Emerging small molecule approaches to enhance the antimyeloma benefit of proteasome inhibitors.

Multiple myeloma (MM) is a clonal plasma cell malignancy which, despite recent treatment advances, remains incurable in the vast majority of the over 118,000 patients in the USA afflicted with this disease. Treatment of MM has dramatically improved in the past decade with the introduction of new drugs into therapeutic strategies in both the frontline and relapse settings that has led to a significant improvement in the median overall survival (OS). These drugs have been incorporated into clinical guidelines and transformed the treatment approach to MM. Numerous classes of antimyeloma agents, i.e., alkylators, steroids, proteasome inhibitors, immunomodulatory agents, deactylase inhibitors, and monoclonal antibodies, are now FDA-approved and can be combined in doublet or triplet regimens. Moreover, many patients do not respond to therapy and those that do eventually relapse. Emerging therapies that may overcome drug resistance and improve MM treatment include that inhibit regulatory and Ub-processing components of the proteasome, a specialized variant of the proteasome known as the immunoproteasome, proteolysis-targeting chimeric molecules (PROTACS and Degronomids). Emerging strategies also include accessory plasmacytoid dendritic cells (pDCs), vaccines, checkpoint inhibitors, and chimeric antigen receptor-engineered T (CAR-T) cells. Advances in understanding proteasome and plasma cell biology may allow for earlier treatment of MM patients using rationally informed combination therapies with curative potential.