Multiple myeloma, relapsed-refractory

Section editor
	Andrew J. Cowan, MD Seattle, WA LinkedIn

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Note: due to its size/complexity, the multiple myeloma page has been split into three sub-pages:

• Induction (transplant eligible and ineligible)
• First-line consolidation and maintenance
• Relapsed/refractory, including subsequent consolidation and maintenance

80 regimens on this page 122 variants on this page

Guidelines

ASCO

• 2018: Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology Clinical Practice Guideline update PubMed

BSH/UKMF

• 2017: Guidelines for the use of imaging in the management of patients with myeloma PubMed
• 2017: Guidelines for screening and management of late and long-term consequences of myeloma and its treatment PubMed
• 2014: Updates to the guidelines for the diagnosis and management of multiple myeloma PubMed

European Myeloma Network (EMN)

• 2018: From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives

ESMO

• 2017: Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

IMWG

• 2016: Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group
• 2016: International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment PubMed
• 2014: International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation
• 2013: International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease

NCCN

• NCCN Guidelines - Multiple Myeloma

Relapsed or refractory, randomized data

Bortezomib monotherapy

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Variant #1, 1 mg/m², 21-day cycle x 8

Study	Evidence	Comparator	Efficacy
Jagannath et al. 2004 (CREST)	Randomized Phase II (E)	Bortezomib +/- Dexamethasone	Seems not superior
Petrucci et al. 2013	Phase II

Note: Petrucci et al. 2013 was a re-treatment trial; the dose used was the same as in the initial treatment (1.0 or 1.3 mg/m²).

Chemotherapy

• Bortezomib (Velcade) 1 mg/m² IV bolus once per day on days 1, 4, 8, 11

21-day cycle for 8 cycles

Subsequent treatment

• CREST: Patients with PD after 2 cycles or SD after 4 cycles could escalate to bortezomib & dexamethasone

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

Study	Evidence	Comparator	Efficacy
Jagannath et al. 2004 (CREST)	Randomized Phase II (E)	Low-dose Bortezomib +/- Dexamethasone	Seems not superior
Richardson et al. 2005 (APEX)	Phase III (E)	High-dose dexamethasone	Seems to have superior OS (*)
Moreau et al. 2011 (MMY-3021)	Phase III (C)	Subcutaneous Bortezomib +/- Dexamethasone	Non-inferior ORR
Petrucci et al. 2013	Phase II
Orlowski et al. 2015	Randomized Phase II (C)	Bortezomib & Siltuximab	Seems not superior

Note: Petrucci et al. 2013 was a re-treatment trial; the dose used was the same as in the initial treatment (1.0 or 1.3 mg/m²).

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11

Supportive medications

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

21-day cycle for 8 cycles (see note)

Subsequent treatment

• CREST: Patients with PD after 2 cycles or SD after 4 cycles could escalate to bortezomib & dexamethasone
• APEX: Bortezomib consolidation
• MMY-3021: Patients with suboptimal response after 4 cycles could escalate to bortezomib & dexamethasone; patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles
• Orlowski et al. 2015: Bortezomib maintenance

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

Study	Evidence	Comparator	Efficacy
Moreau et al. 2011 (MMY-3021)	Phase III (E)	Intravenous Bortezomib +/- Dexamethasone	Non-inferior ORR

Chemotherapy

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

Supportive medications

• Bisphosphonates "according to established guidelines"

21-day cycle for 8 cycles (see note)

Subsequent treatment

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

Variant #4, indefinite 21-day cycles

Study	Evidence	Comparator	Efficacy
Richardson et al. 2003 (SUMMIT)	Phase II
Orlowski et al. 2007	Phase III (C)	Bortezomib & Doxorubicin liposomal	Inferior TTP
Mikhael et al. 2008	Phase IIIb
Dimopoulos et al. 2013 (VANTAGE 088)	Phase III (C)	Bortezomib & Vorinostat	Seems to have inferior PFS

Note: SUMMIT and Mikhael et al. 2008 specified a total of 8 cycles, but those who were deriving clinical benefit could continue beyond this.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11

21-day cycles (see note)

Subsequent treatment

• SUMMIT & Mikhael et al. 2008: patients with PD after 2 cycles or SD after 4 cycles could escalate to bortezomib & dexamethasone

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

Study	Evidence
Hainsworth et al. 2008	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.6 mg/m² IV bolus once per day on days 1, 8, 15, 22

35-day cycle for up to 10 cycles

References

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

Bortezomib & Dexamethasone

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

Variant #1, indefinite 21-day then 28-day cycles

Study	Evidence	Comparator	Efficacy
Jakubowiak et al. 2016 (CA204-009)	Randomized Phase II (C)	EBd	Might have inferior PFS

Chemotherapy

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

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

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

Study	Evidence	Comparator	Efficacy
Moreau et al. 2011 (MMY-3021)	Phase III (E)	IV Bort-Dex	Non-inferior ORR
Palumbo et al. 2016 (CASTOR)	Phase III (C)	DVd	Inferior PFS

Preceding treatment

• MMY-3021: Bortezomib x 4

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 8 cycles (see note)

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

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

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

Chemotherapy, Phase 1

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

21-day cycle for 8 cycles

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

Chemotherapy, Phase 2

• Bortezomib (Velcade) 1.3 mg/m² IV once per week days 1, 8, 22, 29
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 22, 23, 29, 30

42-day cycle for 4 cycles

Variant #4, 21-day cycles, response-adapted

Study	Evidence	Comparator	Efficacy
Hjorth et al. 2012 (NMSG 17/07)	Phase III (E)	Thal-Dex	Seems not superior
Dimopoulos et al. 2013 (CR013165)	Phase II	Not evaluable

Chemotherapy

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

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

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

Study	Evidence	Comparator	Efficacy
Jagannath et al. 2004 (CREST)	Randomized Phase II (E)	Low-dose Bort-Dex	Seems not superior
Moreau et al. 2011 (MMY-3021)	Phase III (C)	SC Bort-Dex	Non-inferior ORR
Kropff et al. 2017 (CR015247)	Phase III (C)	VCD	Seems not superior

Preceding treatment

• CREST: Bortezomib x 2 to 4 cycles
• MMY-3021: Bortezomib x 4

Chemotherapy

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

21-day cycle for 8 cycles (see note)

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

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

Study	Evidence	Comparator	Efficacy
Jagannath et al. 2004 (CREST)	Randomized Phase II (E)	Standard-dose Bort-Dex	Seems not superior

Preceding treatment

• Bortezomib x 2 to 4 cycles

Chemotherapy

• Bortezomib (Velcade) 1 mg/m² IV bolus once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 8 cycles

Variant #7, IV indefinite 21-day cycles

Study	Evidence	Comparator	Efficacy
Richardson et al. 2003 (SUMMIT)	Phase II		RR: 35%
Mikhael et al. 2008 (MMY-3001)	Phase IIIb		ORR: 67%
Dimopoulos et al. 2015 (ENDEAVOR)	Phase III (C)	Kd	Inferior OS (*)

Note: SUMMIT & MMY-3001 specified a total of 8 cycles, but those who were deriving clinical benefit could continue beyond this. Efficacy for ENDEAVOR based on the 2017 update.

Preceding treatment

• SUMMIT & MMY-3001: Bortezomib x 2 to 4 cycles

Chemotherapy

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

21-day cycles

Variant #8, SC indefinite 21-day cycles

Study	Evidence	Comparator	Efficacy
Dimopoulos et al. 2015 (ENDEAVOR)	Phase III (C)	Kd	Inferior OS (*)

Note: efficacy based on the 2017 update.

Chemotherapy

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

21-day cycles

Variant #9, indefinite 35-day cycles

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

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22
• Dexamethasone (Decadron) 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23

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

References

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

Bortezomib, Dexamethasone, Panobinostat

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Regimen

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

Chemotherapy, phase 1

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 8, 10, 12

21-day cycle for 8 cycles

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

Chemotherapy, phase 2

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 22, 29
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 22, 23, 29, 30
• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 8, 10, 12, 22, 24, 26, 29, 31, 33

42-day cycles

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

References

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

Bortezomib & Doxorubicin liposomal

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Regimen

Study	Evidence	Comparator	Efficacy
Orlowski et al. 2007	Phase III (E)	Bortezomib	Superior TTP

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11
• Pegylated liposomal doxorubicin (Doxil) 30 mg/m² IV over at least 1 hour once on day 4, given after Bortezomib (Velcade)

Supportive medications

• Bisphosphonates were used according to established guidelines

21-day cycle for up to 8 cycles

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

References

1. Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. link to original article contains verified protocol PubMed
   1. Update: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. link to original article PubMed

Bortezomib & Vorinostat

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Regimen

Study	Evidence	Comparator	Efficacy
Dimopoulos et al. 2013 (VANTAGE 088)	Phase III (E)	Bortezomib	Seems to have superior PFS

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11
• Vorinostat (Zolinza) 400 mg PO once per day on days 1 to 14

21-day cycles

References

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

Carfilzomib monotherapy

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Variant #1, 20/27 dosing, variant #1

Study	Evidence	Comparator	Efficacy
Hájek et al. 2016 (FOCUS)	Phase III (E)	Cyclophosphamide & Dexamethasone CP	Seems not superior

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

Chemotherapy

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

Supportive medications

• IV and PO hydration required for cycle 1
• Dexamethasone (Decadron) 4 mg PO/IV prior to each cycle 1 dose
• Ciprofloxacin (Cipro) 500 mg PO once per day during cycle 1

28-day cycles

Variant #2, 20/27 dosing, variant #2

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

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

Chemotherapy

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

Supportive medications

• IV and PO hydration required for cycle 1, then as needed
• Dexamethasone (Decadron) 4 mg PO/IV prior to each cycle 1 dose, then as needed
• Prophylactic antibiotics (not specified) in cycle 1
• Acyclovir (Zovirax) for patients with history of herpes infection, in cycle 1

28-day cycles

Variant #3, 20/56 dosing

Study	Evidence	Efficacy
Lendvai et al. 2014	Phase II	ORR: 55%

Chemotherapy

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

Supportive medications

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

28-day cycles

Variant #4, 20/27 dosing, with BSA cap

Study	Evidence	Efficacy
Vij et al. 2012a (PX-171-004 bortezomib-naive)	Phase II	ORR: 42-52%
Siegel et al. 2012 (PX-171-003-A1)	Phase II	ORR: 24%

Chemotherapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² (body surface area capped at 2.2 m²) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycle 2 onwards: 27 mg/m² (body surface area capped at 2.2 m²) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Note: Neither Vij et al. 2012a 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. 2012a 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 modifications

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

28-day cycle for up to 12 cycles

Variant #5, 20/20 dosing

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

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

Chemotherapy

• Carfilzomib (Kyprolis) 20 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16

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

Variant #6, 15/20/27 dosing, for renal impairment

Study	Evidence	ORR: 17%
Badros et al. 2013 (PX-171-005)	Phase II	ORR: 25.5%

Chemotherapy

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

Supportive medications

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

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

Subsequent treatment

• Patients with less than PR after 2 cycles or less than CR after 4 cycles were allowed to escalate to carfilzomib & dexamethasone

References

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

Carfilzomib & Dexamethasone

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Kd: Kyprolis (Carfilzomib) & low-dose dexamethasone

Variant #1, 20/27

Study	Evidence	Comparator	Efficacy
Moreau et al. 2018 (ARROW)	Phase III (C)	Weekly Kd	Inferior PFS

Chemotherapy

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

28-day cycles

Variant #2, 20/56 dosing

Study	Evidence	Comparator	Efficacy
Dimopoulos et al. 2015 (ENDEAVOR)	Phase III (E)	Vd	Superior OS (*)

Note: efficacy based on the 2017 update.

Chemotherapy

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

28-day cycles

Variant #3, 20/70 dosing (weekly)

Study	Evidence	Comparator	Efficacy
Berenson et al. 2016 (CHAMPION-1)	Phase I/II
Moreau et al. 2018 (ARROW)	Phase III (E)	Twice-weekly Kd	Superior PFS

Chemotherapy

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

28-day cycles

Variant #4, 27 dosing

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

Preceding treatment

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

Chemotherapy

• Carfilzomib (Kyprolis) 27 mg/m² IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
• Dexamethasone (Decadron) 20 mg (route not specified) once per day on days 1, 2, 8, 9, 15, 16, given first

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

References

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

Cyclophosphamide & Prednisone

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CP: Cyclophosphamide & Prednisone
CyPred: Cyclophosphamide & Prednisone

Variant #1

Study	Evidence	Comparator	Efficacy
Hájek et al. 2016 (FOCUS)	Phase III (C)	Carfilzomib	Seems not superior

Note: cyclophosphamide was described as optional for the control arm but 95% of patients received it.

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day
• Prednisone (Sterapred) 30 mg PO once every other day

Continued until progression

Variant #2

Study	Evidence
de Weerdt et al. 2001	Non-randomized

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg PO once per day
• Prednisone (Sterapred) 10 to 20 mg PO once per day

Continued until progression or intolerance

References

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

CRd (Carfilzomib)

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

Variant #1

Study	Evidence	Comparator	Efficacy	Toxicity
Stewart et al. 2014 (ASPIRE)	Phase III (E)	Rd	Superior OS (*)	Superior GHS/QoL

Efficacy based on the 2018 update.

Chemotherapy

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

Supportive medications

• Valacyclovir (Valtrex) (dose not specified) or equivalent antiviral while taking Lenalidomide (Revlimid)
• Aspirin (dose not specified) or other anticoagulant or antiplatelet medication such as Clopidogrel (Plavix), low-molecular-weight heparin or Warfarin (Coumadin) while taking Lenalidomide (Revlimid)
• Bisphosphonates while taking Dexamethasone (Decadron)
• Lansoprazole (Prevacid) (dose not specified) or other proton pump inhibitor while taking Dexamethasone (Decadron)
• A prophylactic antibiotic (Ciprofloxacin (Cipro), Amoxicillin, Trimethoprim/Sulfamethoxazole (Bactrim DS) are given as examples)

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

Variant #2

Study	Evidence
Wang et al. 2013	Phase II

Chemotherapy

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

28-day cycle for 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 link to PMC article PubMed
2. ASPIRE: Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. link to original article link to PMC article PubMed
   2. HRQoL analysis: Stewart AK, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Buchanan J, Cocks K, Yang X, Xing B, Zojwalla N, Tonda M, Moreau P, Palumbo A. Health-related quality-of-life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol. 2016 Nov 10;34(32):3921-3930. link to original article PubMed
   3. Update: Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, San-Miguel J, Obreja M, Blaedel J, Stewart AK. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 10;36(8):728-734. Epub 2018 Jan 17. link to original article PubMed

Cyclophosphamide & Dexamethasone

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Regimen

Study	Evidence	Comparator	Efficacy
Hájek et al. 2016 (FOCUS)	Phase III (C)	Carfilzomib	Seems not superior

Note: cyclophosphamide was described as optional for the control arm but 95% of patients received it.

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day
• Dexamethasone (Decadron) 6 mg PO once every other day

Continued until progression

References

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

DRd

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DRd: Daratumumab, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Plesner et al. 2016	Phase I/II
Dimopoulos et al. 2016 (POLLUX)	Phase III (E)	Rd	Superior PFS

Chemotherapy

• Daratumumab (Darzalex) as follows:
  • Cycles 1 & 2: 16 mg/kg IV once per week
  • Cycles 3 to 6: 16 mg/kg IV once every two weeks
  • Cycle 7 onwards: 16 mg/kg IV once per cycle
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
  • POLLUX: Patients with CrCl of 30 to 60 mL/min/1.73m² received 10 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
  • POLLUX: Patients older than 75 years or underweight (BMI less than 18.5) could receive 20 mg PO once per week

28-day cycle for up to 24 months (Plesner et al. 2014) or until progression (POLLUX)

References

1. Plesner T, Arkenau HT, Gimsing P, Krejcik J, Lemech C, Minnema MC, Lassen U, Laubach JP, Palumbo A, Lisby S, Basse L, Wang J, Sasser AK, Guckert ME, de Boer C, Khokhar NZ, Yeh H, Clemens PL, Ahmadi T, Lokhorst HM, Richardson PG. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016 Oct 6;128(14):1821-8. Epub 2016 Aug 16. link to original article contains verified protocol link to PMC article PubMed
2. POLLUX: Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. link to original article link to original protocol contains verified protocol PubMed

DVd

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DVd: Daratumumab, Velcade (Bortezomib), low-dose dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Palumbo et al. 2016 (CASTOR)	Phase III (E)	Vd	Superior PFS

Chemotherapy

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

21-day cycle for 8 cycles

Subsequent treatment

• Daratumumab maintenance

References

1. CASTOR: Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed

EBd

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EBd: Elotuzumab, Bortezomib, low-dose dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Jakubowiak et al. 2016	Randomized Phase II (E)	Bd	Might have superior PFS

Chemotherapy

• Elotuzumab (Empliciti) as follows:
  • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15
  • Cycles 3 to 8: 10 mg/kg IV once per day on days 1 & 11
  • Cycle 9 onwards: 10 mg/kg IV once per day on days 1 & 15
• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² SC/IV once per day on days 1, 4, 8, 11
  • Cycle 9 onwards: 1.3 mg/m² SC/IV once per day on days 1, 8, 15
• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 2:
    • 20 mg PO once per day on days 2, 4, 5, 9, 11, 12
    • 8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to Elotuzumab (Empliciti) on days 1, 8, 15
  • Cycles 3 to 8:
    • 20 mg PO once per day on days 2, 4, 5, 8, 9, 12
    • 8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to Elotuzumab (Empliciti) on days 1 & 11
  • Cycle 9 onwards:
    • 20 mg PO once per day on days 2, 8, 9, 16
    • 8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to Elotuzumab (Empliciti) on days 1 & 15

Supportive medications

• Diphenhydramine (Benadryl) 25 to 50 mg (route not specified) 30 to 90 minutes prior to Elotuzumab (Empliciti)
• Ranitidine (Zantac) 50 mg (route not specified) 30 to 90 minutes prior to Elotuzumab (Empliciti)
• Acetaminophen (Tylenol) 650 to 1000 mg PO 30 to 90 minutes prior to Elotuzumab (Empliciti)

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

References

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

ELd

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ELd: Elotuzumab, Lenalidomide, low-dose dexamethasone

Variant #1

Study	Evidence	Comparator	Efficacy
Lonial et al. 2015 (ELOQUENT-2)	Phase III (E)	Ld	Seems to have superior OS (*)
Richardson et al. 2015 (1703 Study)	Randomized Phase Ib/II (E)	Elotuzumab 20 mg, Lenalidomide, Dexamethasone	Seems not superior

Note: the complex dexamethasone instructions for ELOQUENT-2 were not described in the abstract of Richardson et al. 2015. Efficacy reported for ELOQUENT-2 is based on the 2017 update.

Chemotherapy

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

Supportive medications

• Mandatory premedications 30 to 90 minutes prior to Elotuzumab (Empliciti):
  • Diphenhydramine (Benadryl) 25 to 50 mg (route not specified) or its equivalent
  • Ranitidine (Zantac) 50 mg (route not specified) or its equivalent
  • Acetaminophen (Tylenol) 650 to 1000 mg (route not specified) or its equivalent
• "Thromboembolic prophylaxis (e.g., aspirin, low-molecular-weight heparin, or vitamin K antagonists) was administered according to institutional guidelines or at the discretion of the investigator."

28-day cycles

Variant #2

Study	Evidence	Comparator	Efficacy
Richardson et al. 2015 (1703 Study)	Randomized Phase Ib/II (E)	Elotuzumab 10 mg, Lenalidomide, Dexamethasone	Seems not superior

Chemotherapy

• Elotuzumab (Empliciti) as follows:
  • Cycles 1 & 2: 20 mg/kg IV once per day on days 1, 8, 15, 22
  • Cycle 3 onwards: 20 mg/kg IV once per day on days 1 & 15
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week

28-day cycles

References

1. Phase I: Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK, Jagannath S. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012 Jun 1;30(16):1953-9. link to original article contains verified protocol PubMed
   1. Abstract: Update: Paul G. Richardson, Sundar Jagannath, MD, Philippe Moreau, MD, Andrzej Jakubowiak, MD, PhD, Marc S Raab, MD, PhD, Thierry Facon, MD, Ravi Vij, MBBS, MD, Darrell White, MD, Donna E. Reece, MD, Lotfi Benboubker, MD, PhD, Jeffrey Zonder, MD, L. Claire Tsao, PhD, Kenneth C. Anderson, MD, Eric Bleickardt, MD, Anil K Singhal, MD and Sagar Lonial, MD. Final Results for the 1703 Phase 1b/2 Study of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. ASH 2014 Abstract 302 link to abstract
2. ELOQUENT-2: Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. link to original article contains verified protocol PubMed
   1. Update: Dimopoulos MA, Lonial S, White D, Moreau P, Palumbo A, San-Miguel J, Shpilberg O, Anderson K, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Bleickardt E, Poulart V, Sheng J, Sy O, Katz J, Singhal A, Richardson P. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017 Sep;178(6):896-905. Epub 2017 Jul 5. link to original article PubMed
3. Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, Vij R, White D, Reece DE, Benboubker L, Zonder J, Tsao LC, Anderson KC, Bleickardt E, Singhal AK, Lonial S; 1703 study investigators. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015 Dec;2(12):e516-27. Epub 2015 Nov 16. link to original article contains protocol PubMed

IRd

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

Regimen

Study	Evidence	Comparator	Efficacy
Moreau et al. 2016 (TOURMALINE-MM1)	Phase III (E)	Rd	Superior PFS
Hou et al. 2017 (TOURMALINE-MM1 China Continuation)	Phase III (E)	Rd	Superior OS

Chemotherapy

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

Supportive medications

• Thromboprophylaxis required

28-day cycles

References

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

Ixazomib & Dexamethasone

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Variant #1

Study	Evidence	Comparator	Efficacy
Kumar et al. 2015	Phase II
Kumar et al. 2016	Randomized Phase II (E)	Ixazomib 4 mg & Dexamethasone	Might have superior ORR

Chemotherapy

• Ixazomib (Ninlaro) 5.5 mg PO once per day on days 1, 8, 15
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 15, 16

Supportive medications

• Herpes zoster prophylaxis

28-day cycles until progression

Variant #2

Study	Evidence	Comparator	Efficacy
Kumar et al. 2016	Randomized Phase II (E)	Ixazomib 5.5 mg & Dexamethasone	Might have inferior ORR

Chemotherapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 15, 16

Supportive medications

• Herpes zoster prophylaxis

28-day cycles until progression

References

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

Lenalidomide monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Richardson et al. 2006	Randomized Phase II (E)	Lenalidomide 15 mg PO BID	Seems not superior
Richardson et al. 2009	Phase II

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

Chemotherapy

• Lenalidomide (Revlimid) 30 mg PO once per day on days 1 to 21

28-day cycles

Subsequent treatment

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

References

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

Pomalidomide & Dexamethasone

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PD: Pomalidomide, Dexamethasone
PomDex: Pomalidomide, Dexamethasone
Pom + LoDEX: Pomalidomide, Low-dose Dexamethasone

Variant #1, 4 mg 21/28

Study	Evidence	Comparator	Efficacy
San Miguel et al. 2013 (MM-003)	Phase III (E)	Dexamethasone	Superior OS (*)
Leleu et al. 2013 (IFM 2009-02)	Randomized Phase II (E)	Pom-Dex (28/28)	Seems not superior
Richardson et al. 2014	Randomized Phase II (E)	Pomalidomide	Seems to have superior PFS
Leleu et al. 2015 (IFM 2010-02)	Phase II
Baz et al. 2016	Randomized Phase I/II (C)	PomCyDex	Seems to have inferior ORR rate
Dimopoulos et al. 2016 (STRATUS)	Phase IIIb

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

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Age less than or equal to 75: 40 mg PO once per day on days 1, 8, 15, 22
  • Age greater than 75: 20 mg PO once per day on days 1, 8, 15, 22

Supportive medications

• San Miguel et al. 2013: Thromboprohpylaxis required. "Choice of thromboprophylaxis and use of myeloid and erythroid growth factors was left to the physician's discretion."
• Leleu et al. 2013: Thromboprophylaxis "at the physician's discretion"
• Richardson et al. 2014: Aspirin 81 to 100 mg once per day unless contraindicated
• Baz et al. 2016: Aspirin 81 mg once per day unless contraindicated
• STRATUS: Thromboprophylaxis with low-dose Aspirin, |LMWH, or equivalent was required
• Leleu et al. 2013: G-CSF allowed beginning with cycle 2 and on

28-day cycles

Variant #2, 4 mg continuous

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

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 28
• Dexamethasone (Decadron) 40 mg PO once per day on day 1, 8, 15, 22

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

Variant #3, 2 mg continuous

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

Chemotherapy

• Pomalidomide (Pomalyst) 2 mg PO once per day on days 1 to 28
• Dexamethasone (Decadron) 40 mg PO once per day on day 1, 8, 15, 22

Supportive medications

• Aspirin 325 mg PO once per day
  • low molecular weight heparin or Warfarin (Coumadin) could be substituted at physician discretion

28-day cycles

References

1. Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Kyle RA, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009 Oct 20;27(30):5008-14. Epub 2009 Aug 31. link to original article contains verified protocol PubMed
2. Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV, Buadi F. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010 Nov;24(11):1934-9. Epub 2010 Sep 9. link to original article contains verified protocol link to PMC article PubMed
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 link to PMC article PubMed
4. IFM 2009-02: Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, Mathiot C, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B, Stoppa AM, Hennache B, Bréchignac S, Meuleman N, Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L, Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, Fermand JP, Avet-Loiseau H, Facon T. Pomalidomide plus low dose dexamethasone is active and well tolerated in bortezomib and lenalidomide refractory multiple myeloma: IFM 2009-02. Blood. 2013 Mar 14;121(11):1968-1975. Epub 2013 Jan 14. link to original article contains verified protocol PubMed
5. MM-003: San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-66. Epub 2013 Sep 3. link to original article contains verified protocol PubMed
   1. Update: Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Spencer A, Knop S, Bahlis NJ, Renner C, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel JF. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015 Oct;100(10):1327-33. Epub 2015 Aug 6. link to original article link to PMC article PubMed
6. Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article contains verified protocol link to PMC article PubMed
7. IFM 2010-02: Leleu X, Karlin L, Macro M, Hulin C, Garderet L, Roussel M, Arnulf B, Pegourie B, Kolb B, Stoppa AM, Brechiniac S, Marit G, Thielemans B, Onraed B, Mathiot C, Banos A, Lacotte L, Tiab M, Dib M, Fuzibet JG, Petillon MO, Rodon P, Wetterwald M, Royer B, Legros L, Benboubker L, Decaux O, Escoffre-Barbe M, Caillot D, Fermand JP, Moreau P, Attal M, Avet-Loiseau H, Facon T; Intergroupe Francophone du Myélome (IFM). Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015 Feb 26;125(9):1411-7. Epub 2015 Jan 9. link to original article contains verified protocol PubMed
8. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. link to original article contains verified protocol PubMed
9. STRATUS: Dimopoulos MA, Palumbo A, Corradini P, Cavo M, Delforge M, Di Raimondo F, Weisel KC, Oriol A, Hansson M, Vacca A, Blanchard MJ, Goldschmidt H, Doyen C, Kaiser M, Petrini M, Anttila P, Cafro AM, Raymakers R, San-Miguel J, de Arriba F, Knop S, Röllig C, Ocio EM, Morgan G, Miller N, Simcock M, Peluso T, Herring J, Sternas L, Zaki MH, Moreau P. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016 Jul 28;128(4):497-503. Epub 2016 May 25. link to original article contains verified protocol link to PMC article PubMed

Pomalidomide monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Richardson et al. 2014	Randomized Phase II (C)	POM+LoDEX (PD)	Seems to have inferior PFS

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Supportive medications

• Aspirin 81 to 100 mg per day unless contraindicated

28-day cycles until disease progression or unacceptable toxicity

References

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

PomCyDex

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PomCyDex: Pomalidomide, Cyclophosphamide, Dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Baz et al. 2016	Randomized Phase I/II (E)	PomDex	Seems to have superior ORR rate

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Cyclophosphamide (Cytoxan) 400 mg PO once per day on days 1, 8, 15
• Dexamethasone (Decadron) 40 mg (20 mg for patients greater than 75 years old) PO once per day on days 1, 8, 15, 22

Supportive medications

• Aspirin 81 mg once per day unless contraindicated

28-day cycles until disease progression or unacceptable toxicity

References

1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. link to original article contains verified protocol PubMed

Rd

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

Variant #1, Len @ 25 mg 21/28

Study	Evidence	Comparator	Efficacy	Toxicity
Stewart et al. 2014 (ASPIRE)	Phase III (C)	KRd	Inferior OS (*)	Inferior GHS/QoL
Lonial et al. 2015 (ELOQUENT-2)	Phase III (C)	ELd	Seems to have inferior OS (*)
Moreau et al. 2016 (TOURMALINE-MM1)	Phase III (C)	IRd	Inferior PFS
Dimopoulos et al. 2016 (POLLUX)	Phase III (C)	DRd	Inferior PFS
Hou et al. 2017 (TOURMALINE-MM1 China Continuation)	Phase III (C)	IRd	Inferior OS

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

Chemotherapy

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

Supportive medications

Best described by ASPIRE:

• Valacyclovir (Valtrex) (dose not specified) or equivalent antiviral while taking Lenalidomide (Revlimid)
• Aspirin (dose not specified) or other anticoagulant or antiplatelet medication such as Clopidogrel (Plavix), low-molecular-weight heparin or Warfarin (Coumadin) while taking Lenalidomide (Revlimid)
• Bisphosphonates while taking Dexamethasone (Decadron)
• Lansoprazole (Prevacid) (dose not specified) or other proton pump inhibitor while taking Dexamethasone (Decadron)
• A prophylactic antibiotic (Ciprofloxacin (Cipro), Amoxicillin, Trimethoprim/Sulfamethoxazole (Bactrim DS) are given as examples)

28-day cycles

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

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

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

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycle 5 onwards: 40 mg PO once per day on days 1 to 4

28-day cycles until progression or intolerable side effects

Variant #3, Len @ 30 mg 21/28

Study	Evidence	Comparator	Efficacy
Richardson et al. 2006	Randomized Phase II (E)	Dexamethasone & twice-daily Lenalidomide	Seems not superior

This regimen is essentially of historical interest.

Preceding treatment

• Lenalidomide x 2

Chemotherapy

• Lenalidomide (Revlimid) 30 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 15 to 18

28-day cycles until progression

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

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

Chemotherapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycle 5 onwards: 20 mg PO once per day on days 1 to 4

28-day cycles until progression

References

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

Thal-Dex

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

Variant #1, thalidomide 50->200

Study	Evidence	Comparator	Efficacy
Hjorth et al. 2012 (NMSG 17/07)	Phase III (C)	Bort-Dex	Seems not superior

Chemotherapy

• 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

Variant #2, thalidomide 200

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

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

Chemotherapy

• Thalidomide (Thalomid) 200 mg PO once per day
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive medications

• Enoxaparin (Lovenox) 40 mg SC once per day for primary prophylaxis
• Warfarin (Coumadin) for secondary prophylaxis

21-day cycles for 12 months

Variant #3, thalidomide 200->400

Study	Evidence
Dimopoulos et al. 2001	Phase II

Chemotherapy

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

Monthly cycles

References

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

VDC

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

Variant #1

Study	Evidence	Comparator	Efficacy
Kropff et al. 2017 (CR015247)	Phase III (E)	VD	Seems not superior

Treatment details are from the NCT record.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
• Cyclophosphamide (Cytoxan) 50 mg PO once per day

21-day cycle for up to 8 cycles

Variant #2

Study	Evidence
de Waal et al. 2015	Phase II

Treatment intended for bortezomib-naive patients.

Chemotherapy

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

Supportive medications

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

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

Subsequent treatment

• Patients with PR/CR: Bortezomib & cyclophosphamide maintenance

Variant #3

Study	Evidence
Kropff et al. 2007	Phase II

Treatment intended for bortezomib-naive patients.

Chemotherapy

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

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

References

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

VTD

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VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

Regimen

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

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

Chemotherapy

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

Supportive medications

• Enoxaparin (Lovenox) 40 mg SC once per day for primary prophylaxis; Warfarin (Coumadin) for secondary prophylaxis
• Herpes zoster prophylaxis highly recommended

One year of treatment

References

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

Relapsed or refractory, non-randomized or retrospective data

BBD

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BBD: Bendamustine, Bortezomib, Dexamethasone

Regimen

Study	Evidence
Ludwig et al. 2013	Phase II

Chemotherapy

• Bendamustine 70 mg/m² IV once per day on days 1 & 4
• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 20 mg (route not specified) once per day on days 1, 4, 8, 11

28-day cycle for up to 8 cycles

References

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

BLD

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BLD: Bendamustine, Lenalidomide, Dexamethasone

Regimen

Study	Evidence
Lentzsch et al. 2012	Phase I/II

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

Chemotherapy

• Bendamustine 75 mg/m² IV once per day on days 1 & 2
• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg (no route specified) once per week

Supportive medications

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

28-day cycle for up to 8 cycles

References

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

Bortezomib-HyperCAD

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

Regimen

Study	Evidence
Saraceni et al. 2018	Retrospective

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1 & 4
• Cyclophosphamide (Cytoxan) 300 mg/m² IV q12h on days 1 to 4 (8 doses; total dose per cycle: 2400 mg/m²)
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion on days 1 to 4 (total dose per cycle: 36 mg/m²)
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive Medications

• Pegfilgrastim (Neulasta) 6 mg SC once on day 5 or 6
• Mesna (Mesnex) 350 mg/m²/day IV continuous infusion on days 1 to 4
• Antiviral prophylaxis with Acyclovir (Valtrex) daily (dose not specified)
• "Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"

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

References

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

Bortezomib, Thalidomide, Dexamethasone, Panobinostat

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Regimen

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

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

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1 & 8
• Thalidomide (Thalomid) 100 mg PO once per day
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9
• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 8, 10, 12

21-day cycle for 16 cycles

References

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

BTD

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BTD: Bendamustine, Thalidomide, Dexamethasone

Regimen

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

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

Chemotherapy

• Bendamustine 60 mg/m² IV once per day on days 1 & 8
• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21
  • Note: abstract says days 1 to 21 but body of paper says days 1 to 28
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15, 22

Supportive medications

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

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

References

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

Carfilzomib & Panobinostat

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Regimen

Study	Evidence
Berdeja et al. 2015	Phase II

Chemotherapy

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

28-day cycles until progression or intolerance

References

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

CPD

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

Regimen

Study	Evidence
Shah et al. 2015	Phase I (*)

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

Chemotherapy

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

Supportive medications

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

28-day cycle for 6 cycles

Subsequent treatment

• CPD maintenance

References

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

CPR

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

Variant #1, "REP"

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

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

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Cyclophosphamide (Cytoxan) 50 mg PO once per day
• Prednisone (Sterapred) 20 mg PO once per day

28-day cycles

Variant #2, "CPR"

Study	Evidence
Reece et al. 2014	Phase I/II

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² PO on days 1, 8, 15
• Prednisone (Sterapred) 100 mg PO once every other day
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycles

References

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

CRD (Cyclophosphamide)

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CRD: Cyclophosphamide, Revlimid (Lenalidomide), Dexamethasone

Regimen

Study	Evidence
Schey et al. 2010	Phase I/II

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg PO once per day on days 1 & 8
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 8 to 11

Supportive medications

• Aspirin 75 mg PO once per day

28-day cycles

References

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

CTD

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CTD: Cyclophosphamide, Thalidomide, Dexamethasone

Regimen

Study	Evidence
Dimopoulos et al. 2004	Phase II

Chemotherapy

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

28-day cycles

References

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

Daratumumab monotherapy

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Regimen

Study	Evidence
Lokhorst et al. 2015 (GEN501 part 2)	Phase I/II
Lonial et al. 2016 (SIRIUS)	Phase II

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

Chemotherapy

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

Supportive medications

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

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

Given until progression of disease or unacceptable toxicity

References

1. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. link to original article contains verified protocol link to supplementary appendix link to study protocol PubMed
2. SIRIUS: Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Bladé J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. Epub 2016 Jan 7. link to original article contains protocol PubMed
3. Pooled update: Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, Lokhorst HM, Voorhees PM, Richardson PG, Chari A, Sasser AK, Axel A, Feng H, Uhlar CM, Wang J, Khan I, Ahmadi T, Nahi H. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. Epub 2016 May 23. link to original article link to PMC article PubMed

DCEP

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

Variant #1

Study	Evidence
Lazzarino et al. 2001	Phase II

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

Chemotherapy

• Dexamethasone (Decadron) 40 mg once per day on days 1 to 4
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m²)
• Cisplatin (Platinol) 10 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 40 mg/m²)

Supportive medications

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

One course

Variant #2

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

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

Chemotherapy

• Dexamethasone (Decadron) 40 mg IV bolus once per day on days 1 to 4
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m²)
• Cisplatin (Platinol) 15 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 60 mg/m²)

Supportive medications

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

28-day cycles

References

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

DTPACE

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

Regimen

Study	Evidence
Lee et al. 2003	Prospective

To be completed

Chemotherapy

• Dexamethasone (Decadron)
• Thalidomide (Thalomid)
• Cisplatin (Platinol)
• Doxorubicin (Adriamycin)
• Cyclophosphamide (Cytoxan)
• Etoposide (Vepesid)

References

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

FRD

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

Regimen

Study	Evidence
Chari et al. 2017	Phase II

Chemotherapy

• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 15, 17, 19
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15

28-day cycles

References

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

Hyper-CVAD

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

Variant #1

Study	Evidence
Dimopoulos et al. 1996	Phase II

To be completed.

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Vincristine (Oncovin)
• Doxorubicin (Adriamycin)
• Dexamethasone (Decadron)

Variant #2, modified

Study	Evidence
Saraceni et al. 2018	Retrospective

Note that vincristine is a flat dose.

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² IV q12h on days 1 to 4 (8 doses; total dose per cycle: 2400 mg/m²)
• Vincristine (Oncovin) 0.4 mg/day IV continuous infusion on days 1 to 4 (total dose per cycle: 1.6 mg)
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion on days 1 to 4 (total dose per cycle: 36 mg/m²)
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive Medications

• Pegfilgrastim (Neulasta) 6 mg SC once on day 5 or 6
• Mesna (Mesnex) 350 mg/m²/day IV continuous infusion on days 1 to 4
• Antiviral prophylaxis with Valacyclovir (Valtrex) daily (dose not specified)
• "Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"

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

References

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

Ixazomib monotherapy

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Regimen

Study	Evidence
Kumar et al. 2015	Phase II

Chemotherapy

• Ixazomib (Ninlaro) 5.5 mg PO once per day on days 1, 8, 15

28-day cycles

Subsequent treatment

• Patients with no minor response by end of cycle 2, no PR by end of cycle 4, or progression: Ixazomib & Dexamethasone

References

1. Phase 1: Kumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, Hui AM, Gupta N, Di Bacco A, Yu J, Shou Y, Niesvizky R. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014 Aug 14;124(7):1047-55. Epub 2014 Jun 5. link to original article link to PMC article PubMed
2. Phase 1: Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, Talpaz M, Berg D, Liu G, Yu J, Gupta N, Di Bacco A, Hui AM, Lonial S. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 Aug 14;124(7):1038-46. Epub 2014 Jun 11. link to original article link to PMC article PubMed
3. Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338. link to original article contains verified protocol link to PMC article PubMed

PAD

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

Regimen

Study	Evidence
Cook et al. 2016 (BSBMT/UKMF Myeloma X)	Non-randomized portion of RCT

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

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Doxorubicin (Adriamycin) 9 mg/m² IV once per day on days 1 to 4
  • Could be given as a 4-day continuous infusion or as bolus injections
• Dexamethasone (Decadron) as follows:
  • Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
  • Cycles 2 to 4: 40 mg PO once per day on days 1 to 4

2 to 4 cycles

Subsequent treatment

• High-dose melphalan & autologous hematopoietic cell transplant versus weekly oral cyclophosphamide maintenance

References

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

PCP

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PCP: Pomalidomide, Cyclophosphamide, Prednisone

Regimen

Study	Evidence
Larocca et al. 2013	Phase I/II

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

Chemotherapy

• Pomalidomide (Pomalyst) 2.5 mg PO once per day
• Cyclophosphamide (Cytoxan) 50 mg PO once every other day
• Prednisone (Sterapred) 50 mg PO once every other day

Supportive medications

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

28-day cycle for 6 cycles

Subsequent treatment

• Pomalidomide & prednisone maintenance

References

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

Pomalidomide, Dexamethasone, Daratumumab

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Regimen

FDA-recommended dose

Study	Evidence	Efficacy
Chari et al. 2017 (EQUULEUS)	Phase Ib	ORR: 59% (95% CI, 49-69)

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week
  • Patients older than 75 years or BMI less than 18.5: 20 mg PO once per week
• Daratumumab (Darzalex) as follows:
  • Cycles 1 & 2: 16 mg/kg IV once per week
  • Cycles 3 to 6: 16 mg/kg IV once every 2 weeks
  • Cycle 7 onwards: 16 mg/kg IV once every 4 weeks

Supportive medications

• Dexamethasone (Decadron) 20 mg prior to Daratumumab (Darzalex) infusions
  • For patients receiving the 40 mg/wk dose, the remainder is given after the infusion on day of infusion
• Acetaminophen (Tylenol) prior to Daratumumab (Darzalex)
• An antihistamine prior to Daratumumab (Darzalex)

28-day cycles

References

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

PVD

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PVD: Pomalidomide, Velcade (Bortezomib), Dexamethasone

Regimen

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

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

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Bortezomib (Velcade) 1.3 mg/m² IV/SC once per day on days 1, 8, 15, 22
• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22

Supportive medications

• Aspirin 325 mg PO once per day
  • Full dose anticoagulation with LMWH or Warfarin (Coumadin) could be substituted at physician discretion
• Acyclovir (Zovirax) or equivalent for VZV prophylaxis

28-day cycle for 8 cycles

Subsequent treatment

• Optionally, pomalidomide maintenance

References

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

RVD

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

Regimen

Study	Evidence	ORR
Richardson et al. 2014	Phase II	64%

Chemotherapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1 mg/m² IV once per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

Supportive medications

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

21-day cycle for 8 cycles

Subsequent treatment

• Patients with SD or better: RVD maintenance at previously tolerated dose

References

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

Thalidomide monotherapy

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Regimen

Study	Evidence
Singhal et al. 1999	Non-randomized

Chemotherapy

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

Continued until progression

References

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

Vemurafenib monotherapy

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Regimen

Study	Evidence
Hyman et al. 2015	Basket trial, <20 pts in subgroup

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

Chemotherapy

• Vemurafenib (Zelboraf) 960 mg PO BID

Continued indefinitely

References

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

VMPT

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

Regimen

Study	Evidence
Palumbo et al. 2007	Phase II

Chemotherapy

• Bortezomib (Velcade) 1 to 1.3 mg/m² IV bolus once per day on days 1, 4, 15, 22
• Melphalan (Alkeran) 6 mg/m² PO once per day on days 1 to 5
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 35

35-day cycle for 6 cycles

References

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

ZRd

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

Regimen

Study	Evidence
Sanchez et al. 2016	Phase IIb

Chemotherapy

• Vorinostat (Zolinza) 400 mg PO once per day on days 1 to 7, 15 to 21
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22

28-day cycles

References

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

Consolidation after second-line therapy

Bortezomib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Richardson et al. 2005 (APEX)	Phase III (E)	High-dose dexamethasone	Seems to have superior OS (*)

Note: efficacy is reported based on the 2007 update.

Preceding treatment

• Bortezomib induction

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22

Supportive medications

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

35-day cycle for 3 cycles

References

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

Melphalan, then auto HSCT

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Regimen

Study	Evidence	Comparator	Efficacy
Cook et al. 2014 (NCRI Myeloma X Relapse)	Phase III (E)	Cyclophosphamide	Seems to have superior OS (*)

Efficacy reported is based on the 2016 update.

Preceding treatment

• PAD x 4

Preparative regimen

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

Stem cells re-infused on day 0

References

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

Maintenance after second-line therapy

Bortezomib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Orlowski et al. 2015	Randomized Phase II (C)	Bortezomib & Siltuximab	Seems not superior

Preceding treatment

• Bortezomib induction

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22

35-day cycles

References

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

Bortezomib & Cyclophosphamide

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Regimen

Study	Evidence
de Waal et al. 2015	Phase II

Preceding treatment

• VDC x 6

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV/SC every 2 weeks
• Cyclophosphamide (Cytoxan) 50 mg PO once per day (continuous)

Supportive medications

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

1-year course

References

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

CPD

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

Regimen

Study	Evidence
Shah et al. 2015	Phase I (*)

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

Preceding treatment

• CPD x 6

Chemotherapy

• Carfilzomib (Kyprolis) 27 mg/m² IV over 30 minutes once per day on days 1, 2, 15, 16
• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Dexamethasone (Decadron) 20 mg PO/IV once per week on days 1, 8, 15, 22

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

Daratumumab monotherapy

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Regimen

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

Preceding treatment

• DVd x 8

Chemotherapy

• Daratumumab (Darzalex) 16 mg/kg IV once on day 1

28-day cycles until progression

References

1. CASTOR: Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed

Pomalidomide monotherapy

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Regimen

Study	Evidence	ORR
Paludo et al. 2017	Phase I/II	86%

Preceding treatment

• PVD x 8

Chemotherapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Supportive medications

• Aspirin 325 mg PO once per day
  • Full dose anticoagulation with LMWH or Warfarin (Coumadin) could be substituted at physician discretion
• Acyclovir (Zovirax) or equivalent for VZV prophylaxis

28-day cycles

References

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

Pomalidomide & Prednisone

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Regimen

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

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

Preceding treatment

• PCP x 6

Chemotherapy

• Pomalidomide (Pomalyst) 1 mg PO once per day
• Prednisone (Sterapred) 25 mg PO once every other day

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 Oct 17;122(16):2799-806. Epub 2013 Aug 16. link to original article contains verified protocol PubMed

RVD

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

Regimen

Study	Evidence
Richardson et al. 2014	Phase II

Preceding treatment

• Salvage RVD

Chemotherapy

• Lenalidomide (Revlimid) (at previously tolerated dose) PO once per day on days 1 to 14
• Bortezomib (Velcade) (at previously tolerated dose) IV once per day on days 1 & 8
• Dexamethasone (Decadron) 10 mg PO once per day on days 1, 2, 8, 9

Supportive medications

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

21-day cycles until progression or intolerance

References

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

Investigational agents

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

• Afuresertib (GSK2110183)
• Dinaciclib (SCH 727965)
• Isatuximab (SAR-650984)
• MOR202
• Perifosine (KRX-0401)
• Ricolinostat (ACY-1215, Rocilinostat)
• Selinexor (KPT-330)

Response criteria

• IMWG international uniform response criteria for multiple myeloma. (Durie et al. Leukemia 2006) PubMed
  • Make note of these errors which remain in the online version of the IMWG criteria as of 7/7/2013.
  • Clarification of the definition of complete response in multiple myeloma (Leukemia 2015) PubMed
• Disease progression criteria (Durie et al. Leukemia 2006).
• European Blood and Marrow Transplant (EBMT) criteria. (Bladé et al. Br J Hematol 1998) PubMed

Prognosis

Durie-Salmon Staging System - 1975

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Composed of four factors with a modifier based on renal function

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

Risk stratification

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

Modifier

• A: relatively normal creatinine (less than 2 mg/dL)
• B: creatinine greater than or equal to 2 mg/dL

References

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

International Staging System (ISS) - 2005

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Composed of two factors

• Serum albumin level
• Serum beta-2 microglobulin level

Risk stratification

• Stage I: Median survival of 62 months
  • Beta-2 microglobulin less than 3.5 mg/l
  • Albumin greater than or equal to 3.5 g/dl
• Stage II: Median survival of 44 months
  • Not meeting stage I or stage III criteria
• Stage III: Median survival of 29 months
  • Beta-2 microglobulin greater than or equal to 5.5 mg/l

References

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

IMWG consensus on risk stratification - 2013

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Composed of four factors

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

Risk stratification

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

References

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

Revised International Staging System (R-ISS) - 2015

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Composed of four factors

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

Risk stratification

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

References

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

Miscellaneous

1. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007 Apr 15;109(8):3489-95. Epub 2007 Jan 5. link to original article PubMed
2. Avet-Loiseau H, Hulin C, Campion L, Rodon P, Marit G, Attal M, Royer B, Dib M, Voillat L, Bouscary D, Caillot D, Wetterwald M, Pegourie B, Lepeu G, Corront B, Karlin L, Stoppa AM, Fuzibet JG, Delbrel X, Guilhot F, Kolb B, Decaux O, Lamy T, Garderet L, Allangba O, Lifermann F, Anglaret B, Moreau P, Harousseau JL, Facon T. Chromosomal abnormalities are major prognostic factors in elderly patients with multiple myeloma: the Intergroupe Francophone du Myélome experience. J Clin Oncol. 2013 Aug 1;31(22):2806-9. Epub 2013 Jun 24. link to original article link to PMC article PubMed

External links

• Mayo Clinic mSMART (Stratification for Myeloma And Risk-adapted Therapy)