Multiple Myeloma (MM)

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

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About 140,000 cases of MM are diagnosed globally each year4

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Incident cases from 1990 to 2016 increased by 126% globally4

Incidence & Mortality

About 97% of multiple myeloma (MM) cases are diagnosed in persons older than 44 years.5

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

An estimated 140,000 persons globally were diagnosed with MM during 2016, and 99,000 persons died from the disease.4

53.9% of patients in the U.S will survive 5 years past diagnosis.5

MM is unique biologically and clinically from leukemia and lymphoma.6

MM is typically defined as "a clonal plasma cell malignant neoplasm." In reality, it is a collection of several different cytogenetically distinct plasma cell malignant neoplasms.7

It is hypothesized that transformation from an MM precursor cell into a malignant one occurs in a multistep process initiated during class switch recombination.8

  • Normal homeostatic mechanisms fail to prevent the expansion of post-germinal center plasma cells9
  • Interactions with the bone marrow microenvironment lead to active proliferation of the neoplastic plasma cells8,9

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.9

  • In MM pathogenesis, overexpression of pro-survival proteins, BCL-2, BCL-XL and MCL-1, results in resistance to apoptosis thereby maintaining survival of myeloma cells resulting in their accumulation in the BM10,11,12

Patients with MM most commonly present with fatigue (due to anemia) or bone pain or fracture at diagnosis.7

Tests used to confirm a diagnosis of MM:7

  • Serum and urinary protein electrophoresis
  • Serum immunofixation
  • Either a serum free light chain (FLC) assay or 24-hour urinary protein electrophoresis with immunofixation

MM may be morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level, suggesting that diagnosis should include cytogenetics and FISH analyses of bone marrow plasma cells.7

In 2014, the IMWG updated the disease definition of MM to include validated biomarkers, referred to as the SLiMCRAB Criteria

Both criteria MUST be met:

  • Clonal BM plasma cells ≥10% or biopsy-proven plasmacytoma
  • Any one or more of the following myeloma defining events:
    • (≥60%) clonal BM plasma cells (Sixty)
    • Involved/uninvolved serum free Light chain ratio ≥100 (involved FLC level must be ≥100 mg/L)
    • >1 focal lesions on MRI (at least 5 mm in size)
    • Evidence of end-organ damage (CRAB features):
      • HyperCalcemia: >11 mg/dL
      • Renal insufficiency: creatinine clearance <40 mL/min or serum creatinine >2 mg/dL
      • Anemia: hemoglobin <10 g/dL or >2 g/dL below the lower limit of normal
      • Bone lesions: one or more osteolytic lesions
Risk Group Percentage of Newly Diagnosed Patients

Standard Risk
  •   Trisomies
  •   t(11;14)
  •   t(6;14)


75%

Intermediate Risk
  •   t(4;14)
  •   gain(1q)


10%

High Risk
  •   t(14;16)
  •   t(14;20)
  •   del(17p)


15%

Patients with t(11;14) have traditionally been classified as standard risk MM, based on studies conducted before novel agents were available. Recent observations suggest that patients with t(11;14) may have unfavorable outcomes when compared to other standard risk patients.14

  • 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
Frequency 5-year OS rate

28%

82%

62%

62%

10%

40%

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.7

  • Nearly all patients will eventually relapse, including those who experience a complete response (CR) to initial therapy.16,17
    • Approximately 21% to 43% of patients are estimated to require three or more lines of treatment.16
    • Almost 20% of patients die within a year of diagnosis.5
  • Despite enormous progress in the treatment of MM in 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.16-18
  • t(11;14) disease is quite common, occurring in an estimated 15-20% of MM patients.19
    • When treated with current therapies, t(11;14) patients have shown lower response rates, reduced PFS and OS compared with patients with other traditional standard risk markers.14

An improved understanding of the biology of MM has led to the introduction of new effective treatments over the last 15 years.20

  • 5-year survival rate has approximately doubled over the past 25 years.5

Continued introduction of new agents with non-overlapping mechanisms of action will not only allow for novel multi-agent combinations, but may contribute to continued improvements in outcomes.18,21

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. Cowan AJ, et al. Global Burden of Multiple Myeloma. JAMA Oncol. 2018;4(9):1221-1227.
  5. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2017, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2017/, based on November 2019 SEER data submission, posted to the SEER web site, April 2020.
  6. Radovic VV. J Med Biochem. 2010;29:1-8.
  7. Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2016;91(1):101-119.
  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. 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.
  10. Punnoose EA, et al. Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models. Mol Cancer Ther. 2016;15(5):1132-1144.
  11. Trudel S, et al. The Bcl-2 Family Protein Inhibitor, ABT-737, Has Substantial Antimyeloma Activity and Shows Synergistic Effect with Dexamethasone and Melphalan. Clin Cancer Res. 2007;13(2):621-629.
  12. Touzeau C, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28:210-2012.
  13. Rajkumar SV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-48.
  14. Lakshman, A., et al. Natural history of t(11;14) multiple myeloma. Leukemia 2017, 32(1), 131-138.
  15. 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.
  16. 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.
  17. 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.
  18. Maes A, Menu E, Veirman K, et al. The therapeutic potential of cell cycle targeting in multiple myeloma. Oncotarget. 2017;8(52):90501-90520.
  19. Paszekova, et al. High-Risk Multiple Myeloma: Different Definitions, Different Outcomes? Clinical Lymphoma, Myeloma and Leukemia, 2014;14(1):24-30.
  20. Moreau P, Touzeau C. Multiple myeloma: from front-line to relapsed therapies. Am Soc Clin Oncol Educ Book. 2015:e504-e511.
  21. 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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