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 cells^8,9

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 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 FLC assay, and bone marrow examination

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

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, as well as take into account if multiple high risk chromosomal abnormalities were present. This was in an effort to overcome the limitations of the R-ISS where the majority of the patients fell into R-ISS II.²⁷

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

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), and monoclonal antibodies, 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), 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 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.