Review Series MULTIPLE MYELOMA: FROM THE BENCH TO BEDSIDE Treatment options for relapsed and refractory multiple myeloma

Treatment choices for myeloma patients at each phase of their disease has become a complex decision-making process, in large part because of the deeper understanding of plasma cell biology, which resulted in more therapeutic options at each stage of treatment. Treatment of relapsed/refractory multiple myeloma (RRMM) presents a special therapeutic challenge, because of the heterogeneity of disease at relapse and the absence of clear biological-based recommendations regarding the choice of salvage therapies at various time points of disease progression. With increasing recognition of the inherent clonal heterogeneity and genomic instability of the plasma cells influencing both inherent and acquired therapeutic resistance, the identification of the optimal choice and sequence of therapies has become critical. Positively, several new agents and targets are currently under development and show considerable promise. The next-generation proteasome inhibitors (PIs) (ixazomib, marizomib, and oprozomib), other molecularly-targeted therapies directed at specific cell-signaling pathways (including histone deacetylase inhibitors, PI3K/AKT/mTOR inhibitors, Hsp90 inhibitors, cell-cycle inhibitors, kinesin spindleprotein inhibitors) are currently in development. Even newer approaches such as monoclonal antibodies targeting SLAMF7, CD38, CD138, and others have also demonstrated promising antimyeloma activity. This review focuses on evaluating various available treatment choices and options of treatment strategies at relapse, describes the rationality of combinations with established and newer agents, and highlights the emerging drugs currently under investigation and in various stages of clinical development.