Emerging Therapeutic Strategies to Overcome Drug Resistance in Multiple Myeloma

SIMPLE SUMMARY: Multiple myeloma is a deadly blood cancer, but fortunately drug development has substantially prolonged the lifespan of patients to average more than a decade after diagnosis with optimal therapy. As a result, the population of patients living with multiple myeloma has grown considerably. Through its course, patients suffer repeated relapses for which they require new lines of treatment. Currently, the key drug classes for treatment are immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. The goal of this review is to summarize the understanding of the problem of resistance to these drugs, which is ultimately responsible for patient fatality. In addition, we will focus on how new agents that are promising in clinical trials overcome resistance. ABSTRACT: Multiple myeloma is a malignant plasma cell neoplasm that remains incurable and is ultimately fatal when patients acquire multi-drug resistance. Thus, advancing our understanding of the mechanisms behind drug resistance in multi-relapsed patients is critical for developing better strategies to extend their lifespan. Here, we review the understanding of resistance to the three key drug classes approved for multiple myeloma treatment: immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. We consider how the complex, heterogenous biology of multiple myeloma may influence the acquisition of drug resistance and reflect on the gaps in knowledge where additional research is needed to improve our treatment approaches. Fortunately, many agents are currently being evaluated preclinically and in clinical trials that have the potential to overcome or delay drug resistance, including next-generation immunomodulatory drugs and proteasome inhibitors, novel small molecule drugs, chimeric antigen receptor T cells, antibody-drug conjugates, and bispecific antibodies. For each class, we discuss the potential of these strategies to overcome resistance through modifying agents within each class or new classes without cross-resistance to currently available drugs.