Introduction. There is an urgent need for new therapeutic options with alternative targets or mechanisms of action for patients (pts) with relapsed and refractory multiple myeloma (RRMM). Arlocabtagene autoleucel (arlo-cel; CC-95266; BMS-986393) is a chimeric antigen receptor (CAR) T cell therapy targeting GPRC5D that is being evaluated in the multicohort phase 1 trial (NCT04674813). We report updated safety and efficacy data for the cohort of pts with 1–3 prior lines of therapy.Methods. Pts had 1–3 prior anti-MM regimens, including a proteasome inhibitor and an immunomodulatory agent. Anti-CD38 therapy was not required; BCMA-directed therapies, including CAR T cells, were allowed. After screening and leukapheresis (bridging therapy optional), pts received lymphodepleting chemotherapy followed by a single infusion of arlo-cel 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.Results. As of June 6, 2025, 31 pts had been enrolled and 100% received arlo-cel following successful manufacturing; 61% (19/31) received optional systemic bridging therapy. Median age was 62 y (range 31–78); 68% were male. Overall, 26% had high-risk cytogenetics (del17p, t4;14, and/or t14;16), 68% had 1q21 gain/amp, and 32% had extramedullary disease. Pts had a median of 2 prior regimens; 29% received 3 prior regimens. All 31 pts had a treatment-emergent (TE) adverse event (AE); 87% had grade (G) 3/4 TEAEs. No deaths were attributed to AEs. Treatment-related AEs occurred in 97% (48% G3/4). Cytokine release syndrome occurred in 84% (all G1/2 resolved); no pts had macrophage activation syndrome/hemophagocytic lymphohistiocytosis. Immune effector cell-associated neurotoxicity syndrome occurred in 10% (all G1/2 resolved). On-target/off-tumor nail, skin, and oral TEAEs were reported in 36%, 26% and 42%, respectively. Other select neurotoxicity occurred in 6.5% of patients, including 1 event of ataxia, 1 event of dysarthria, 2 events of gait disturbance; all events were grade ≤2 and ongoing. TE infections occurred in 55% (all G1/2). In the efficacy-evaluable population (n=24), after a median 18.3 mo follow-up (range 3.8–24.3 mo) the ORR was 96% (23/24) and CR rate was 67% (16/24); 11/23 responses were still ongoing. The 12-mo PFS rate was 74%. Of 16 pts with minimal residual disease (MRD) data, the MRD negative (10−5 depth) CR rate was 56.3%.Conclusion. A one-time administration of arlo-cel in pts with RRMM and 1–3 prior lines of therapy was well tolerated and led to a high response rate that deepened over time, with few early relapses after 18.3 mo median follow-up. The favorable benefit-risk profile for this dose and population was consistent with prior disclosures. Notably, frequency and grade of infections were lower than those reported for BCMA-targeted therapies. These data support arlo-cel as a safe and effective potential early-line treatment in RRMM, with a phase 3 trial (QUINTESSENTIAL 2; NCT06615479) underway.
Bal et al. (Sun,) studied this question.