Multiple myeloma

Section editor
	Andrew J. Cowan, MD University of Washington Seattle, WA andrewcowanmd LinkedIn

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!.
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

This page will remain as a consolidated location for guidelines and prognostic information.

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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: Caers et al. European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when
• 2018: Gay et al. From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives

ESMO

• 2017: Moreau et al. 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

First-line therapy, intensification

VDC

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

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Jackson et al. 2018 (UK NCRI Myeloma XI)	Phase III (E-esc)	No intensification	Superior PFS (*)

Note: reported efficacy is based on the 2019 manuscript specifically addressing the issue of intensification.

Preceding treatment

• CTD versus CRd induction, with minimal or partial response

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² SC or IV once per day on days 1, 4, 8, 11
• Cyclophosphamide (Cytoxan) 500 mg/m² PO once per day on days 1, 8, 15
• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for up to 8 cycles

Subsequent treatment

• See paper for details

References

1. UK NCRI Myeloma XI: Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Hockaday A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Jenner MW, Cook G, Russell NH, Kaiser MF, Drayson MT, Owen RG, Gregory WM, Morgan GJ; UK NCRI Haemato-oncology Clinical Studies Group. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):57-73. Epub 2018 Dec 14. link to original article link to PMC article PubMed
   1. Update: Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Waterhouse A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Wilson JN, Jenner MW, Cook G, Kaiser MF, Drayson MT, Owen RG, Russell NH, Gregory WM, Morgan GJ; UK NCRI Haematological Oncology Clinical Studies Group. Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol. 2019 Dec;6(12):e616-e629. Epub 2019 Oct 14. link to original article contains protocol 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)

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, San Miguel J, 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. 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)
• Myeloma Patient FAQs by Dr. Vincent Rajkumar (Twitter)