First Results from a Phase 1 Study of BMS-986393, a GPRC5D-Targeted CAR T-Cell Therapy, in Patients with RRMM

Preliminary data support the use of BMS-986393 in patients with RRMM despite prior BCMA-directed therapy.

G protein–coupled receptor class C group 5 member D (GPRC5D) is a receptor expressed on multiple myeloma (MM) cells that has limited expression in normal tissue and has become a novel treatment focus in the development of therapies for MM. BMS-986393 is a GPRC5D-targeted autologous chimeric antigen receptor (CAR) T-cell therapy currently being investigated in patients with relapsed/refractory MM (RRMM). At the 2022 American Society of Hematology meeting, Jesus Berdeja presented interim results from the dose-escalation stage (part A) of CC-95266-MM-001, a phase 1, first-in-human, multicenter, dose-finding study of BMS-986393 in patients with RRMM.

Eligible patients had more than 3 prior lines of therapy, prior B-cell maturation antigen (BCMA)-directed and CAR T-cell therapies, and progressed within 12 months of their last treatment. Thirty-three patients have been enrolled to date and were treated at 5 dose levels: 25 × 10⁶, 75 × 10⁶, 150 × 10⁶, 300 × 10⁶, and 450 × 10⁶. A total of 48.5% of patients had high-risk cytogenetics (del [17p], t[4;14], and/or t[14;16]), and 45.5% had extramedullary disease. A total of 54.5% had prior BCMA-directed therapy, and 39.4% had prior BCMA-directed CAR T-cell therapy. Treatment-related adverse events (TRAEs) were reported in 88% of patients, with 73% of patients experiencing grade 3 or 4. The most frequent grade 3 or 4 TRAEs were hematologic: 61% experienced neutropenia and 21% had thrombocytopenia. Dose-limiting toxicities of prolonged neutropenia and/or thrombocytopenia were reported in 2 patients. TRAEs affecting the skin, nails, and dysgeusia/dysphagia were all grade 1 and most did not require any intervention. Cytokine release syndrome (CRS) was reported in 64% of patients at all dose levels, but most were grade 1 or 2 with a median onset and duration of 3 and 4 days, respectively. Immune effector cell–associated neurotoxicity syndrome (ICANS)–type neurotoxicity was reported in 2 patients, and both were low grade and reversible with steroids. Responses were seen across all dose levels, and the overall response rate (ORR) was 89.5%. ORR in patients with no prior BCMA therapy was 100%, with a complete response (CR) rate of 50%. In patients with prior BCMA therapy, ORR was 78% and CR rate was 44%. There were 4 efficacy-evaluable patients with available data on minimal residual disease (MRD) negativity who had the best overall response of CR, and all 4 were MRD negative (10^-5) at month 3. Twenty-seven patients are still undergoing treatment.

At all doses, BMS-986393 had a tolerable safety profile with low-grade CRS and ICANS. Dose escalation is still ongoing but preliminary efficacy suggested promising results with observed antitumor responses. Selection for part B is currently underway as part of the dose-expansion cohort.

Reference

1. Bal S, Kocoglu MH, Nadeem O, et al. Clinical activity of BMS-986393 (CC-95266), a G protein–coupled receptor class C group 5 member D (GPRC5D)–targeted chimeric antigen receptor (CAR) T cell therapy, in patients with relapsed and/or refractory (R/R) multiple myeloma (MM): first results from a phase 1, multicenter, open-label study. Presented at: 2022 American Hematology Society meeting; December 10-13; New Orleans, LA. Abstract 364.