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Introduction: Despite advances in RRMM therapy, new approaches are needed for patients (pts) that relapse. GPRC5D, an orphan receptor expressed on MM cells with limited expression in other tissues, is a promising therapeutic target for MM. Previously, we presented interim results from the dose escalation and expansion parts 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 RRMM (Bal S et al. ASH 2022, P364; Bal S et al. EHA 2023, S193). Here, we present updated safety and efficacy data from the study. Methods: Eligible pts received ≥ 3 prior treatment regimens and must have received a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 therapy, and an autologous stem cell transplant (if eligible); prior BCMA-directed and CAR T-cell therapies were allowed. After screening and leukapheresis, pts received bridging therapy, if needed, and underwent lymphodepletion followed by a single infusion of BMS-986393. In dose escalation, BMS-986393 was used at doses of 25, 75, 150, 300, and 450 × 10 6 CAR T cells. In dose expansion, additional pts received 75, 150, 300, or 450 × 10 6 CAR T cells. Safety, tolerability, and determination of maximum tolerated dose and/or recommended phase 2 dose (RP2D) of BMS-986393 were primary objectives; secondary objectives included evaluation of preliminary efficacy. Results: As of May 24, 2023, 70 pts received BMS-986393 at doses of 25 (n = 6), 75 (n = 10), 150 (n = 26), 300 (n = 17), and 450 (n = 11) × 10 6 CAR T cells. 32 pts (46%) had high-risk cytogenetics (del17p, t4;14, and/or t14;16), 40 (57%) had 1q21amp, and 30 (43%) had extramedullary plasmacytomas; 32 (46%) pts had received prior BCMA-targeted therapy, including BCMA-directed CAR T-cell therapy in 25 (36%) pts. 24 (34%) pts had penta-refractory MM. Grade (G) 3/4 treatment-emergent adverse events (AEs) occurred in 64/70 (91%) pts; the most frequent were neutropenia (69%), anemia (31%), and thrombocytopenia (30%). Any-grade infections occurred in 30 (43%) pts (G 3/4 in 11 16% pts). Cytokine release syndrome (CRS) occurred in 59 (84%) pts (G ≥ 3 in 3 4% pts, with 1 1% G5 event); 3 (4%) pts had hemophagocytic lymphohistiocytosis, all G3. On-target off-tumor treatment-related AEs (TRAEs), all G1/2, included skin (17 24%) and nail (11 16%) TRAEs and dysgeusia/dysphagia (2 3%). Immune effector cell-associated neurotoxicity syndrome (ICANS)-type neurotoxicity occurred in 8 (11%) pts (G3 in 2 3% pts). The most frequent non-ICANS neurologic TRAEs were headache (10 14%), dizziness (6 9%), ataxia (5 7%), dysarthria (3 4%), neurotoxicity (3 4%, including events termed cerebellar toxicity in 2 pts), and paresthesia, gait disturbance, and nystagmus (1 pt each 1%). Aside from headache and paresthesia, incidence of the listed non-ICANS neurologic TRAEs appeared to be dose-related, and reversibility of some events was observed. Overall response rate (ORR) across doses was 86% (55/64) in efficacy-evaluable pts and 75% (21/28) in pts treated with prior BCMA-directed therapies, including CAR T cells. Complete response (CR) rate was 38% (24/64). In pts refractory to prior BCMA-directed therapies, ORR was 85% (11/13), and CR rate was 46% (6/13). Median follow-up for all treated pts was 5.9 mo (range, 0.0-24.0). At the time of data cutoff, 75% of responses (41/55) were ongoing. All 10 pts (100%) with available minimal residual disease (MRD) data and a best overall response of CR were MRD-negative (10 −5 depth) at ≥ month 3. BMS-986393 reduced soluble BCMA levels (indicative of tumor burden reduction) across all dose levels and showed a dose-dependent increase in cellular expansion. Conclusions: In this first-in-human study, BMS-986393 showed a manageable safety profile and deep and durable responses, including MRD negativity, at all tested dose levels, including in pts refractory to prior BCMA-directed therapies. CRS and ICANS-type neurotoxicity were mostly low-grade, with increased G ≥ 3 events at the 300 and 450 × 10 6 CAR T-cell doses. On-target off-tumor TRAEs, all G1/2, occurred in a minority of pts. These data support GPRC5D-directed CAR T-cell therapy with BMS-986393 as a potential treatment in RRMM, irrespective of prior BCMA-directed therapy. Dose expansion is continuing to define the RP2D. Updated data will be presented.
Bal et al. (Thu,) studied this question.