Difference between revisions of "Multiple myeloma"

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# '''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. [http://bloodjournal.hematologylibrary.org/content/122/8/1376.long link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23775712 PubMed]
 
# '''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. [http://bloodjournal.hematologylibrary.org/content/122/8/1376.long link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23775712 PubMed]
  
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==Prednisone (Sterapred)==
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==Prednisone==
  
 
===Regimen #1, Berenson et al. 2002 (SWOG 9210)===
 
===Regimen #1, Berenson et al. 2002 (SWOG 9210)===

Revision as of 01:45, 5 September 2014

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Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.


Untreated (including transplant ineligible)

BDD

BDD: Bortezomib, Doxorubicin, Dexamethasone

Regimen

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

BiRD: Biaxin, Revlimid, Dexamethasone

Phase II Retrospective improved PFS Retrospective increased toxicity

Regimen

Supportive medications:

28-week 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
  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
  3. 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

CCyd

CCyd: Carfilzomib, Cyclophosphamide, dexamethasone

Regimen

Phase II

28-day cycles x 9 cycles, followed by maintenance therapy:

Maintenance therapy

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

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

Regimen

Phase II, <20 patients reported

It is not clear from the abstract when the 20 mg/m2 vs. 36 mg/m2 dose of carfilzomib is used, nor was it clear what doses were used with oral vs. IV dexamethasone.

28-day cycles x 8 cycles; patients who had at least stable disease then received:

28-day cycles x 12 cycles

References

  1. 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

CTD, CTDa

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

Regimen #1, Morgan et al. 2011 (CTDa, MRC Myeloma IX)

Phase III

CTDa is intended for elderly or non-transplant-eligible patients

Supportive medications:

  • For the first 12 weeks of treatment, thromboprophylaxis--for example, with Warfarin (Coumadin) or low molecular weight heparin--was recommended
  • Patients in the study were randomized to a bisphosphonate and received one of the following until progression:

28-day cycles x 6 to 9 cycles

Regimen #2, Morgan et al. 2012 (CTD, MRC Myeloma IX)

Phase III

Supportive medications:

  • Venous thromboembolism (VTE) prophylaxis was given at physician discretion, but it was suggested that low-risk patients receive Aspirin and high-risk patients receive Warfarin (Coumadin) or low molecular weight heparin according to risk categories as described by Palumbo A et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414–23. link to original article PubMed
  • Patients in the study were randomized to a bisphosphonate and received one of the following until progression:

21-day cycles x up to 6 cycles

References

  1. Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article contains verified protocol PubMed
  2. Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. link to original article contains verified protocol PubMed
  3. 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 Aug 30. [Epub ahead of print] link to original article PubMed

CVAD

CVAD: Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone

Regimen, Morgan et al. 2012 (MRC Myeloma IX)

Phase III

The reference paper has unclear wording about the schedule and total number of doses of vincristine and doxorubicin. Please contact the editors of this site if you are able to provide a clarification.

Supportive medications:

21-day cycles x up to 6 cycles

References

  1. Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. link to original article contains verified protocol--see comment above 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 Aug 30. [Epub ahead of print] link to original article PubMed

CyBorD, CVD, VCD

CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone
CVD: Cyclophosphamide, Velcade, Dexamethasone

Regimen #1, 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

Regimen #2, Kumar et al. 2012 (EVOLUTION/VDC-mod)

Randomized Phase II, <20 per arm

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 #3 is the number of cyclophosphamide doses.

Induction

Supportive medications:

21-day cycles x 8 cycles, then

Consolidation

Supportive medications:

42-day cycles x 4 cycles

Regimen #3, Kumar et al. 2012 (EVOLUTION/VDC)

Randomized Phase II, >20 per arm

The only difference between this and regimen #2 is the number of cyclophosphamide doses.

Induction

Supportive medications:

21-day cycles x 8 cycles, then

Consolidation

Supportive medications:

42-day cycles x 4 cycles

Regimen #4, Reeder et al. 2010 (once per week bortezomib)

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

28-day cycles x 4 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
  3. 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
  4. Meta-Analysis: Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. link to original article PubMed

DEX (Dexamethasone)

DEXamethasone

Regimen #1, Facon et al. 2006 (IFM 95-01)

Phase III

6-week cycles x 12 cycles

Regimen #2, Rajkumar et al. 2006

Phase III

28-day cycles

Regimen #3, Rajkumar et al. 2008

Phase III

28-day cycles

References

  1. 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
  2. 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
  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

DEX-IFN

DEXamethasone, IFN: Interferon alfa-2b

Regimen, Facon et al. 2006 (IFM 95-01)

Phase III

6-week cycles 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, DVd, VAD doxil

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

Regimen #1, Hussein et al. 2002 (DVd)

Phase II

Supportive medications:

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

4-week cycles x 6 to 8 cycles

Regimen #2, Rifkin et al. 2006 (DVD)

Phase III

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

Regimen #3, Dimopoulos et al. 2003 & Zervas et al. 2007 (VAD doxil)

Phase III

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

4-week cycles x 4 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
  2. Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A, Katodritou I, Kokkini G, Terpos E, Vyniou N, Tzilianos M, Chatzivassili A, Kyrtsonis MC, Panayiotidis P, Maniatis A; Greek Myeloma Study Group. Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol. 2003 Jul;14(7):1039-44. link to original article contains protocol PubMed
  3. 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
  4. Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol. 2007 Aug;18(8):1369-75. link to original article contains verified protocol PubMed

MP, M-DEX

MP: Melphalan, Prednisone/rednisolone
M-DEX: Melphalan, DEXamethasone

Regimen #1, Facon et al. 2006 (IFM 95-01)

Phase III

6-week cycles x 12 cycles

Regimen #2, San Miguel et al. 2008 & 2012, Mateos et al. 2010 (VISTA)

Phase III

6-week cycles x 9 cycles

Regimen #3

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

Regimen #4, Facon et al. 2006, Facon et al. 2007 (IFM 95-01, IFM 99-06)

Phase III

  • Melphalan (Alkeran) 0.25 mg/kg PO 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 for cycles 1 to 2; 40 mg PO once per day on days 1 to 4 of cycles 3 to 12

6-week cycles x 12 cycles

Regimen #5, Hulin et al. 2009 (IFM 01/01)

Phase III

6-week cycles x 12 cycles

Regimen #6, Palumbo et al. 2012 (MM-015)

Phase III

Supportive medications:

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

28-day cycles x 9 cycles

Regimen #7, Wijermans et al. 2010 (HOVON 49)

Phase III

Supportive medications:

28-day cycles x 8 cycles

Regimen #8, Morgan et al. 2011 (MRC Myeloma IX study)

Phase III

Supportive medications:

28-day cycles x 6 to 9 cycles

Regimen #9, Palumbo et al. 2006

Phase III

28-day cycles x 6 cycles

References

  1. Kyle RA. Monoclonal gammopathy and multiple myeloma in the elderly. Baillieres Clin Haematol. 1987 Jun;1(2):533-57. PubMed
  2. 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
  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. 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
  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
  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. 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
  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. Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article contains verified protocol PubMed
  12. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jędrzejczak 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
  13. 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
  14. 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 Aug 30. [Epub ahead of print] link to original article PubMed

MPR, MPR-R, MPL, RP-MPR-RP

MPR: Melphalan, Prednisone, Revlimid
MPR-R: Melphalan, Prednisone, Revlimid, Revlimid maintenance
MPL: Melphalan, Prednisone, Lenalidomide
RP-MPR-RP: Revlimid, Prednisone, Melphalan, Prednisone, Revlimid, Revlimid, Prednisone

Regimen #1, Palumbo et al. 2007 & Palumbo et al. 2012 (MPR-R)

Phase III

Induction therapy

28-day cycles x 9 cycles, then:

Maintenance therapy

28-day cycles, to continue until relapsed or refractory disease

Supportive medications (varies depending on reference):

Regimen #2, Palumbo et al. 2012 (MM-015)

Phase III

Supportive medications:

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

28-day cycles x 9 cycles

Regimen #3, Falco et al. 2012 (RP-MPR-RP)

Phase II

Induction

28-day cycle x 4 cycles

Consolidation

28-day cycle x 6 cycles, then:

Maintenance therapy

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

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.

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-Jędrzejczak 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. 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

MPT

MPT: Melphalan, Prednisone, Thalidomide

Regimen #1, Facon et al. 2007 (IFM 99-06)

Phase III

42-day cycles x 12 cycles

Regimen #2, Palumbo et al. 2006 (GIMEMA)

Phase III

Induction therapy

Supportive medications:

28-day cycles x 6 cycles, then proceed to maintenance therapy

Maintenance therapy

Regimen #3, Hulin et al. 2009 (IFM 01/01)

Phase III

42-day cycles x 12 cycles

Regimen #4, Wijermans et al. 2010 (HOVON 49)

Phase III

Induction therapy

28-day cycles x 8 cycles, then

28-day course, then

Maintenance therapy

Supportive medications (for induction & maintenance periods):

  • Bisphosphonate use recommended with Pamidronate (Aredia) or Clodronate (Bonefos); "a maximum treatment period of 2 years was recommended in patients without active disease."
  • Recommended thromboprophylaxis:
    • During induction therapy, low molecular weight heparin use recommended with nadroparin 2,850 units anti-Xa (for patients >90 kg, dose of 5,700 units anti-Xa)
    • During maintenance therapy, "low-dose aspirin was advised"

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
  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. 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
  4. 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
  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

RD, RevDex, Rd, Len-Dex

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

Regimen #1, Rajkumar et al. 2010 (ECOG E4A03)

Phase III

This is the high-dose dexamethasone arm of ECOG E4A03.

Supportive medications:

  • One of the following bisphosphonates:
  • Aspirin (80 mg or 325 mg per physician discretion) once per day as thrombosis prophylaxis.

28-day cycles

Regimen #2, 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

Regimen #3, Rajkumar et al. 2010 (ECOG E4A03) & Gay et al. 2010

Phase III

This is the low-dose dexamethasone arm of ECOG E4A03.

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

28-day cycles, either given x 4 cycles prior to transplant, or 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
  2. 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 original article contains verified protocol PubMed
  3. 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

RVD, VDR, VRD

RVD: Revlimid, Velcade, Dexamethasone
VDR: Velcade, Dexamethasone, Revlimid
VRD: Velcade, Revlimid, Dexamethasone

Regimen #1, Richardson et al. 2010

Phase II

Induction therapy

Supportive medications:

21-day cycles x 4 to 8 cycles

Maintenance therapy

Patients who responded and tolerated therapy could proceed to maintenance therapy at previously tolerated dose with a different schedule:

21-day cycles, indefinitely

Regimen #2, Kumar et al. 2012 (EVOLUTION)

Randomized Phase II, >20 per arm

Induction therapy

21-day cycles x 8 cycles, then proceed to consolidation:

Consolidation therapy

42-day cycles x 4 cycles

Supportive medications:

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. 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

RVDC: Revlimid, Velcade, Dexamethasone, Cyclophosphamide
VDCR: Velcade, Dexamethasone, Cyclophosphamide, Revlimid

Regimen, Kumar et al. 2012 (EVOLUTION)

Randomized Phase II, >20 per arm

Induction therapy

21-day cycles x 8 cycles, then proceed to consolidation:

Consolidation therapy

42-day cycles x 4 cycles

Supportive medications:

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

TD

TD: Thalidomide, Dexamethasone

Regimen #1, Rajkumar et al. 2008

Phase III

28-day cycles

Regimen #2, Rajkumar et al. 2002 & Rajkumar et al. 2006

Phase III

28-day cycles

Regimen #3, Cavo et al. 2010 & Cavo et al. 2012 (GIMEMA)

Induction therapy

21-day cycles 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 therapy

35-day cycles x 2 cycles, then proceed to dexamethasone maintenance therapy

Dexamethasone maintenance therapy

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

Supportive medications:

Regimen #4, Rosiñol et al. 2012

Phase III Decreased PFS Decreased toxicity

Supportive medications:

  • Low-molecular weight heparin or Aspirin recommended

28-day cycles x 6 cycles

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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 (Velcade); PAD

VAD: Velcade, Adriamycin, Dexamethasone
PAD: PS-341, Adriamycin, Dexamethasone

Regimen #1, Broyl et al. 2010 & Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)

Phase III

Induction therapy

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 cycles x 3 cycles; stem cells collected 4 to 6 weeks after induction therapy

Stem-cell transplant

High dose melphalan single (HOVON-65) or tandem (GMMG-HD4)

Maintenance

Bortezomib maintenance x 2 years, starting 4 weeks after last transplant

Regimen #2, Oakervee et al. 2005

Phase II

21-day cycles 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
  2. Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, el Jarari L, Bertsch U, Lokhorst HM, Durie BG, Goldschmidt H, Sonneveld P. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. Epub 2010 Sep 21. link to original article contains verified protocol PubMed
  3. 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 (Vincristine), VAD-P

VAD: Vincristine, Adriamycin, Dexamethasone
VAD-P: Vincristine, Adriamycin, Dexamethasone, Prednisone

Regimen #1, 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, Segeren et al. 1999

Phase II

Supportive medications:

4-week cycles

Regimen #3, Berenson et al. 2002 (SWOG 9210)

Phase III

  • 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.

Regimen #4, Dimopoulos et al. 2003

Phase III

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

4-week cycles x 4 cycles

Regimen #5, Rifkin et al. 2006

Phase III

28-day cycles

Regimen #6, Harousseau et al. 2010 (IFM 2005-01)

Phase III

Supportive medications:

28-day cycles

Regimen #7, Facon et al. 2007 (IFM 99-06)

Phase III

28-day cycles x 2 cycles

Followed by stem-cell mobilization and RIC transplant, to be completed

Regimen #8, Broyl et al. 2010 & Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)

Phase III

Induction therapy

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 cycles x 3 cycles; stem cells collected 4 to 6 weeks after induction therapy

Stem-cell transplant

High dose melphalan single (HOVON-65) or tandem (GMMG-HD4)

Maintenance

Thalidomide maintenance x 2 years, starting 4 weeks after last 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. 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
  4. 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
  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. 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
  7. 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
  8. Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, el Jarari L, Bertsch U, Lokhorst HM, Durie BG, Goldschmidt H, Sonneveld P. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. Epub 2010 Sep 21. link to original article contains verified protocol PubMed
  9. 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-DCEP

VAD: Vincristine, Adriamycin, Dexamethasone

DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol

Regimen

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

VAD-P/Q

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

Regimen, Berenson et al. 2002 (SWOG 9210)

Phase III

  • Vincristine (Oncovin) 0.4 mg/day (total dose per cycle: 1.6 mg) IV continuous infusion over 4 days on days 2 to 5
  • Doxorubicin (Adriamycin) 9 mg/m2/day (total dose per cycle: 36 mg/m2) IV continuous infusion over 4 days on days 2 to 5
    • 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 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

VD (Velcade)

VD: Velcade, Dexamethasone

Regimen #1, Harousseau et al. 2010 (IFM 2005-01)

Phase III

Supportive medications:

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

21-day cycles x 4 cycles

Regimen #2, Moreau et al. 2011 (IFM 2007-02)

Phase III

21-day cycle x 4 cycles, followed by 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
  2. 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
  3. 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

VDD; PAD

VDD: Velcade, Doxil, Dexamethasone
PAD: PS-341, liposomal Adriamycin, Dexamethasone

Regimen #1, Jakubowiak et al. 2009 & Dytfeld et al. 2011

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, 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
  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
  3. 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
  4. 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

VMP: Velcade, Melphalan, Prednisone

Regimen #1, San Miguel et al. 2008 & 2012, Mateos et al. 2010 (VISTA); Palumbo et al. 2010 & 2014

Phase III

Supportive medication:

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

42-day cycles x 9 cycles

Regimen #2, Palumbo et al. 2010 & 2014 & Bringhen et al. 2010 (weekly bortezomib)

Post-hoc analysis

35-day cycles x 9 cycles

Regimen #3, Gasparetto et al. 2010 ("Short-course" bortezomib)

Phase II

Supportive medications:

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

Regimen #4, Mateos et al. 2010

Phase III

Induction therapy

42-day cycle x 1 cycle, then

35-day cycles x 5 cycles, then

Maintenance therapy

3-month cycles x up to 3 years

Supportive medications:

  • "Patients with bone disease received bisphosphonates, and prophylactic aciclovir was recommended."
  • Patients receiving Thalidomide (Thalomid) needed to have thromboprophylaxis with either aspirin or low molecular weight heparin

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
  2. 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
  3. 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
  4. Gasparetto C, Gockerman JP, Diehl LF, de Castro CM, Moore JO, Long GD, Horwitz ME, Keogh G, Chute JP, Sullivan KM, Neuwirth R, Davis PH, Sutton LM, Anderson RD, Chao NJ, Rizzieri D. "Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma. Biol Blood Marrow Transplant. 2010 Jan;16(1):70-7. Epub 2009 Sep 3. link to original article contains verified protocol PubMed
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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 Jan 21. [Epub ahead of print] link to original article contains verified protocol PubMed

VMPT-VT

VMPT-VT: Velcade, Melphalan, Prednisone, Thalidomide, Velcade maintenance, Thalidomide maintenance

Regimen #1, Palumbo et al. 2010 & 2014

Phase III Improved OS

Induction therapy

42-day cycles x 9 cycles, then

Maintenance therapy

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

Regimen #2, Palumbo et al. 2010 & 2014, Bringhen et al. 2010

Phase III Improved OS

This represents a mid-protocol change where cycle length was decreased from 6 to 5 weeks and bortezomib was changed to weekly dosing.

35-day cycles x 9 cycles, then

Maintenance therapy:

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

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
  2. 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
  3. 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
  4. Update: Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival. J Clin Oncol. 2014 Jan 21. [Epub ahead of print] link to original article contains verified protocol PubMed

VTD

VTD: Velcade (bortezomib), Thalidomide, Dexamethasone

Regimen #1, Cavo et al. 2010 & Cavo et al. 2012 (GIMEMA)

Phase III

Induction therapy

21-day cycles 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 bortezomib, thalidomide, dexamethasone therapy

Bortezomib, thalidomide, dexamethasone therapy

35-day cycles x 2 cycles, then proceed to dexamethasone maintenance therapy

Dexamethasone maintenance therapy

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

Supportive medications:

Regimen #2, Moreau et al. 2011 (IFM2007-02)

Phase III

21-day cycle x 4 cycles, followed by high dose melphalan autologous stem cell transplant

Regimen #3, Rosiñol et al. 2012

Phase III Improved PFS Increased toxicity

Supportive Medications:

  • Low molecular weight heparin (LMWH) or Aspirin recommended

28-day cycles x 6 cycles

Regimen #4, Lok et al. 2014 (SC bortezomib)

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 #5, Kaufman et al. 2010

Retrospective

Supportive medications:

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

21-day cycles 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. 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
  3. 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
  4. 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
  5. 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
  6. Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous Bortezomib incorporated into the Bortezomib-Thalidomide-Dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Feb 14. [Epub ahead of print] link to original article contains verified protocol PubMed
  7. Meta-Analysis: Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. link to original article PubMed

VTD-PACE

VTD-PACE: Velcade, Thalidomide, Dexamethasone, Platinum (cisplatin), Adriamycin (doxorubicin), Cyclophosphamide, Etoposide

Regimen, Barlogie et al. 2007 (Total Therapy 3)

Prospective

Induction therapy

  • 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

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

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

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
  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
  3. Kapoor P, Ramakrishnan V, Rajkumar SV. Bortezomib combination therapy in multiple myeloma. Semin Hematol. 2012 Jul;49(3):228-42. Review. link to original article PubMed
  4. Retrospective: 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

VTP

VTP: Velcade (bortezomib), Thalidomide, Prednisone

Regimen

Phase III

Induction therapy

42-day cycle x 1 cycle, then

35-day cycles x 5 cycles, then

Maintenance therapy

3-month cycles x up to 3 years

Supportive medications:

  • "Patients with bone disease received bisphosphonates, and prophylactic aciclovir was recommended."
  • Patients receiving Thalidomide (Thalomid) needed to have thromboprophylaxis with either Aspirin or low-molecular-weight heparin

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

Post-transplant maintenance/consolidation

Bortezomib (Velcade)

Regimen #1, Mellqvist et al. 2013

Phase III

This trial only included bortezomib-naive patients

Beginning 3 months after ASCT, 21-day cycles x 2 cycles, then

Supportive medications:

  • "Bisphosphonates were administered according to national guidelines."

28-day cycles x 4 cycles

Regimen #2, Broyl et al. 2010 & Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)

Phase III

  • Bortezomib (Velcade) 1.3 mg/m2 IV once every two weeks x 2 years, starting 4 weeks after autologous stem cell transplant

References

  1. Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, el Jarari L, Bertsch U, Lokhorst HM, Durie BG, Goldschmidt H, Sonneveld P. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. Epub 2010 Sep 21. 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

DCEP

DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol

Regimen

Phase III

Induction

See details under VD (velcade) or VAD (Vincristine), VAD-P

Consolidation

28-day cycles x 2 cycles

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

Lenalidomide (Revlimid)

Regimen #1, Attal et al. 2012

Phase III

Consolidation

28-day cycles x 2 cycles, then

Maintenance therapy

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

Supportive medications:

  • "Thromboprophylaxis was not used"

Regimen #2, McCarthy et al. 2012

Phase III

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 #3, 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 cycles x 4 cycles, then proceed to maintenance therapy

Maintenance

28-day cycles, given until relapsed disease

Supportive medications:

References

  1. 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
  2. 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
  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
  4. 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

Prednisone

Regimen #1, Berenson et al. 2002 (SWOG 9210)

Phase III

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:

Regimen #2, Berenson et al. 2002 (SWOG 9210)

Phase III

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:

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

Thalidomide (Thalomid)

Regimen #1, Abdelkefi et al. 2007

Phase III

  • Thalidomide (Thalomid) 100 mg PO once daily x 6 months, starting 3 months after autologous stem cell transplant

Regimen #2, Broyl et al. 2010 & Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)

Phase III

  • Thalidomide (Thalomid) 50 mg PO once per day x 2 years, starting 4 weeks after autologous stem cell transplant

References

  1. 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
  2. Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, el Jarari L, Bertsch U, Lokhorst HM, Durie BG, Goldschmidt H, Sonneveld P. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. Epub 2010 Sep 21. link to original article contains verified protocol PubMed
  3. 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

Thalidomide & Prednisone

Regimen, Stewart et al. 2013 (NCICCTG Myeloma 10 Trial)

Levels of Evidence:

Phase III Improved PFS Decreased QOL

Supportive Medications:

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

Begin after autologous transplant and give for four years or until disease progression

References

  1. 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

VTD

VTD: Velcade (bortezomib), Thalidomide, Dexamethasone

Regimen #1, Cavo et al. 2010 & Cavo et al. 2012 (GIMEMA)

Phase III Improved PFS Increased toxicity

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

VTD consolidation

35-day cycles x 2 cycles, then proceed to dexamethasone maintenance therapy

Dexamethasone maintenance

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

Supportive medications:

Regimen #2, Ladetto et al. 2010

Phase II

Patients in Ladetto et al. 2010 had at least a very good partial response (VGPR) after autologous stem cell transplantation.

35-day cycles 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
  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
  3. 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

Relapsed/refractory

BBD

BBD: Bendamustine, Bortezomib, Dexamethasone

Regimen, 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. 2013 Nov 13. [Epub ahead of print] link to original article contains verified protocol PubMed

BD, Bort-Dex

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

Regimen #1, Fukushima et al. 2011 (BD)

Phase II

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

Regimen #2, Hjorth et al. 2012; Dimopoulos et al. 2013

Phase III

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. 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
  2. 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
  3. 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

BLD

BLD: Bendamustine, Lenalidomide, Dexamethasone

Regimen

Phase II

This study involved dose escalation. Dosages listed are the determined maximally tolerated doses (MTD).

Supportive medications:

  • Aspirin 325 mg PO once per day
  • "Gastroprotectant" (H2-blocker or PPI)

28-day cycles 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)

Regimen #1, Richardson et al. 2003, Richardson et al. 2005, Richardson et al. 2007 (APEX)

Phase III

Richardson et al. 2003 only described the first 8 cycles of treatment

21-day cycles x 8 cycles, then

35-day cycles x 3 cycles

Supportive medications (described in Richardson et al. 2005):

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

Regimen #2, Moreau et al. 2011 (Subcutaneous vs. intravenous Bortezomib (Velcade) +/- Dexamethasone)

Phase III

  • Bortezomib (Velcade) 1.3 mg/m2 SC/IV 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
    • IV injections are 1 mg/mL (3.5 mg bortezomib reconstituted in 3.5 mL NS), given IV push over 3-5 seconds
  • 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 daily on days 1, 2, 4, 5, 8, 9, 11, 12

Supportive medications:

  • Bisphosphonates "according to established guidelines"

21-day cycles x 8 to 10 cycles

Regimen #3, Dimopoulos et al. (VANTAGE 088)

Phase III

21-day 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
  2. 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
  3. 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. 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
  5. 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
  6. 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 & Doxorubicin liposomal

Regimen

Phase III

Supportive medications:

  • "Bisphosphonates were used according to established guidelines"

21-day cycles x up to 8 cycles, 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

Regimen, Dimopoulos et al. 2013 (VANTAGE 088)

Phase III

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

Carfilzomib (Kyprolis)

Regimen #1, Lendvai et al. 2014 (20/56 dosing)

Phase II

  • Carfilzomib (Kyprolis) 20 mg/m2 IV over 30 minutes once on days 1, 2 of cycle 1, then increased to 56 mg/m2 for days 8, 9, 15, and 16 and all days of subsequent cycles (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, Vij et al. 2012 (PX-171-004); Siegel et al. 2012 (PX-171-003-A1)

Phase II

  • Carfilzomib (Kyprolis) 20 mg/m2 (body surface area capped at 2.2 m2) IV over 2 to 10 minutes once per day on days 1 to 2, 8 to 9, 15 to 16 of cycle 1; then on subsequent cycles, Carfilzomib (Kyprolis) 27 mg/m2 (body surface area capped at 2.2 m2) IV over 2 to 10 minutes once per day on days 1 to 2, 8 to 9, 15 to 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-week cycles x up to 12 cycles, given until progression of disease or unacceptable toxicity

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. 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
  3. 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 May 14. [Epub ahead of print] link to original article PubMed
  4. 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

Car-Pom-d

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

Regimen

Phase II

There is some ambiguity about the Shah, et al. 2013 regimen if one only reviews the abstract or presentation. The following is based on reconciling both. Patients in Shah, et al. 2013 needed to be refractory to prior lenalidomide therapy.

Initial therapy

Supportive medications:

  • "Anti-viral therapy"
  • Aspirin 81 mg PO once per day
    • Low molecular weight heparin was used in patients intolerant of aspirin

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

Maintenance cycles

Maintenance cycles were from cycle 7 and on.

Supportive medications:

  • "Anti-viral therapy"
  • Aspirin 81 mg PO once per day
    • Low molecular weight heparin was used in patients intolerant of aspirin

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

References

  1. Jatin J. Shah, MD, Edward A. Stadtmauer, MD, Rafat Abonour, MD, Adam D. Cohen, MD, William I. Bensinger, MD, Cristina Gasparetto, MD, Jonathan L. Kaufman, MD, Suzanne Lentzsch, MD, Dan T. Vogl, MD, Robert Z. Orlowski, MD, PhD, Erica L. Kim, MPH, Marti McKinley, BSN, MBA, Brian G.M. Durie, MD. A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma. 2013 ASH Annual Meeting abstract 690. link to abstract link to presentation contains verified protocol

CRd

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

Regimen

Phase II

28-day cycles 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

DCEP

DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol

Regimen #1, 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, 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

  1. 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)

Regimen, Miguel et al. 2013 (MM-003)

Phase III

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

References

  1. Miguel JS, 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

PCP

PCP: Pomalidomide, Cyclophosphamide, Prednisone

Regimen, Larocca et al. 2013

Phase II

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

Induction

Supportive medications:

  • Aspirin 100 mg PO once per day or low-molecular-weight heparin "according to patient risk"

28-day cycles x 6 cycles, followed by:

Maintenance

Supportive medications:

  • Aspirin 100 mg PO once per day or low-molecular-weight heparin "according to patient risk"

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 Aug 16. [Epub ahead of print] link to original article contains verified protocol PubMed

PD

PD: Pomalidomide, Dexamethasone

Regimen #1, Leleu et al. 2013 (IFM 2009-02); Miguel et al. 2013 (MM-003); Richardson et al. 2014

Phase III

Supportive medications:

  • 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 per day unless contraindicated

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

Regimen #2, Lacy et al. 2011; Leleu et al. 2013 (IFM 2009-02)

Randomized Phase II, >20 per arm

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, Lacy et al. 2009; Lacy et al. 2010; 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. Miguel JS, 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. link to original article contains verified protocol PubMed

RD

RD: Revlimid, Dexamethasone

Regimen, Dimopoulos et al. 2007; Weber et al. 2007

Phase III

28-day cycles

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

RVD

RVD: Revlimid, Velcade, Dexamethasone

Regimen, Richardson et al. 2014

Phase II

Induction therapy

Supportive medications:

  • Aspirin 81 mg or 325 mg PO once per day
  • Antiviral therapy for VZV prophylaxis

21-day cycles x 8 cycles

Maintenance therapy

Patients who had at least stable disease and tolerated therapy could proceed to maintenance therapy at previously tolerated dose with a different schedule:

21-day cycles, indefinitely

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 Jan 15. [Epub ahead of print] link to original article contains verified protocol PubMed

TD, Thal-Dex

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

Regimen #1, Garderet et al. 2012 (MMVAR/IFM 2005-04)

Phase III

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

Supportive medications:

One year of treatment

Regimen #2, Hjorth et al. 2012

Phase III

  • 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

VMPT

VMPT: Velcade, Melphalan, Prednisone, Thalidomide

Regimen, 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

VTD: Velcade (bortezomib), Thalidomide, Dexamethasone

Regimen, Garderet et al. 2012 (MMVAR/IFM 2005-04)

Phase III

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

  • Bortezomib (Velcade) on two schedules:
    • 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11 of a 21-day cycle for 8 cycles, followed by
    • 1.3 mg/m2 IV bolus once per week on days 1, 8, 15, 22 of a 42-day cycle for 4 cycles
  • 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

Response criteria

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

Staging

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. ↑ 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
  3. ↑ 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
  4. ↑ 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. PubMed
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