Randomized Phase II Dexamethasone & twice-daily Lenalidomide

This regimen is essentially of historical interest, and was preceded by lenalidomide monotherapy x 2 cycles.

28-day cycles until progression

References

  1. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. link to original article link to PMC article contains verified protocol PubMed
  2. 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
  3. 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. Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; the ASPIRE Investigators. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article contains verified protocol PubMed

RVD

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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone

Regimen

Study Evidence
Richardson et al. 2014 Phase II

Supportive medications:

21-day cycle x 8 cycles

Patients who had at least stable disease and tolerated therapy could proceed to maintenance RVD at previously tolerated dose.

References

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

TD, Thal-Dex

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

Regimen #1

Study Evidence Comparator
Garderet et al. 2012 (MMVAR/IFM 2005-04) Phase III VTD

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

Supportive medications:

One year of treatment

Regimen #2

Study Evidence Comparator Efficacy
Hjorth et al. 2012 Phase III Bort-Dex Equivalent PFS
  • Thalidomide (Thalomid) 50 mg PO once per day, increased by 50 mg every 3 weeks to a maximum of 200 mg PO once per day "unless sufficient response was achieved by a lower dose"
  • Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive medications:

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

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

References

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

Thalidomide (Thalomid)

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Regimen

Study Evidence
Singhal et al. 1999 Non-randomized
  • Thalidomide (Thalomid) 200 mg PO once per day, increased by 200 mg every two weeks for six weeks, to final dose of 800 mg per day

Continued until progression

References

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

Vemurafenib (Zelboraf)

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Regimen

Study Evidence
Andrulis et al. 2013 Case report

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

References

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

VMPT

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

Regimen

Study Evidence
Palumbo et al. 2007 Phase II

35-day cycles x 6 cycles

References

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

VTD

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VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

Regimen

Study Evidence Comparator
Garderet et al. 2012 (MMVAR/IFM 2005-04) Phase III TD

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

  • Bortezomib (Velcade) as follows:
    • Cycles 1 to 8: 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11 of a 21-day cycle
    • Cycles 9 to 12: 1.3 mg/m2 IV bolus once per week on days 1, 8, 15, 22 of a 42-day cycle
  • Thalidomide (Thalomid) 200 mg PO once per day
  • Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of a 21-day cycle

Supportive medications:

One year of treatment

References

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

Maintenance after salvage therapy

Bortezomib & Cyclophosphamide

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Regimen

Study Evidence
de Waal et al. 2015 Phase II

Treatment preceded by bortezomib, cyclophosphamide, dexamethasone x 6.

Supportive medications:

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

1-year course

References

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

Car-Pom-d

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Car-Pom-d: Carfilzomib, Pomalidomide, (low-dose) dexamethasone

Regimen

Study Evidence
Shah et al. 2015 Phase I

'This is the MTD reported for the phase I portion of the trial.

Treatment preceded by Car-Pom-d x 6.

Supportive medications:

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

References

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

Pomalidomide & Prednisone

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Regimen

Study Evidence
Larocca et al. 2013 Phase I/II

Details are for the phase II portion of the published phase I/II trial. Treatment preceded by PCP x 6 cycles.

Supportive medications:

Continuously until any signs of relapse or progression

References

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

RVD

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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone

Regimen

Study Evidence
Richardson et al. 2014 Phase II

Treatment preceded by salvage RVD.

Supportive medications:

21-day cycles until progression or intolerance

References

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

Investigational agents

These are drugs under study with at least some promising results for this disease.

Response criteria

Make note of these errors which remain in the online version as of 7/7/2013.

Prognosis

Durie-Salmon Staging System - 1975

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Composed of four factors with a modifier based on renal function

  • Serum levels of monoclonal protein (only defined for IgM, IgA, and Bence-Jones)
  • Number of lytic bone lesions
  • Hemoglobin
  • Serum calcium level

Risk stratification

  • Stage I: (must meet ALL criteria)
    • Hemoglobin >10 g/dL
    • Calcium normal or ≤12 mg/dL
    • Skeletal survey with normal bone structure (scale 0) or solitary bone plasmacytoma only
    • Monoclonal protein relatively small (IgG M-spike value <5 g/dL OR IgA M-spike value <3 g/dL OR urine light chain protein <4 g/24 hr)
  • Stage II: not stage I or stage III
  • Stage III: (if meets ANY of the criteria)
    • Hemoglobin <8.5 g/dL
    • Calcium >12 mg/dL
    • Skeletal survey with extensive skeletal destruction and major fractures
    • Monoclonal protein relatively large (IgG M-spike value >7 g/dL OR IgA M-spike value >5 g/dL OR urine light chain protein >12 g/24 hr)

Modifier

  • A: relatively normal creatinine (<2 mg/dL)
  • B: creatinine ≥2 mg/dL

References

  1. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975 Sep;36(3):842-54. link to original article PubMed

International Staging System (ISS) - 2005

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Composed of two factors

  • Serum albumin level
  • Serum beta-2 microglobulin level

Risk stratification

  • Stage I: Median survival of 62 months
    • Beta-2 microglobulin <3.5 mg/l
    • Albumin ≤3.5 g/dl
  • Stage II: Median survival of 44 months
    • Not meeting stage I or stage III criteria
  • Stage III: Median survival of 29 months
    • Beta-2 microglobulin ≥5.5 mg/l

References

  1. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J. International staging system for multiple myeloma. J Clin Oncol. 2005 May 20;23(15):3412-20. Epub 2005 Apr 4. link to original article PubMed
  2. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009 Jan;23(1):3-9. Epub 2008 Oct 30. link to original article PubMed

IMWG consensus on risk stratification - 2013

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Composed of four factors

  • Serum albumin level
  • Serum beta-2 microglobulin level
  • Age
  • Chromosomal abnormalities detected by interphase fluorescent in situ hybridization (FISH)

Risk stratification

  • Low risk: (must meet all criteria) Median survival of > 10 years
    • ISS Stage I or II
    • Age < 55 years
    • Absence of the following: del(17p13), t(4;14), +1q21
  • Standard risk: Median survival of 7 years
    • Not meeting low risk or high risk criteria
  • High risk: (if meets both criteria) Median survival of 2 years
    • ISS Stage II or III
    • Either of the following: del(17p13) or t(4;14)

References

  1. Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, Miguel JS, Sonneveld P, Cavo M, Usmani S, Durie BG, Avet-Loiseau H; International Myeloma Working Group. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014 Feb;28(2):269-77. Epub 2013 Aug 26. Review. link to original article PubMed

Revised International Staging System (R-ISS) - 2015

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Composed of four factors

  • Serum albumin level
  • Serum beta-2 microglobulin level
  • Serum LDH
  • Chromosomal abnormalities detected by interphase fluorescent in situ hybridization (FISH)

Risk stratification

  • Low risk: 5-year overall survival = 82%
    • Beta-2 microglobulin <3.5 mg/l
    • Albumin ≤3.5 g/dl
    • LDH less than the upper limit of normal range
    • Absence of the following: del(17p), t(4;14), t(14;16)
  • Intermediate risk: 5-year overall survival = 62%
    • Not meeting low risk or high risk criteria
  • High risk: (if meets ANY of the criteria) 5-year overall survival = 40%
    • Beta-2 microglobulin ≥5.5 mg/l
    • LDH greater than the upper limit of normal range
    • Any of the following: del(17p), t(4;14), t(14;16)

References

  1. Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015 Sep 10;33(26):2863-9. Epub 2015 Aug 3. link to original article

External links

References

  1. ↑ 1.0 1.1 Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006 Sep;20(9):1467-73. Epub 2006 Jul 20. link to original article PubMed
  2. ↑ Bladé J, Samson D, Reece D, Apperley J, Björkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998 Sep;102(5):1115-23. link to original article PubMed
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