GPRC5D CAR T Cells Are Active in BCMA CAR T–Refractory Multiple Myeloma

Chimeric antigen receptor (CAR) T-cell therapy has shown great promise in treating hematologic malignancies. In multiple myeloma, CAR T-cell therapy targeting B-cell maturation antigen (BCMA) has demonstrated deep responses, but most patients will relapse and have limited treatment options. Previous studies have indicated that G protein–coupled receptor class C, group 5, member D (GPRC5D) is highly expressed on myeloma cells, and preclinical studies have demonstrated that CAR T cells that target GPRC5D have antitumor activity both in vitro and in vivo even in a model of BCMA antigen escape. Due to the promising preclinical results of GPRC5D CAR T cells, Mailankody and colleagues conducted a phase I dose-escalation study of MCARH109, a second-generation GPRC5D CAR T, in 17 patients with relapsed or refractory multiple myeloma, including those who had previously received BCMA-directed therapies. Dose escalation included four different CAR T-cell concentrations: 25 × 10⁶, 50 × 10⁶, 150 × 10⁶, and 450 × 10⁶, with the maximum tolerated dose determined as 150 × 10⁶ CAR T cells. Cytokine release syndrome was observed in 15 patients (88%), with the patient treated with the highest dose of CAR T cells demonstrating grade 4 cytokine release syndrome. Additionally, grade 4 immune effector cell–associated neurotoxicity syndrome and macrophage activation syndrome were also only seen in the 450 × 10⁶ CAR T-cell dose, constituting dose-limiting toxicities. Evaluation of clinical responses indicated a partial response or better in 12 patients (71%) across all four doses, with six patients (35%) having a complete response or stringent complete response. Of the three lower doses, seven of the 12 patients (58%) had an objective response, and seven of the 10 patients (70%) who previously received BCMA-targeted therapies had a partial response or better. Overall, the results of this study provide the maximum tolerated dose of MCARH109 in patients with relapsed or refractory multiple myeloma as well as demonstrate the efficacy of this treatment most notably in patients refractory to BCMA therapy.

Mailankody S, Devlin SM, Landa J, Nath K, Diamonte C, Carstens EJ, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med 2022;387:1196–206.

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