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A New Destination for Myeloma CAR T-Cell Therapy
Monoclonal antibody and cellular immunotherapeutic agents have improved outcomes for patients with multiple myeloma, but durable remission and cure remain elusive. Investigators now report an industry-funded, phase 1 trial of a second-generation anti-myeloma CAR T-cell product (MCARH109) that targets GPRC5D, a G-protein–coupled receptor expressed on myeloma cells, normal plasma cells, and certain cutaneous tissues. The study tested four CAR T-cell doses: 25, 50, 150, and 450 × 106 cells.
Eligible patients had relapsed or refractory myeloma and had previously received proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies; prior treatment with anti–B-cell maturation antigen (BCMA) CAR T-cell or bispecific T-cell–engaging antibodies was also allowed. Bridging anti-myeloma therapy was permitted after apheresis to collect T-cells. The primary endpoint was safety; secondary endpoints were response and measurable residual disease (MRD) by bone marrow flow cytometry.
All 18 patients who underwent apheresis had successful CAR T-cell production; 1 patient withdrew prior to CAR T-cell infusion due to rapid disease progression. Median age was 60 years. Patients had received a median of 6 prior lines of therapy; eight patients had received BCMA CAR T-cell therapy, and two received an anti-BCMA bispecific antibody. In vivo CAR T-cell expansion was confirmed at all four dose levels.
Serious adverse events included cerebellar toxicity in the highest-dose group; the 150 x 106 cell dose was recommended for phase 2 study. Overall, 12 patients (71%) had a response, including 10 (59%) with very good partial response or better and 6 (35%) with complete response. Response was also observed in 7 of 10 patients with relapse after prior anti-BCMA therapy. MRD-negative response at one or more time points was observed in 8 of the 12 responders. At a median follow-up of 10 months, 6 of the 12 patients with partial or better response remained without disease progression.
This early-phase trial confirms a meaningful clinical response to MCARH109. However, the cerebellar toxicity is of concern and will require careful assessment in subsequent trials to determine if it represents a nonspecific neurotoxicity, as observed with other CAR T-cell products, or is related to GPRC5D expression. Results from ongoing clinical trials using the bispecific monoclonal antibody talquetamab, which also targets GPRC5D, will be of interest.
Mailankody S et al.
Title: GPRC5D-targeted CAR T cells for myeloma.
Source: N Engl J Med 2022 Sep 29; [e-pub]. (Abstract/FREE Full Text)