Multiple Myeloma (MM)

Exploring epigenetic modulation and inducing apoptosis as potential therapeutic approaches for patients with multiple myeloma.1-3

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Median age at diagnosis is 69 years.4

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of patients present with osteolytic skeletal lesions.5

Incidence & Mortality

96.5% of multiple myeloma (MM) cases are diagnosed in persons older than 44 years.4

  • MM is most frequently diagnosed among people aged 65 to 74 years.
  • The median age at diagnosis is 69 years.

An estimated 154,000 persons globally were diagnosed with MM during 2015, and 101,000 persons died from the disease.6

49.6% of patients will survive 5 years past diagnosis.4

MM is usually defined as "a clonal plasma cell malignant neoplasm." In actuality, it is a collection of several different cytogenetically distinct plasma cell malignant neoplasms.5

It is hypothesized that transformation from an MM precursor cell into a malignant one occurs in a multistep process initiated during class switch recombination.7

  • Normal homeostatic mechanisms fail to prevent the expansion of post-germinal center plasma cells.8
  • Interactions with the bone marrow microenvironment lead to active proliferation of the neoplastic plasma cells.7,8

Dysregulated signaling pathways have been identified that contribute to MM tumor cell growth and survival, immunologic responses in the bone marrow microenvironment, and the development of resistance to therapy.7

  • Malignant myeloma cells from both the bone marrow and peripheral blood express high levels of the antiapoptotic members of the BCL-2 family.8-10

Patients with MM most commonly present with fatigue (due to anemia) or bone pain or fracture at diagnosis.5

Tests used to confirm a diagnosis of MM5:

  • Serum protein electrophoresis
  • Serum immunofixation
  • Either a serum free light chain (FLC) assay or 24-hour urinary protein electrophoresis with immunofixation
International Myeloma Working Group Diagnostic Criteria5
Both criteria MUST be met:
  1. Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma
  2. Any one or more of the following events:
    • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
      • Hypercalcemia—serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
      • Renal insufficiency—creatinine clearance <40 mL/min or serum creatinine >177 μmol/L (>2 mg/dL)
      • Anemia—hemoglobin value of >2 g/dL below the lower limit of normal or <10 g/dL
      • Bone lesions—one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography CT (PET-CT)
    • Clonal bone marrow plasma cell percentage ≥60%
    • Involved-to-uninvolved serum FLC ratio ≥100 (involved FLC level must be 100 mg/L)
    • >1 focal lesion on magnetic resonance imaging (MRI) studies (≥5 mm in size)
Revised International Staging System11
Stage I (low risk)-serum albumin ≥3.5 g/dL, serum β2-microglobulin <3.5 mg/L, no high-risk cytogenetics, normal LDH
Stage II (intermediate risk)-not R-ISS Stage I or III
Stage III (high risk)-serum β2-microglobulin ≥5.5 mg/L and either presence of high-risk cytogenetics [t(4;14), t(14;16) or del(17p)] or elevated LDH

Treatment for MM includes initial therapy, SCT (if eligible), consolidation/maintenance therapy, and treatment at relapse. Specific therapy and agent(s) utilized are determined by risk, stem cell transplant (SCT) eligibility, and patient fitness and age.12

  • Nearly all patients will eventually relapse, including those who experience a complete response (CR) to initial therapy.12,13
    • Approximately 21% to 43% of patients are estimated to require three or more lines of treatment.12
    • Almost 20% of patients die within a year of diagnosis.4
  • Despite enormous progress in the treatment of MM the past 5 years, the development of drug resistance remains a therapeutic challenge.14
    • As MM progresses to a more aggressive stage, the increasing genetic complexity contributes to resistance to therapy.12-14

An improved understanding of the biology of MM has led to the introduction of new effective treatments over the last 15 years.15

  • Survival rates have approximately doubled over the past 10 years.

Continued introduction of new agents with different mechanisms of action will not only allow for novel multi-agent combinations, but may contribute to continued improvements in outcomes.14,16

AbbVie is committed to helping address these challenges and is actively conducting research in this area to help address this unmet need.

Relevant Biomarker Pathways

  1. Bui MH, Lin X, Albert DH, et al. Preclinical characterization of BET family bromodomain inhibitor ABBV-075 suggests combination therapeutic strategies. Cancer Res. 2017;77(11):2976-2989.
  2. Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017 Oct 10. [Epub ahead of print]
  3. Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017 Aug 28. [Epub ahead of print]
  4. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015.
  5. Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2016;91(1):101-119.
  6. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):524-548.
  7. Kyrtsonis MC, Bartzis V, Papanikolaou X, et al. Genetic and molecular mechanisms in multiple myeloma: a route to better understand disease pathogenesis and heterogeneity. Appl Clin Genet. 2010;3:41-51.
  8. Zhang B, Gojo I, Fenton RG. Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood. 2002;99(6):1885-1893.
  9. Puthier D , Pellat-Deceunynck C, Barillé S, et al. Differential expression of Bcl-2 in human plasma cell disorders according to proliferation status and malignancy. Leukemia. 1999;13(2):289-294.
  10. Schwarze MM, Hawley RG. Prevention of myeloma cell apoptosis by ectopic bcl-2 expression or interleukin 6-mediated up-regulation of bcl-xL. Cancer Res. 1995;55:2262-2265.
  11. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-2869.
  12. Richardson PG, Kumar S, Laubach JP, et al. New developments in the management of relapsed/refractory multiple myeloma - the role of ixazomib. J Blood Med. 2017;8:107-121.
  13. Richardson P, Mitsiades C, Schlossman R, et al. The treatment of relapsed and refractory multiple myeloma. Hematology Am Soc Hematol Educ Program. 2007;317-323.
  14. Maes A, Menu E, Veirman K, et al. The therapeutic potential of cell cycle targeting in multiple myeloma. Oncotarget. 2017;8(52):90501-90520.
  15. Moreau P, Touzeau C. Multiple myeloma: from front-line to relapsed therapies. Am Soc Clin Oncol Educ Book. 2015:e504-e511.
  16. Larocca A, Mina R, Gay F, Bringhen S, Boccadoro M. Emerging drugs and combinations to treat multiple myeloma. Oncotarget. 2017;8(36):60656-60672.

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