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

Introduction: CAR T cell therapies targeting B‑cell maturation antigen (BCMA) have resulted in unprecedented depth and duration of response in R/R MM. However, relapses are frequent, and the development of novel approaches is critical. GPRC5D, an orphan receptor expressed on MM cells with limited expression in other tissues, has emerged as a promising therapeutic target for MM. MCARH109, a GPRC5D-directed CAR T cell therapy, demonstrated promising initial safety and efficacy in patients (pts) with R/R MM (Mailankody S et al. Blood. 2021), warranting further study of this CAR T target. We present interim results from the dose-escalation part (Part A) of CC‑95266‑MM‑001 (NCT04674813), a phase 1, first‑in-human, multicenter, open-label, dose-finding study evaluating BMS-986393 (CC‑95266), a GPRC5D-targeted autologous CAR T cell therapy, in pts with R/R MM.

Methods: Part A includes pts with ≥ 3 prior lines of therapy containing a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 therapy, and, unless ineligible, a stem cell transplant. Prior BCMA-directed and CAR T cell therapies are allowed. The study follows a modified toxicity probability interval design with ≥ 3 pts per dose level. After screening and leukapheresis, pts received bridging therapy if needed, then lymphodepleting chemotherapy (fludarabine 30 mg/m² + cyclophosphamide 300 mg/m² daily for 3 days) followed by a single infusion of BMS-986393. Primary objectives are to determine the safety, tolerability, and maximum tolerated dose (MTD) and/or recommended phase 2 dose of BMS-986393.

Results: As of May 24, 2022, 21 pts enrolled and 17 pts received BMS-986393 at doses of 25 (n = 5), 75 (n = 9), and 150 (n = 3) × 10⁶ CAR T cells. Among treated pts, 8 (47%) pts had high-risk cytogenetics (del[17p], t[4;14], and/or t[14;16]) and 8 (47%) pts had extramedullary plasmacytomas. Seven (41%) pts received prior BCMA-targeted therapies, including 6 (35%) pts treated with BCMA-directed CAR T cell therapy (Table). Four (24%) pts had penta-refractory MM.

Grade 3/4 treatment-emergent adverse events related to BMS-986393 (TRAEs) were reported in 11/17 (65%) pts; of these, the most frequent were neutropenia (41%) and thrombocytopenia (35%). TRAEs consistent with on-target, off-tumor activity affecting the skin (18%) and nails (12%), as well as dysgeusia/dysphagia (12%) were reported, all grade 1. Dose-limiting toxicities of prolonged (out to day 42) neutropenia and/or thrombocytopenia were reported in 2 pts; MTD has not been exceeded. Cytokine release syndrome (CRS) was reported in 11/17 (65%) pts, all grade 1/2 (median onset, day 3 [range, 2–4]; median duration, 2 days). Immune effector cell–associated neurotoxicity syndrome (ICANS)–type neurotoxicity was reported in 2/17 (12%) pts, both grade 1 (duration, 1–3 days), and was reversible with steroid treatment (Table).

Responses were reported in 12 of 14 pts evaluable for initial (1‑month) clinical response (overall response rate, 86%), including in 4/6 and 3/5 pts treated with prior BCMA‑directed and BCMA-directed CAR T cell therapies, respectively. Median duration of response has not been reached for any dose level, with median follow-up of 4.0 months (range, 1.0–13.1; Table). At the time of analysis, 15/17 (88%) pts remained in follow-up; 2 (12%) pts discontinued due to progressive disease.

In preliminary pharmacodynamic analyses, greater reductions in soluble BCMA levels were associated with increasing dose from 25 to 75 × 10⁶ CAR T cells, and all 3 pts with complete response (CR) at the 25 × 10⁶ CAR T-cell dose level were minimal residual disease (MRD)–negative (10⁻⁵ depth) at month 3, with follow-up ongoing.

Preliminary cellular pharmacokinetic analyses demonstrated a dose-dependent increase in BMS-986393 exposure (Table).

Conclusions: At all tested dose levels, BMS-986393 demonstrated a favorable safety profile; both CRS and neurotoxicity were low-grade, and neurotoxicity was infrequent and short-lived. Dose escalation is ongoing; MTD has not been exceeded. Preliminary efficacy appeared promising; antitumor responses were observed, including pts with CR who were MRD-negative at month 3. These initial data support GPRC5D-directed CAR T cell therapy with BMS-986393 as a new treatment paradigm in R/R MM. Selection of the dose(s) for expansion in Part B is underway, and updated data will be presented.