KEY TAKEAWAYS
- The phase I trial aimed to present an updated analysis of the safety and efficacy profile of BMS-986393 in RRMM patients.
- The primary endpoints were to determine MTD and RP2D.
- BMS-986393 showed promise as a safe and effective RRMM treatment with deep & durable responses even in BCMA-resistant patients, warranting further dose optimization.
Despite advancements in treating relapsed/refractory multiple myeloma (RRMM), there remains a need for innovative approaches. GPRC5D, expressed primarily on MM cells, emerges as a promising target. Preliminary findings from the ongoing phase 1 study (NCT04674813) assessing BMS-986393 (CC‑95266), a GPRC5D-targeted CAR T-cell therapy, have been previously reported in dose escalation and expansion phases.
To address the need for novel strategies in RRMM, Susan Bal and her team conducted the study that aimed to provide updated safety and efficacy outcomes from the ongoing phase 1 study (NCT04674813) assessing BMS-986393 (CC-95266), a GPRC5D-targeted autologous CAR T-cell therapy.
Eligible patients, having undergone ≥ 3 prior treatment regimens and receiving essential therapies, including a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 therapy, and autologous stem cell transplant (if eligible), with allowance for prior BCMA-directed and CAR T-cell therapies, underwent screening, leukapheresis, and optional bridging therapy.
Following lymphodepletion, a single infusion of BMS-986393 was administered. Dose escalation involved 25, 75, 150, 300, and 450 × 106 CAR T cells, while dose expansion included additional patients receiving 75, 150, 300, or 450 × 106 CAR T cells. Primary endpoints were safety, tolerability, and determination of the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of BMS-986393, with secondary endpoint focusing on the preliminary evaluation of efficacy.
About 70 patients were administered BMS-986393, with doses distributed as follows: 25 (n = 6), 75 (n = 10), 150 (n = 26), 300 (n = 17), and 450 (n = 11) × 106 CAR T cells. Among them, 32 patients (46%) exhibited high-risk cytogenetics (del[17p], t[4;14], and/or t[14;16]), 40 (57%) had 1q21amp, and 30 (43%) presented with extramedullary plasmacytomas. Prior BCMA-targeted therapy was reported in 32 patients (46%), including BCMA-directed CAR T-cell therapy in 25 (36%) individuals. Additionally, 24 patients (34%) were diagnosed with penta-refractory MM.
Grade (G) 3/4 treatment-emergent adverse events (TEAEs) occurred in 91% (64/70) patients; the most frequent were neutropenia (69%), anemia (31%), and thrombocytopenia (30%). Any-grade infections occurred in 43% (30 patients) (G 3/4 in 11 [16%] patients).
Cytokine release syndrome (CRS) occurred in 84% (59 patients) (G ≥ 3 in 3 [4%] patients, with 1 [1%] G5 event); 3 (4%) patients 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 11% (8 patients) (G3 in 2 [3%] patients). 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 patients), 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.
The overall response rate (ORR) across doses was 86% (55/64) in efficacy-evaluable patients, with a 38% complete response (CR) rate. In patients treated with prior BCMA-directed therapies, including CAR T cells, the ORR was 75% (21/28). Among those refractory to prior BCMA-directed therapies, the ORR was 85% (11/13), with a CR rate of 46% (6/13).
At the median follow-up of 5.9 months (range, 0.0–24.0), 75% of responses (41/55) were ongoing. All 10 patients (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 demonstrated a reduction in soluble BCMA levels across all dose levels, indicative of tumor burden reduction, and exhibited a dose-dependent increase in cellular expansion.
The results showed that BMS-986393 had a well-tolerated safety profile and robust responses, supporting its potential as a GPRC5D-directed CAR T-cell therapy for relapsed/refractory multiple myeloma. Ongoing dose expansion will further refine its RP2D.
Research is sponsored by Juno Therapeutics, a Subsidiary of Celgene.
Source: https://ash.confex.com/ash/2023/webprogram/Paper181857.html
Clinical Trial: https://clinicaltrials.gov/study/NCT04674813
Bal S, Htut M, Nadeem O, et al.(2023)’’BMS-986393 (CC-95266), a G Protein–Coupled Receptor Class C Group 5 Member D (GPRC5D)–Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from a Phase 1 Study.’’ Presented at ASH 2023 (219).
