Fully Human anti-GPRC5D CAR T-Cell Therapy RD118 Induces Durable Remissions in Relapsed/Refractory Multiple Myeloma

Abstract

GPRC5D has emerged as a promising therapeutic target in relapsed/refractory multiple myeloma (RRMM), particularly following progression after BCMA-directed CAR T-cell therapies. RD118 is a novel CAR T-cell therapy incorporating a fully human single-domain antibody fragment (VHH) targeting GPRC5D. In this phase 1 study, 18 relapsed/refractory patients (17 multiple myeloma, 1 with a history of primary plasma cell leukemia [pPCL]) received a single infusion of RD118 at 1.0, 2.0, or 3.0 × 106 CAR+ T cells/kg. At a median follow-up of 17.0 months, the overall response rate (ORR) was 94.4%, including 72.2% complete or stringent complete responses. Among seven patients previously exposed to BCMA-directed CAR T-cell therapy, ORR reached 85.7%. Median progression-free survival (PFS) was 18.2 months (95% CI, 14.4-not estimable), with 12-month PFS and overall survival (OS) rates of 82.1% and 93.3%, respectively. Cytokine release syndrome occurred in 88.9% of patients, primarily grade 1-2. One patient developed grade 3 immune effector cell-associated neurotoxicity which resolved within 72 hours. No cerebellar toxicities or treatment-related deaths were reported. These findings support that RD118 is a highly effective and safe therapeutic option for heavily pretreated RRMM. This trial is registered at ClinicalTrials.gov as NCT05759793 and NCT05219721.