GPRC5D CAR-T cell therapy

BACKGROUND: For patients with multiple myeloma progression after anti-BCMA  chimeric antigen receptor (CAR) T-cell therapy, the optimal salvage treatment  strategies remain unclear. GPRC5D-directed CAR T cell might be a potential  option. The aim of this trial was to investigate the activity and safety of  anti-GPRC5D CAR T cells in patients with progressive multiple myeloma after  anti-BCMA CAR T-cell therapy. 

METHODS: In this phase 2, open-label, single-arm, phase 2 trial, at the  Affiliated Hospital of Xuzhou Medical University in China, we enrolled patients  (aged 18-70 years old) with relapsed or refractory multiple myeloma who had  progressed disease after anti-BCMA CAR T-cell therapy and a life expectancy of  more than 12 weeks without active infections, serious liver, heart, or other  diseases. Patients were assigned to receive a single dose of intravenous  anti-GPRC5D CAR T cell at 2 × 10^6 cells per kg. The primary endpoint was the  overall response rate, including stringent complete response, complete response,  very good partial response, and partial response, according to the standard  International Myeloma Working Group response assessment criteria. Activity and  safety analyses were done in the patients who received a dose of anti-GPRC5D CAR  T cell as defined in the protocol. This trial is registered with the Chinese  Clinical Trial Registration Center, ChiCTR2100048888, and is ongoing. 

FINDINGS: Between Dec 1, 2021, and May 1, 2024, 42 patients were screened, 37  were enrolled and received anti-GPRC5D CAR T-cell therapy. Median age was 59  years (IQR 51-65), 17 (46%) of 37 patients were male and 20 (54%) female. All  patients were Asian. At a median follow-up of 12·6 months (IQR 8·2-20·8), the  overall response rate was 84% (95% CI 68-94, 31 of 37 patients), including 13  (35%) complete responses or better. The most common grade 3-4 adverse events  were haematological toxicities, including leukopenia (34 [92%] of 37 patients),  lymphopenia (36 [97%]), neutropenia (29 [78%]), anaemia (23 [62%]), and  thrombocytopenia (23 [62%]). 26 (70%) of 37 patients had cytokine release  syndrome, which was of grade 3 in two (5%) patients. One case of grade 1 immune  effector cell-associated neurotoxicity syndrome was observed. There were no  treatment-related deaths in the trial. 

INTERPRETATION: Anti-GPRC5D CAR T-cell salvage therapy induced a high response  rate, and could be a potential treatment option in relapsed or refractory  multiple myeloma patients who have progressed after anti-BCMA CAR T-cell  treatment. Further investigations are warranted to establish the long-term  efficacy and safety of this therapeutic approach. 

FUNDING: National Natural Science Foundation of China and the General Project of  Jiangsu Commission of Health.