BMS-986393, a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted CAR T Cell Therapy, in Patients (pts) with Relapsed/Refractory (RR) Multiple Myeloma (MM) and 1-3 Prior Regimens: Updated Phase 1 Safety and Efficacy Results
Authors: Bal Susan , Htut Myo , Berdeja Jesús G. , Anderson Larry D , Rossi Adriana , Gregory Tara , Martin Thomas G , Costa Luciano J. , Hu Hongxiang , Chen Jinjie , Mei Chaoqun , Sarkis Naomey , Shrestha Alok , Ziyad Safiyyah , Kao Wei-Ming , Kaeding Allison J , Burgess Michael R. , Nadeem Omar 
Published: December 2024

Introduction
The increasing use of quadruplet induction and monoclonal antibody-based maintenance therapies in the management of MM results in the disease becoming refractory to existing therapy classes relatively early in its course. Therefore, new therapy classes are needed for pts with early treatment-refractory disease. BMS-986393 is an autologous chimeric antigen receptor (CAR) T cell therapy targeting GPRC5D that showed a favorable safety profile and promising efficacy from a single infusion in a phase 1 trial. The first data from patients with 1-3 prior lines of therapy also suggested promising safety and efficacy (Nadeem et al, EHA 2024); here, we report updated safety and efficacy from these pts.
Methods
Pts had 1-3 prior anti-MM regimens including a proteasome inhibitor and an immunomodulatory agent. Anti-CD38 therapy was not required; B-cell maturation antigen (BCMA)-directed and CAR T cell therapies were allowed. After screening and leukapheresis (bridging therapy optional), pts received lymphodepleting chemotherapy followed by a single infusion of BMS-986393 at the recommended phase 2 dose (150 × 106 CAR T cells). The primary objective was safety; secondary objectives included clinical activity per IMWG Uniform Response Criteria and pharmacokinetics (PK).
Results
As of May 20, 2024, 31 pts had been enrolled and received BMS-986393; manufacturing was successful for 100%. Median age was 62 years (range 31-78); 68% were male; 68% were White and 19% Black or African American. Overall, 26% had high-risk cytogenetics (del[17p], t[4;14], and/or t[14;16]), 65% had 1q21 gain/amp, and 29% had extramedullary disease. Pts had received a median of 2 prior regimens; 29% had received 3 prior regimens. 52% had received prior stem cell transplantation, 71% anti-CD38 therapy, and 1 pt had a BCMA-targeted therapy. Most (90%) had MM refractory to the most recent regimen; 90% had lenalidomide-refractory, 55% triple-class refractory, and 6% penta-class refractory MM.
All pts experienced a treatment-emergent (TE) adverse event (AE), 84% had grade (G) 3/4 TEAEs; there were no AE-related deaths. Treatment-related (TR) AEs occurred in 97%; 45% had a G3/4 TRAE. Cytokine release syndrome occurred in 84% (all G1/2; all resolved); no pts had macrophage activation syndrome/hemophagocytic lymphohistiocytosis. TR neurologic AEs including immune effector cell-associated neurotoxicity syndrome (ICANS), and other select neurotoxicities were observed. ICANS occurred in 10% of pts (all G1/2; all resolved). Other select neurotoxicity was reported in 1 pt (3%; G2 TR ataxia). In addition, 2 pts had low-grade TR dizziness that was transient, of short duration, and required no intervention. On-target/off-tumor nail, skin and oral TRAEs were reported in 29%, 23% and 39% of pts, respectively (all G1/2). On-target/off-tumor TEAEs resolved in 7 of 19 pts overall, with a median duration of 58 days. One pt experienced TR weight loss (G1/2), and TE infections occurred in 12 (39%) pts (all G1/2).
After a median 5.9 months follow-up (range, 3.8-12.1 months) for 24 efficacy evaluable pts, ORR was maintained at 96% and CRR at 46%; 78% of responses (18/23) were still ongoing. Considering disease characteristics, ORR was 100% in pts with high-risk cytogenetics (7/7), 93% for triple-class refractory disease (13/14), and 100% for extramedullary disease (6/6). Of 5 pts with minimal residual disease (MRD) data and a CR or better, 100% were MRD-negative (10−5 depth; at any time point within 3 months prior to achieving CR or better, until the time of progression or death). PK analyses showed fast and robust cellular expansion with a median time to peak transgene level of 14 days and a peak transgene level comparable to that seen in heavily pretreated pts. Longitudinal assessment of soluble BCMA levels suggested that BMS-986393 infusion caused deep tumor clearance.
Conclusions
A single administration of the GPRC5D-targeted CAR T therapy, BMS-986393, at the RP2D in pts with RRMM and 1-3 prior lines of therapy was well-tolerated and led to a high rate of response that deepened over time, with little early relapse. While follow-up was limited, the safety profile was favorable with no new signals. Notably, the frequency and grade of infections was improved over some BCMA-targeted therapies. These data support BMS-986393 as a potential early-line treatment in RRMM. The trial is ongoing and a further update with longer follow-up will be presented.