Cellular and T cell engager Immunotherapy

Category: Cellular and T cell engager Immunotherapy

Arlocabtagene autoleucel, a GPRC5D-Targeted CAR T-Cell Therapy for Patients With Relapsed/Refractory Multiple Myeloma: Updated Phase 1 Safety and Efficacy Results in Patients With 1–3 Prior Regimens

(PA-080) Arlocabtagene autoleucel, a GPRC5D-Targeted CAR T-Cell Therapy for Patients With Relapsed/Refractory Multiple Myeloma: Updated Phase 1 Safety and Efficacy Results in Patients With 1–3 Prior Regimens

Thursday, September 18, 2025

Omar Nadeem, MD

Clinical Director
Dana-Farber Cancer Institute

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 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 (RP2D, 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 April 4, 2025, 31 pts had been enrolled and 100% received arlo-cel following successful manufacturing; 68% received optional bridging therapy. Median age was 62 y (range 31–78); 68% were male. Overall, 26% had high-risk cytogenetics (del[17p], t[4;14], and/or t[14;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 39%, 42% and 42%, respectively (all G1/2). Other select neurotoxicity occurred in 6.5%: 1 pt with G2 gait disturbance and G2 ataxia and 1 pt with G1 gait disturbance (resolved) and G1 dysarthria. TE infections occurred in 55% (all G1/2).

After a median 15.8 mo follow-up (range 3.8–21.5 mo) for 24 efficacy-evaluable pts, overall response rate was 96% and complete response (CR) rate was 63%; 15/24 responses were still ongoing. Median progression free survival (PFS) was not reached; 12-mo PFS rate was 74%. Of 16 pts with minimal residual disease (MRD) data, the MRD negative (10⁻⁵ depth) rate was 75%.

Conclusions: A single administration of arlo-cel at the RP2D 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 15.8 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 improved over some BCMA-targeted therapies. These data support arlo-cel as a potential early-line treatment in RRMM.