Chimeric antigen receptor T cell therapy in multiple myeloma: promise and challenges.

Despite a sea change in the therapeutic landscape, multiple myeloma (MM), a cancer of antibody producing plasma cells, remains incurable requiring continued intervention for disease control. In this context, chimeric antigen receptor (CAR) T cell therapy has emerged as a promising immunotherapeutic approach with unprecedented results in heavily treated relapsed and/or refractory MM patients. Although B cell maturation antigen (BCMA) is the current lead target for CAR-T cell therapy in MM, several other antigenic targets are also being investigated. Relapses, however, are inevitable in spite of the promising early responses, and may be mediated by antigenic modulation, poor persistence and "immunostat" in tumor microenvironment. Akin to multi-agent chemotherapy, multi-targeted CAR-T antigens and combinatorial approaches are underway to overcome the resistance mechanisms. Further, CAR-T specific toxicity concerns such as cytokine release syndrome and neurotoxicity, as well as manufacturing time lag are other key challenges. Allogeneic CAR that offers "off-the-shelf" options, and mRNA transfected CAR are being developed to mitigate the access and safety issues. In this review we provide the comprehensive review of the most current clinical trial data for CAR-T in myeloma, challenges associated with this therapy and discuss its future in myeloma therapeutics.