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 176,000 cases of MM are diagnosed globally each year23

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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 176,000 persons globally were diagnosed with MM during 2021, and 117,000 persons died from the disease.23

55.6% of patients in the U.S will survive 5 years past diagnosis.22

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
Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART)
Risk Group Percentage of Newly Diagnosed Patients
Standard Risk
  • Trisomies
  • t(11;14)
  • t(6;14)


75%

High Risk
  • t(4;14)
  • t(14;16)
  • t(14;20)
  • del(17p)
  • gain(1q)
  • Double-hit: any two high-risk factors
  • Triple-hit: any three or more high-risk factors


25%

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 Frequency 5-year OS rate
Stage I (low risk)
  • serum albumin ≥3.5 g/dL
  • serum β2-microglobulin <3.5 mg/L
  • no high-risk cytogenetics
  • normal LDH

28%

82%

Stage II (intermediate risk)
  • not R-ISS Stage I or III

62%

62%

Stage III (high risk)
  • serum β2-microglobulin <3.5 mg/L and
  • either presence of high-risk cytogenetics [t(4;14, t(14;16) or del(17p)] or elevated LDH

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.25

  • Despite recent advances with the advent of proteosome inhibitors (PI), immunomodulatory agents (IMiDs), monoclonal antibodies, and histone deactylase inhibitors (HDACi), most patients with multiple myeloma (MM) ultimately relapse, and after each relapse, disease becomes more aggressive with shortened subsequent progression free survival (PFS).16
    • Relapsed/progressive MM acquires additional mutation or genetic alterations that render the disease more resistant, leading to progressively shorter durations of remission or response to each salvage therapy.17
    • It is estimated that one in eight patients under the age of 65 and one in four patients over the age of 65 in the US will die in the first year after diagnosis of MM.20
    • An international "real world" study showed that approximately 40% of MM patients would not reach a subsequent line of therapy.26
  • 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

Within the past few years, clinical outcomes of MM have improved due to the introduction of several new agents such as the third-generation immunomodulators (IMiD), next-generation proteasome inhibitors (PIs), monoclonal antibodies (mAbs), and a histone deacetylase inhibitor (HDACi).16

  • However, 5-year survival in the US remains at 55.6%.22 Despite multiple novel therapeutic options, the optimal combination as well as sequencing of therapy for individual patients remains an important challenge which needs to be addressed.

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. Durer C, et al. Treatment of relapsed multiple myeloma: Evidence-based recommendations. Blood Rev. 2020;39:100616.
  17. Chim CS, et al. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia. 2018;32(2):252-262.
  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. Bal S, et al. New regimens and directions in the management of newly diagnosed multiple myeloma. Am J Hematol. 2021;96(3):367-378.
  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.
  22. NCI. Cancer Stat Facts: Myeloma. https://seer.cancer.gov/statfacts/html/mulmy.html. Accessed September 2021.
  23. Global Burden of Disease Cancer Collaboration; Sung H; Ferlay J, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: Cancer J. Clin. 2021;71(3):209-249.
  24. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-567.
  25. Rajkumar SV, Kumar S. Multiple myeloma current treatment algorithms. Blood Cancer J. 2020 Sep 28;10(9):94.
  26. Yong K, Delforge M, Driessen C, et al. Multiple myeloma: patient outcomes in real-world practice. Br J Haematol. 2016;175(2):252-264.

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