CAR T Cells and Other Cellular Therapies for Multiple Myeloma: 2018 Update

Abstract

Cellular therapies are a rapidly evolving approach to myeloma treatment, which bring a unique mechanism of action with the potential to overcome drug resistance and induce long-term remissions. Two primary approaches are being studied: non-gene-modified strategies, which rely on the endogenous anti-myeloma T-cell repertoire, and gene-modified strategies, which introduce a new T-cell receptor (TCR) or a chimeric antigen receptor (CAR) to confer novel antigen specificity. CAR T cells show the greatest activity to date. Multiple antigen targets, including B-cell maturation antigen (BCMA), CD19, CD38, CD138, and SLAMF7, are being explored for myeloma, and BCMA has emerged as the most promising. Preliminary data from four phase I studies of BCMA CAR T cells, each using a different CAR construct, that involved 90 evaluable patients with relapsed/refractory disease have been reported. These data show response rates of 60% to 100%, including minimal residual disease (MRD)-negative complete remissions, at effective doses (> 10⁸ CAR-positive cells) after lymphodepleting conditioning. Response durability has been more variable, likely related to differences in CAR T-cell products, lymphodepleting regimens, patient selection criteria, and/or underlying biology/prognostic factors. In the two most recent studies, however, most patients remained progression free with median follow-up time of 6 to 10 months; some ongoing remissions lasted more than 1 year. Toxicities are similar to those from CD19 CAR T cells and include cytokine release syndrome and neurotoxicity that is reversible but can be severe. Multiple BCMA CAR T-cell studies are ongoing. Future directions include combinations with immunomodulatory drugs, checkpoint inhibitors, or other CAR T cells, as well as use of gene-edited cellular products to enhance the safety and efficacy of this approach.