Multiple myeloma - historical

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Forde et al. 2022 (CheckMate 816)	2017-2019	Phase 3 (C)	1a. CP & Nivolumab 1b. CVb & Nivolumab 1c. DC & Nivolumab	Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details. This study was conducted in the United States. The reason for the study was that an unanswered question at the time was whether adding an immune checkpoint inhibitor would improve outcomes.

Biomarker eligibility criteria

• CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 or 6 IV once on day 1
• Paclitaxel (Taxol) 175 or 200 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Complete resection

References

1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript PubMed NCT02998528

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only.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

49 regimens on this page 88 variants on this page

First-line therapy

C-VAMP

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

Regimen

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg IV once per day on days 1, 8, 15
  • Cyclophosphamide was omitted in patients with a serum creatinine greater than 3.4 mg/dL
• Vincristine (Oncovin) 0.4 mg IV once per day on days 1 to 4 (total dose per cycle: 1.6 mg)
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion over 4 days (total dose per cycle: 36 mg/m²) on days 1 to 4
• Methylprednisolone (Solumedrol) 1000 mg/m² (maximum dose per cycle of 1500 mg) PO/IV once per day on days 1 to 5

21-day cycles, given until maximal response was achieved

A minimum of 3 cycles given before stem cell harvest. Patients in MRC Myeloma VII proceeded to cyclophosphamide & G-CSF stem cell mobilization and high-dose melphalan & methylprednisolone with auto HSCT.

References

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

Dexamethasone monotherapy

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Regimen #1, indefinite with 35-day induction cycles

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

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

Chemotherapy

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

Supportive medications

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

28-day cycles (*)

Regimen #2, indefinite with 28-day induction cycles

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 (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h.

Chemotherapy

• Dexamethasone (Decadron) as follows:
  • 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 #3, indefinite with alternating dexamethasone intensity

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 (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h.

Chemotherapy

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

28-day cycles

Regimen #4, 12 cycles total

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.

Chemotherapy

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

42-day cycle for 12 cycles

References

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

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.

Chemotherapy

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

42-day cycle for 12 cycles

References

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

EDAP

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

Regimen

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

Given as a component of Total Therapy.

Chemotherapy

• Etoposide (Vepesid)
• Dexamethasone (Decadron)
• Cytarabine (Cytosar)
• Cisplatin (Platinol)

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

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.

Chemotherapy

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

42-day cycle for 12 cycles

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	Seems not superior
		MPR-R	Inferior PFS

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

Chemotherapy

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

Supportive medications

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

28-day cycle for 9 cycles

Regimen #2

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

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

Chemotherapy

• Melphalan (Alkeran) 7 mg/m² PO once per day on days 1 to 4
• Prednisolone (Millipred) 40 mg PO once per day on days 1 to 4

Supportive medications

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

28-day cycle for 6 to 9 cycles

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

Regimen #3

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

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

Chemotherapy

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

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

Regimen #4

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

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

Chemotherapy

• Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 4

42-day cycles

Treatment was continued until plateau phase.

Regimen #5

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.

Chemotherapy

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

Supportive medications

• Bisphosphonate use recommended with Pamidronate (Aredia) or Clodronate (Bonefos); "a maximum treatment period of 2 years was recommended in patients without active disease."

28-day cycle for 8 cycles

Regimen #6

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

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

Chemotherapy

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

42-day cycle for 12 cycles

Regimen #7

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, then MEL100	Seems not superior

In IFM 95-01 this regimen was intended for patients aged between 65 and 75 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria. Some stage I patients were allowed; see text for details. In IFM 99-06 this regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 75 years.

Chemotherapy

• Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
• Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4

42-day cycle for 12 cycles

Regimen #8

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.

Chemotherapy

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

28-day cycle for 6 cycles

Regimen #9

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

Chemotherapy

• Melphalan (Alkeran) 0.15 mg/kg PO once per day on days 1 to 7
• Prednisone (Sterapred) 20 mg PO TID on days 1 to 7

42-day 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. 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
3. Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, Voillat L, Dorvaux V, Hulin C, Lepeu G, Harousseau JL, Eschard JP, Ferrant A, Blanc M, Maloisel F, Orfeuvre H, Rossi JF, Azaïs I, Monconduit M, Collet P, Anglaret B, Yakoub-Agha I, Wetterwald M, Eghbali H, Vekemans MC, Maisonneuve H, Troncy J, Grosbois B, Doyen C, Thyss A, Jaubert J, Casassus P, Thielemans B, Bataille R; Intergroupe Francophone du Myélome (IFM) group. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006 Feb 15;107(4):1292-8. Epub 2005 Sep 20. link to original paper contains verified protocol PubMed
4. 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
5. 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
6. 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
7. 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
8. Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, Carlson K, Dahl IM, Forsberg K, Gulbrandsen N, Haukås E, Hjertner O, Hjorth M, Karlsson T, Knudsen LM, Nielsen JL, Linder O, Mellqvist UH, Nesthus I, Rolke J, Strandberg M, Sørbø JH, Wisløff F, Juliusson G, Turesson I; Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010 Sep 2;116(9):1405-12. Epub 2010 May 6. link to original article contains verified protocol PubMed
9. 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
10. Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N, Sucak G, Kaygusuz I, Karakus S, Kaya E, Ali R, Gulbas Z, Ozet G, Goker H, Undar L. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011 Jan;86(1):16-22. Epub 2010 Nov 22. link to original article contains protocol PubMed
11. 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. contains verified protocol link to PMC article 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
12. 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
13. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. link to original article contains verified protocol PubMed

RD

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RD: Revlimid (Lenalidomide) & high-dose Dexamethasone

Regimen

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

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

Chemotherapy

• Lenalidomide (Revlimid) 25 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, 17 to 20

Supportive medications

• One of the following bisphosphonates:
  • Pamidronate (Aredia) 90 mg IV over 2 to 4 hours once every 28 days
  • Zoledronic acid (Zometa) 4 mg IV over 15 minutes once every 28 days
• Thromboprophylaxis mandatory (added mid-protocol after excess rates of DVT)

28-day cycle for 4 cycles (see below)

Responding patients could choose after 4 cycles to proceed to high-dose melphalan with autologous hematopoietic 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. Erratum in: Lancet Oncol. 2010 Jan;11(1):14. link to original article contains verified protocol link to PMC article 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, then transplant, then maintenance bortezomib compared with induction VAD, then transplant, then maintenance thalidomide.

Chemotherapy

• Vincristine (Oncovin) 0.4 mg IV once per day on days 1 to 4
• Doxorubicin (Adriamycin) 9 mg/m² IV once per day on days 1 to 4
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20

Supportive medications

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

28-day cycle for 3 cycles

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

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 less than or equal to 65 years with untreated symptomatic MM with measurable paraprotein in serum (greater than 1.0 g/dL) or urine (greater than 0.2 g/24 h).

Chemotherapy

• Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 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

• Pamidronate (Aredia) 90 mg or Zoledronic acid (Zometa) 4 mg IV once every 28 days until first transplant
• "Antibiotics, antifungal agents, and antiviral prophylaxis in accordance with local practice."

28-day cycle for 4 cycles

Patients were then randomized to DCEP consolidation or went directly to autologous hematopoietic 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 greater than or equal to 18 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria.

Chemotherapy

• Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 1.6 mg)
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 36 mg/m²)
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

28-day cycles

Regimen #4, VAD bolus

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

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

Chemotherapy

• Vincristine (Oncovin) 0.4 mg IV over 30 minutes once per day on days 1 to 4
• Doxorubicin (Adriamycin) 9 mg/m² IV over 30 minutes once per day on days 1 to 4
• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycles 2 & 4: 40 mg PO once per day on days 1 to 4

Supportive medications

• Fluconazole (Diflucan) 200 mg PO once per day
• Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO BID for "prophylaxis"

28-day cycle for 4 cycles

Regimen #5

Study	Evidence
Barlogie et al. 1984	Phase II
Barlogie et al. 2006 (SWOG S9321)	Non-randomized portion of RCT

Chemotherapy

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

Supportive medications

• Cimetidine (Tagamet) prophylaxis (dose not specified)
• Trimethoprim/Sulfamethoxazole prophylaxis (dose not specified)

35-day cycles

In Barlogie et al. 1984, treatment was given "until a maximum reduction in myeloma protein had occurred" and patients received four additional cycles of therapy beyond their best response. In SWOG S9321, patients with at least stable disease were randomized after 4 cycles to VBMCP versus melphalan & TBI, then auto HSCT.

Regimen #6

Study	Evidence
Segeren et al. 1999	Phase II

Chemotherapy

• Vincristine (Oncovin) 0.4 mg IV over 30 minutes once per day on days 1 to 4
• Doxorubicin (Adriamycin) 9 mg/m² IV over 30 minutes once per day on days 1 to 4
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 of odd-numbered cycles only

Supportive medications

• Fluconazole (Diflucan) 200 mg PO once per day
• Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO BID for "prophylaxis"

28-day cycles

Regimen #7

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

This regimen was intended for patients with a confirmed diagnosis of symptomatic or progressive MM, an upper age limit of 60 years, and previously untreated.

Chemotherapy

• Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 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 for 4 cycles

Responders were randomized to single autologous hematopoietic cell transplant versus tandem autologous hematopoietic 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. Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A, Katodritou I, Kokkini G, Terpos E, Vyniou N, Tzilianos M, Chatzivassili A, Kyrtsonis MC, Panayiotidis P, Maniatis A; Greek Myeloma Study Group. Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol. 2003 Jul;14(7):1039-44. link to original article contains protocol PubMed
4. Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006 May 1;107(9):3474-80. Epub 2006 Jan 5. link to original article PubMed
   1. Update: Moreau P, Garban F, Attal M, Michallet M, Marit G, Hulin C, Benboubker L, Doyen C, Mohty M, Yakoub-Agha I, Leyvraz S, Casassus P, Avet-Loiseau H, Garderet L, Mathiot C, Harousseau JL; IFM Group. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Nov 1;112(9):3914-5. link to original article PubMed
   2. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
5. 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
6. Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. link to original article PubMed
   1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
7. 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
8. Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, McCoy J, Moore DF Jr, Dakhil SR, Lanier KS, Chapman RA, Cromer JN, Salmon SE, Durie B, Crowley JC. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006 Feb 20;24(6):929-36. Epub 2006 Jan 23. Erratum in: J Clin Oncol. 2006 Jun 10;24(17):2687. Moore, Dennis F Jr [added]. link to original article refers to protocol in Barlogie et al. 1984 PubMed
   1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
9. Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article contains verified protocol PubMed
10. 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
11. 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

VAMP

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VAMP: Vincristine, Adriamycin (Doxorubicin), MethylPrednisolone

Regimen

Study	Evidence	Comparator
Raje et al. 1997	Phase III	C-VAMP

Chemotherapy

• Vincristine (Oncovin)
• Doxorubicin (Adriamycin)
• Methylprednisolone (Solumedrol)

References

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

VBMC

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

Regimen

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

Chemotherapy

• Vincristine (Oncovin)
• Carmustine (BiCNU)
• Melphalan (Alkeran)
• Cyclophosphamide (Cytoxan)

Followed by interferon alfa maintenance.

References

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

VBMCP

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

Regimen

Study	Evidence	Comparator
Barlogie et al. 2006 (SWOG S9321)	Phase III	Melphalan & TBI, then auto HSCT

Chemotherapy

• Vincristine (Oncovin)
• Carmustine (BiCNU)
• Melphalan (Alkeran)
• Cyclophosphamide (Cytoxan)
• Prednisone (Sterapred)

References

1. Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, McCoy J, Moore DF Jr, Dakhil SR, Lanier KS, Chapman RA, Cromer JN, Salmon SE, Durie B, Crowley JC. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006 Feb 20;24(6):929-36. Epub 2006 Jan 23. Erratum in: J Clin Oncol. 2006 Jun 10;24(17):2687. Moore, Dennis F Jr [added]. link to original article PubMed
   1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed

VBMCP/VBAD

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

Regimen

Study	Evidence	Comparator	Efficacy
Bladé et al. 2005 (PETHEMA)	Phase III	VBMCP/VBAD, then MEL-200, then auto HSCT VBMCP/VBAD, then MEL-140 & TBI, then auto HSCT	Seems not superior

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

Chemotherapy, VBMCP portion

• Vincristine (Oncovin)
• Carmustine (BiCNU)
• Melphalan (Alkeran)
• Cyclophosphamide (Cytoxan)
• Prednisone (Sterapred)

Chemotherapy, VBAD portion

• Vincristine (Oncovin)
• Carmustine (BiCNU)
• Doxorubicin (Adriamycin)
• Dexamethasone (Decadron)

References

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

VMCP

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VMCP: Vincristine, Melphalan, Cyclophosphamide, Prednisone

Regimen

Study	Evidence	Comparator	Efficacy
Fermand et al. 2005	Phase III	VAMP, then auto HSCT	Might have inferior EFS

Chemotherapy

• Vincristine (Oncovin) 1.4 mg/m² IV once on day 1
• Melphalan (Alkeran) 6 mg/m² PO once per day on days 1 to 4
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• Prednisone (Sterapred) 80 mg/m² PO once per day on days 1 to 4

Monthly cycles

References

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

VMCP/BVAP

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VMCP: Vincristine, Melphalan, Cyclophosphamide, Prednisone
BVAP: BiCNU (Carmustine), Vincristine, Adriamycin (Doxorubicin), Prednisone

Regimen

Study	Evidence	Comparator	Efficacy
Attal et al. 1996	Phase III	VMCP/BVAP alone	Seems to have superior OS

Chemotherapy, VMCP portion

• Vincristine (Oncovin) 1 mg IV once on day 1
• Melphalan (Alkeran) 5 mg/m² PO once per day on days 1 to 4
• Cyclophosphamide (Cytoxan) 110 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

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

Chemotherapy, BVAP portion

• Carmustine (BiCNU) 30 mg/m² IV once on day 1
• Vincristine (Oncovin) 1 mg IV once on day 1
• Doxorubicin (Adriamycin) 30 mg/m² IV once on day 1
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

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

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

Patients with a WHO performance status less than 3, creatinine less than 1.7 mg/dL (150 µmol/L), and bone marrow (collected after cycle 4) with greater than 200 million nucleated cells/kg would proceed to melphalan, total body irradiation (TBI), and autologous transplant.

References

1. 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

Consolidation after first-line therapy

Melphalan monotherapy

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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.

Chemotherapy

• Melphalan (Alkeran) 100 to 140 mg/m² IV once

References

1. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983 Oct 8;2(8354):822-4. link to original article PubMed
2. Sonneveld P, van der Holt B, Segeren CM, Vellenga E, Croockewit AJ, Verhoe GE, Cornelissen JJ, Schaafsma MR, van Oers MH, Wijermans PW, Westveer PH, Lokhorst HM; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term follow-up of the Dutch Cooperative Group HOVON 24 trial. Haematologica. 2007 Jul;92(7):928-35. link to original article PubMed

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

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Regimen

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

Chemotherapy, first transplant

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

Stem cells re-infused on day 0

Chemotherapy, second transplant

• Melphalan (Alkeran) 120 mg/m² IV once on day -4
• Busulfan (Myleran) 4 mg/kg PO from day -5 to -3

Stem cells re-infused on day 0

References

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

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

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Regimen

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

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

Preceding treatment

• VAD induction x 4

Chemotherapy, first transplant

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

Stem cells re-infused on day 0

Chemotherapy, second transplant

• Melphalan (Alkeran) 220 mg/m² IV once on day -2
• Dexamethasone (Decadron) 40 mg (route not specified) over 4 days (days not specified)

Stem cells re-infused on day 0

No further treatment.

References

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

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

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Regimen

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

This regimen was intended for patients not achieving at least PR after the first transplant.

Chemotherapy, first transplant

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

Stem cells re-infused on day 0

Chemoradiotherapy, second transplant

• Melphalan (Alkeran) 140 mg/m² IV once on day -4
• TBI dose of 850 to 1020 cGy in 5 to 6 fractions delivered on days -3 to -1

Stem cells re-infused on day 0

References

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

Melphalan, then auto HSCT, then RIC allo HSCT

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Regimen

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

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

Preceding treatment

• VAD induction x 4

Chemotherapy, first transplant

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

Stem cells re-infused on day 0

After an interval of 2 months, patients proceeded to allogeneic transplant with busulfan, fludarabine, ATG conditioning.

References

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

Melphalan & Methylprednisolone, then auto HSCT

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Regimen

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

Preceding treatment

• VAMP induction

Chemotherapy

• Melphalan (Alkeran)
• Methylprednisolone (Solumedrol)

Followed by interferon alfa maintenance.

References

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

Melphalan & TBI, then auto HSCT

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Regimen

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

Preceding treatment

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

Chemoradiotherapy

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

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

Followed by interferon alfa maintenance.

References

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

Maintenance after first-line therapy

Dexamethasone monotherapy

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Regimen #1, 1 year

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

Preceding treatment

• High-dose melphalan with autologous hematopoietic stem cell transplant

Chemotherapy

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

28-day cycle for 12 months or until disease progression

Regimen #2, indefinite

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

Preceding treatment

• TD versus VTD consolidation

Chemotherapy

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

Supportive medications

• Acyclovir (Zovirax) prophylaxis recommended

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 contains verified protocol PubMed

Interferon alfa monotherapy

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Regimen

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

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

Immunotherapy

• Interferon alfa-2a (Roferon-A) or Interferon alfa-2b (Intron-A)

References

1. 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
   1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
2. 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
3. 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
4. Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article PubMed
5. 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
6. Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. link to original article contains verified protocol PubMed

Interferon alfa & Dexamethasone

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Regimen

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

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

Chemoimmunotherapy

• Interferon alfa-2a (Roferon-A) or Interferon alfa-2b (Intron-A)
• Dexamethasone (Decadron)

References

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

Interferon alfa & Thalidomide

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Regimen

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

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

Chemoimmunotherapy

• Interferon alfa-2a (Roferon-A) or Interferon alfa-2b (Intron-A)
• Thalidomide (Thalomid)

References

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

Observation

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Regimen

Study	Evidence	Comparator	Efficacy
Attal et al. 2006 (IFM 99-02)	Phase III	Thalidomide	Inferior OS
Morgan et al. 2012 (MRC Myeloma IX)	Phase III	Thalidomide	Inferior PFS
Attal et al. 2012 (IFM 2005-02)	Phase III	Lenalidomide	Inferior PFS
McCarthy et al. 2012 (CALGB 100104)	Phase III	Lenalidomide	Seems to have inferior OS
Stewart et al. 2013 (NCICCTG Myeloma 10 Trial)	Phase III	Thalidomide & Prednisone	Inferior PFS
Mellqvist et al. 2013 (NMSG 15/05)	Phase III	Bortezomib	Might have inferior PFS
Palumbo et al. 2014 (GIMEMA RV-MM-PI-209)	Phase III	Lenalidomide	Inferior PFS

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
   1. Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article PubMed
2. Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG; Blood Marrow Transplant Clinical Trials Network (BMT CTN). Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203. Epub 2011 Sep 29. link to PMC article PubMed
3. 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
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 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. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Seiler M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1770-81. link to original article link to supplementary appendix link to PMC article PubMed
   1. Update: Holstein SA, Jung SH, Richardson PG, Hofmeister CC, Hurd DD, Hassoun H, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, van Besien K, Gentile TG, Isola L, Maziarz RT, Bashey A, Landau H, Martin T, Qazilbash MH, Rodriguez C, McClune B, Schlossman RL, Smith SE, Hars V, Owzar K, Jiang C, Boyd M, Schultz C, Wilson M, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Linker C, Anderson KC, McCarthy PL. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol. 2017 Sep;4(9):e431-e442. Epub 2017 Aug 17. link to original article PubMed
6. Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, Reiman T, Roy J, Shustik C, Kovacs MJ, Rubinger M, Cantin G, Song K, Tompkins KA, Marcellus DC, Lacy MQ, Sussman J, Reece D, Brundage M, Harnett EL, Shepherd L, Chapman JA, Meyer RM. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013 Feb 28;121(9):1517-23. Epub 2013 Jan 7. link to original article link to PMC article PubMed
7. Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, Steingrimsdottir H, Abildgaard N, Ahlberg L, Blimark C, Dahl IM, Forsberg K, Gedde-Dahl T, Gregersen H, Gruber A, Guldbrandsen N, Haukås E, Carlson K, Kvam AK, Nahi H, Lindås R, Andersen NF, Turesson I, Waage A, Westin J; Nordic Myeloma Study Group. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013 Jun 6;121(23):4647-54. Epub 2013 Apr 24. link to original article link to PMC article PubMed
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 PubMed

Prednisolone monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Spencer et al. 2009	Phase III	Thalidomide & Prednisolone	Inferior OS

Preceding treatment

• High-dose melphalan & auto HSCT

Chemotherapy

• Prednisolone (Millipred) 50 mg PO once every other day

Given until disease progression

References

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

Prednisone monotherapy

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Regimen #1, high-dose

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

Preceding treatment

• VAD-P versus VAD-P/Q

Chemotherapy

• Prednisone (Sterapred) 50 mg PO once every other day

Given until disease progression

Regimen #2, low-dose

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

Preceding treatment

• VAD-P versus VAD-P/Q

Chemotherapy

• Prednisone (Sterapred) 10 mg PO once every other day

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

Relapsed or refractory

Dexamethasone monotherapy

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Regimen #1

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

Note: efficacy reported is based on the 2015 update.

Chemotherapy

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

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

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

Chemotherapy

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

28-day cycles until progression or intolerable side effects

Regimen #3, limited duration

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

Note: efficacy reported is based on the 2007 update.

Chemotherapy

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

35-day cycle for 4 cycles, then 28-day cycle for 4 cycles

References

1. 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 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
   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. 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. San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-66. Epub 2013 Sep 3. link to original article contains verified protocol PubMed
   1. Update: Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Spencer A, Knop S, Bahlis NJ, Renner C, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel JF. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015 Oct;100(10):1327-33. Epub 2015 Aug 6. link to original article link to PMC article PubMed

EDAP

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

Regimen

Study	Evidence
Barlogie et al. 1989	Non-randomized

Chemotherapy

• Etoposide (Vepesid)
• Dexamethasone (Decadron)
• Cytarabine (Cytosar)
• Cisplatin (Platinol)

References

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

Pembrolizumab, Pomalidomide, Dexamethasone

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Regimen

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

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

Chemoimmunotherapy

• Pembrolizumab (Keytruda)
• Pomalidomide (Pomalyst)
• Dexamethasone (Decadron)

References

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