An update: Safety and efficacy of GPRC5D targeting CAR-T cell therapy in relapsed/refractory multiple myeloma patients

Abstract Background: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have shown breakthrough therapeutic efficacy on treating relapsed/refractory (R/R) multiple myeloma (MM) patients. However, relapse occurs commonly on patients with BCMA-low or -negative tumor cells. G protein-coupled receptor, class-C group-5 member-D (GPRC5D) was discovered as a new target for MM, its expression is independent of BCMA. Hence, targeting GPRC5D may potentially eliminate tumor cells with low BCMA density. To investigate the safety and efficacy of GPRC5D CAR-T cell therapy, we have developed a second generation CAR with GPRC5D-targeting scFv, and initiated a phase I dose-escalation clinical trial for the treatment of R/R MM (trial registration: NCT05739188). Here, we presented updated results of this ongoing clinical trial with more patients and longer follow-up. In addition, we compared the results from patients who received CAR-T cells manufactured through a novel next-day fast-CAR-T process with those who received CAR-T cells prepared under the standard method. Methods: From February 2023 to July 2025, 17 eligible R/R MM patients were enrolled in this study. Thirteen patients were treated with a single infusion of standard GPRC5D CAR-T cells in escalating dosing cohorts, the other 4 patients were treated with a single dose of fast-GPRC5D CAR-T cells. All patients received standard lymphodepletion regimens cyclophosphamide (300 mg/m2/day) and fludarabine (30 mg/m2/day) for 3 days prior to autologous CAR-T cell infusion. The clinical responses and safety profiles were evaluated. Results: As of data cut-off of July 18th, 2025, with a median of 296 days (range, 92-751) of follow-up, and completed 3 months or longer time follow-up evaluations. Thirteen patients received single standard GPRC5D CAR-T cell infusions at dose levels from 3E6 to 1E7 CAR-T cells/kg, 4 patients received single infusions of total 5E7 fast-GPRC5D CAR-T cells. The median age was 52 years (range, 33-72), and 9 of 17 patients were male. The median time from MM diagnosis to GPRC5D CAR-T cell infusion was 40 months (range, 5-86). Five patients had high-risk cytogenetic features. Eight patients had extramedullary lesions at baseline. Twelve patients had received more than 3 prior lines of therapy. Fourteen patients were refractory to anti-CD38 monoclonal antibodies. Five patients had undergone previous autologous stem-cell transplantation. Five patients had received prior BCMA CAR-T cell therapy. The overall response rate (ORR) was 92.3% (12/13) for standard CAR-T, and 100% (4/4) for fast-CAR-T. Eight (8/13, [61.5%]) patients achieved complete response (CR) or better, 4 (4/13, [30.8%]) patients reached partial response (PR) or better after receiving standard CAR-T therapies. Three (3/4, [75%]) patients achieved CR or better and 1 (1/4, [25%]) patient reached PR after receiving fast-CAR-T therapies. The patient with no-response to standard GPRC5D CAR-T therapy showed no expression of GPRC5D on tumor cells confirmed by flow cytometry analysis. No dose-limiting toxicities were observed. The most common grade 3 or worse AEs were hematological toxicities. Leukopenia (15/17, [88.2%]), neutropenia (16/17, [94.1%]), lymphopenia (16/17, [94.1%]), anemia (14/17, [82.4%]), and thrombocytopenia (10/17, [58.8%]) were observed among all patients, which might be a result of lymphodepleting chemotherapy. All patients experienced grade 1 CRS. No neuro-toxicities were observed. Nail disorder was observed in 2 patients, which was due to the on-target, off-tumor toxic effects associated with GPRC5D expression in the skin and keratinized tissue. The median time to peak of CAR-T cell expansion in peripheral blood was 12 days (range, 8-36) for standard CAR-T cells, and 19 days (range, 16-27) for fast-CAR-T cells, respectively. Conclusion: This GPRC5D CAR-T product showed a manageable safety profile and promising clinical responses for the treatment of R/R MM. The ORR was 92.3% (12/13) with 61.5% (8/13) achieving CR for standard CAR-T therapy, and 100% ORR (4/4) with 75% (3/4) achieving CR for fast-CAR-T therapy, respectively. In conclusion, our study demonstrated that GPRC5D-targeted CAR-T therapy could be a promising treatment option for patients with R/R MM, especially for those who were refractory to BCMA-targeted CAR-T therapy.