Results from the First Phase 1 Clinical Study of the B-Cell Maturation Antigen (BCMA) Nex T Chimeric Antigen Receptor (CAR) T Cell Therapy CC-98633/BMS-986354 in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: CC‑98633/BMS-986354 is a next-generation CAR T-cell product that contains the same fully human BCMA-targeted CAR construct as orvacabtagene autoleucel (orva-cel; Harrington K et al. Blood. 2017) and is manufactured using the NEX-T process. The NEX-T process was designed to shorten manufacturing time and improve the potency and phenotypic attributes of the CAR T-cell drug product with the aim of enhancing depth and durability of response. In vivo studies have shown that BMS-986354 is a less differentiated CAR T-cell product with improved potency and tumor control vs orva-cel. Here, we present phase 1 clinical data from the ongoing CC-98633-MM-001 trial (NCT04394650).

Methods: This is a multicenter, phase 1 trial investigating BMS-986354 in pts with RRMM who received ≥ 3 prior regimens, including an autologous stem cell transplant, proteasome inhibitor, immunomodulatory drugs, and an anti-CD38 monoclonal antibody. Following leukapheresis, patient T cells were purified and engineered with reduced ex vivo expansion and manufacturing time of 5 or 6 days. Pts received a single BMS-986354 infusion 2–7 days after lymphodepleting chemotherapy (3 days fludarabine [30 mg/m²] and cyclophosphamide [300 mg/m²]).

Results: As of May 12, 2022, 66 pts have been enrolled, 55 have been treated with BMS-986354, and 54 were evaluable for disease response. In the dose-escalation phase (Part A), pts were treated with 20 × 10⁶ (dose level [DL] 1, n = 7), 40 × 10⁶ (DL2, n = 24), or 80 × 10⁶ (DL3, n = 11) CAR+ T cells; DL2 was selected for dose expansion (Part B), and an additional 13 pts were treated. Enrolled pts had a median age of 62.5 years (range, 43–75). Median time from diagnosis was 6.2 years (range, 0.7–24.6) with a median of 5 prior regimens (range, 3–13). During dose escalation, no pts had dose-limiting toxicities (DLTs) at DL1, 4 had DLTs at DL2 (prolonged neutropenia and thrombocytopenia [n=1], prolonged neutropenia [n = 2], decreased fibrinogen [n = 1]), and 3 had DLTs at DL3 (prolonged neutropenia [n = 2], prolonged thrombocytopenia [n = 1]); all DLs were tolerable per prespecified criteria.

Cytokine release syndrome (CRS) occurred in 80.0% of all treated pts, with most experiencing grade 1 (63.6%) or grade 2 (14.5%); only 1 pt experienced ≥ grade 3 (grade 4) CRS. Median onset was day 4 (range, 2–8), median duration was 4 days (range, 1–8), and common treatments included tocilizumab (n = 38), steroids (n = 25), and anakinra (n = 9). Neurotoxicity occurred in 6 (10.9%) pts (grade 1, n = 5; grade 4, n = 1); all events resolved after a median of 2.5 days (range, 2–21). No neurotoxicity events had an onset beyond day 9. Overall, with a median follow-up of 4.9 months, the objective response rate was 98.1%, with 57.4% of pts achieving a very good partial response or better, 29.6% achieving complete response or better, and 76.4% of responses ongoing.

Compared with orva-cel, BMS-986354 drug product is less differentiated, composed primarily of naive-like and central memory CAR T cells with fewer effector and terminally differentiated CAR T cells. Following CAR stimulation, BMS-986354 led to higher antigen-specific cytokine (interferon-gamma, tumor necrosis factor alpha, and interleukin-2) production than orva-cel (Figure).

Pharmacokinetic analysis of transgene levels using droplet-digital polymerase chain reaction demonstrated robust cellular expansion across all DLs (geometric mean maximum concentration [C_max] of 8.67 × 10⁴ gag copies/µg, area under the curve 0 to 28 days [AUC_0–28] of 85 × 10⁴ days × gag copies/µg, median time to C_max of 14 days at DL2). Flow cytometry analysis during dose escalation showed that similar C_max and AUC_0–28 were reached with a > 11-fold lower dose of BMS-986354 than orva-cel, demonstrating increased proliferative capacity for BMS-986354 (geometric mean C_max of 399 cells/µL, AUC_0–28 of 3674 days × cells/µL at DL2 vs C_max of 328 cells/µL, AUC_0–28 of 3890 days × cells/µL at 450 × 10⁶ cells).

Conclusions: BMS-986354, a NEX-T investigational BCMA-targeted CAR T-cell product, is a less differentiated, more potent cellular drug product than orva-cel and can be manufactured with a more rapid processing time. At low doses, BMS-986354 demonstrated a favorable safety profile and promising efficacy, including deep and durable responses in pts with heavily pretreated RRMM. The study continues to enroll patients in the dose-expansion phase. Updated safety, efficacy, and translational data will be presented.