GPRC5D-Targeted CAR T-Cell Therapy Shows Promise After BCMA Treatment Failure

Over 80% of patients with relapsed, refractory multiple myeloma (RRMM) who progressed after BCMA chimeric antigen receptor (CAR) T-cell therapy achieved favorable responses to GPRC5D CAR T-cell therapy, according to data from a small study in China (ChiCTR2100048888). The authors from the Affiliated Hospital of Xuzhou Medical University published their findings in Lancet Haematology.¹

CAR T-cells illustration | Image Credit: © Zeeshan - stock.adobe.com

CAR T-cell therapy and the discovery of biomarkers such as BCMA, CD19, and GPRC5D have led to significantly improved outcomes for patients with RRMM. These biomarkers are among the most prominent targets for CAR therapies; for example, GPRC5D is found in about 90% of patients with MM. Despite the substantial success of these therapies, resistance and relapse remain key barriers to optimal treatment outcomes.²

Optimal salvage treatment strategies are unknown for patients with RRMM who progress after receiving BCMA-targeting CAR T-cell therapy. This led the researchers to investigate the potential efficacy and safety of GPRC5D-directed CAR T-cell therapy for these patients. The phase 2, open-label, single-arm, phase 2 trial enrolled 37 patients (median age 59 years (IQR 51–65), 46% male and 54% female) with RRMM who progressed after anti-BCMA CAR T-cell therapy and had a life expectancy of more than 12 weeks without active infections, serious liver, heart, or other diseases. Each patient received a single dose of intravenous anti-GPRC5D CAR T-cells at 2 × 10⁶ cells per kg.¹

The primary end point of the study was overall response rate (ORR), inclusive of stringent complete response, complete response, very good partial response, and partial response. The researchers also performed activity and safety analyses.¹

At the median follow-up of 12.6 months, the ORR was 84% (95% CI 68 to 94, 31 of 37 patients), including 22% stringent complete responses, 14% complete responses, 14% very good partial responses, and 35% partial responses.^1,3

The most common adverse events were hematologic toxicities such as leukopenia (34 [92%] of 37 patients), lymphopenia (36 [97%]), neutropenia (29 [78%]), anemia (23 [62%]), and thrombocytopenia (23 [62%]), all of which were grade 3 or 4. Twenty-six patients developed cytokine release syndrome, of which 2 were grade 3.¹

"Anti-GPRC5D CAR T-cell salvage therapy induced a high response rate and could be a potential treatment option in patients with [RRMM] who had progressed after anti-BCMA CAR T-cell treatment," the authors wrote. " Further investigations are warranted to establish the long-term efficacy and safety of this therapeutic approach.”¹

These findings highlight the potential of GPRC5D-directed CAR T-cell therapy as a promising salvage option for patients with RRMM following BCMA-targeted treatment failure. Continued research and longer follow-up will be essential to confirm the durability of responses and further define its role in the evolving MM treatment landscape. As of May 5, 2025, the trial is ongoing.

REFERENCES

1. Xia J, Sun Q, Zhou D, et al. Anti-GPRC5D CAR T-cell therapy as a salvage treatment in patients with progressive multiple myeloma after anti-BCMA CAR T-cell therapy: a single-centre, single-arm, phase 2 trial. The Lancet Haematology. April 11, 2025. doi: 10.1016/S2352-3026(25)00048-1

2. Targeting resistance: Navigating the complexity of the tumor microenvironment and CAR T-cell efficacy. Pharmacy Times. August 16, 2024. https://www.pharmacytimes.com/view/targeting-resistance-navigating-the-complexity-of-the-tumor-microenvironment-and-car-t-cell-efficacy

3. High response rate in myeloma with novel CAR-T after anti-BCMA failure. MedPage Today. April 23, 2025. Accessed May 5, 2025. https://www.medpagetoday.com/hematologyoncology/myeloma/115242?xid=nl_mpt_DHE_2025-04-23&mh=6d2b5f4f91352444bdf817a9c17750bc&zdee=gAAAAABm4uL9FCoIf1N83nrcwYYqnQUvN6Iw4dbaY-dGva4sOp57nSM2Ew3wD87ohRuoseQBDbCp1MG30J6ETpHXK1wNpp0NgnGTMFXrtFaNfWUoL5ekf-Y%3D&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%20Evening%20-%20Randomized%202025-04-23&utm_term=NL_Daily_DHE_dual-gmail-definition