Multiple myeloma is characterized by recurrent relapses7

While outcomes have improved with the recent availability of targeted agents and combination therapies, most patients with multiple myeloma (MM) inevitably relapse.15,16 With each subsequent line of therapy, the duration and quality of response deteriorates, and the risk of another relapse increases.15,17,18

With each successive relapse, time to progression and depth of response decrease17

A Heterogeneic Disease

At the time of diagnosis, the cellular and genetic architecture of multiple myeloma is highly complex and heterogeneous across patients.10,19 Many patients harbor anywhere from three to seven detectable subclones.20 Within each patient clonal diversity continuously evolves throughout the treatment continuum.10 Somatic mutations, chromosomal translocations and deletions, and epigenetic modifications accumulate over time within myeloma clones as the disease advances. This evolution may occur through branching pathways, where mutations create different clones that may drive disease evolution and treatment resistance.8 Genetic heterogeneity of these myeloma cells highlight the need for simultaneously targeting multiple mechanisms of disease, including protein degradation.21,22

Myeloma cell heterogeneity can evolve over time10

High-Risk Patients7

High-risk (such as patients who relapsed after < 1 year from primary therapy) multiple myeloma patients have poorer survival outcomes.7,23,24 Several chromosomal mutations can occur in the genes responsible for normal antibody development in multiple myeloma. These mutations include deletion of 17p, translocation t(4:14) and/or translocation t(14:16).7 Risk factor classification, including cytogenetic factors, can change as multiple myeloma progresses and patients can develop high-risk features at relapse or progression. Evaluation of cytogenetic and other risk factors at relapse is important for staging and treatment designation.25

Revised International Staging System (R-ISS)7

  • Patients with R-ISS stage I:
    • Serum β2-microglobulin < 3.5 mg/L, serum albumin ≥ 3.5 g/dL
    • No high-risk chromosomal abnormality and normal LDH < ULN

High-risk MM

  • Patients with R-ISS stage II:
    • Not R-ISS stage I or III
  • Patients with R-ISS stage III:
    • Serum β2-microglobulin ≥ 5.5 mg/L
    • High-risk chromosomal abnormalities including presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16) or LDH > ULN

LDH = lactate dehydrogenase; ULN = upper limit of normal