MULTIPLE MYELOMA (MM)

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

176,000

About 176,000 cases of MM are diagnosed globally each year23

‚ģ≠ 126%

Incident cases from 1990 to 2016 increased by 126% globally4

INCIDENCE AND MORTALITY

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

  • In the US, an estimated 35,730 people in the US will be diagnosed during 2023, and 12,590 people will die from the disease.22
  • 59.8% of patients in the U.S will survive 5 years past diagnosis.22

About 97% of MM cases are diagnosed in people 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.

MM is biologically and clinically unique 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 the pro survival proteins, BCL-2, BCL-XL¬†and MCL-1, results in resistance to apoptosis thereby maintaining the survival of myeloma cells and resulting in their accumulation in the bone marrow(BM).10,11,12

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

Baseline diagnostic work up for the diagnosis of MM includes:7

  • Complete blood count, serum calcium, serum creatinine, serum and urine protein electrophoresis with immunofixation, serum free light chain (FLC) assay, and BM examination
Osteolytic bone lesions are detected with low-dose whole-body computed tomography (CT), or fluoro-deoxyglucose (FDG) positron emission tomography/CT (PET/CT); or at minimum, plain radiographs of the entire skeleton are required.7
 
In patients with suspected smoldering MM(SMM) and whenever the diagnosis of MM is in doubt, magnetic resonance imaging (MRI) of the whole body or spine/pelvis is needed to look for focal bone marrow lesions.7
 
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 fluorescence in situ hybridization (FISH) analyses of bone marrow plasma cells.7

In 2014, the International Myeloma Working Group (IMWG) updated the disease definition of MM to include validated biomarkers that are referred to as the SLiMCRAB Criteria

Both criteria MUST be met:

  • Clonal BM plasma cells ‚Č•10% or biopsy-proven plasmacytoma
  • Any one or more of the following myeloma-defining events:
    • (Greater than or equal to¬†60%) clonal BM plasma cells (Sixty)
    • Involved/uninvolved serum free¬†Light chain ratio ‚Č•100 (involved FLC level must be ‚Č•100 mg/L)
    • Greater than¬†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

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

Most recently, the R-ISS was modified to include the additional prognostic marker, 1q gain, and account for the presence of multiple high-risk chromosomal abnormalities. These modifications were made in an effort to overcome the limitations of the R-ISS, in which the majority of the patients were categorized as R-ISS II.27

Second Revision of the International Staging System (R2-ISS)

Treatment for MM includes initial therapy, stem cell transplaint (SCT; if eligible), consolidation/maintenance therapy, and treatment at relapse. The specific therapy and agent(s) used are determined by risk, SCT eligibility, and patient fitness and age.25

  • Despite recent advances with the advent of proteosome inhibitors (PI), immunomodulatory agents (IMiDs), and monoclonal antibodies, most patients with MM ultimately relapse; 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, most often due to adverse events, comorbidities and old age.26
  • t(11;14) disease is quite common and occurrs in an estimated 15%-20% of MM patients.19
    • When treated with current therapies, t(11;14) patients have shown lower response rates and 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 third-generation IMiD, next-generation PIs, anti-CD38 monoclonal antibodies (mAbs), B-cell maturation antigen (BCMA) antibody drug conjugates (ADCs), BCMA-directed chimeric antigen receptor (CAR) T-cell therapy, and GPRC5D x CD3 and BCMA x CD3 bispecific T-cell engagers.16

  • However, 5-year survival in the US remains at 59.8%.22

Despite multiple novel therapeutic options, the optimal combination and sequencing of therapy for individual patients remains an important challenge that 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 Cancer Targets

BCL-2

Learn about how BCL-2 plays a role in tumor survival and is a rational target for therapeutic intervention. MORE>


CD3xBCMA BISPECIFICS

Learn about CD3 on T cells and bispecific targeting of BCMA. MORE>


  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;130(22):2401-2409.
  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;130(22):2392-2400
  4. Cowan AJ, et al. Global Burden of Multiple Myeloma. JAMA Oncol. 2018;4(9):1221-1227.
  5. Howlader N, Noone AM, Krapcho M, et al (eds). National Cancer Institute. SEER Cancer Statistics Review, 1975-2017. Updated April 2020 based on November 2019 SEER data submission. https://seer.cancer.gov/csr/1975_2017/.
  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. National Cancer Institute. Cancer Stat Facts: Myeloma. Accessed March 2024. https://seer.cancer.gov/statfacts/html/mulmy.html. 
  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;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.
  27. D’Agostino M, et al. Second Revision of the International Staging System (R2-ISS) for Overall Survival in Multiple Myeloma: A European Myeloma Network (EMN) Report Within the HARMONY Project. J Clin Oncol. 2022 Oct 10;40(29):3406-3418.