Arlocabtagene autoleucel: a GPRC5D-targeted CAR T-cell therapy for heavily pretreated relapsed/refractory multiple...

Patients with relapsed/refractory multiple myeloma (RRMM) have limited treatment options. Arlocabtagene autoleucel (arlo-cel; BMS-986393) is an autologous chimeric antigen receptor (CAR) T-cell therapy targeting G protein-coupled receptor class C group 5 member D (GPRC5D). This phase 1, dose-escalation/expansion study enrolled adult patients with RRMM and ≥3 previous antimyeloma treatment regimens, including an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody. Patients (N = 84) had a median of 5 prior regimens, and 49% had previously received B-cell maturation antigen-targeted therapy. Arlo-cel was administered as a single IV infusion of 25 to 450 × 106 CAR T cells. Primary end points were safety and maximum tolerated dose (MTD); secondary end points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Data cutoff was 23 August 2024. Cytokine release syndrome (CRS) occurred in 82% of patients, immune effector cell-associated neurotoxicity syndrome in 10%, and other select neurotoxicities in 12%; most were grade 1/2 and frequency appeared dose-dependent. One death occurred from CRS at the highest dose level. On-target/off-tumor skin (30%), nail (19%), and oral (32%) adverse events were transient and grade 1/2; most resolved without intervention. MTD was not reached. With a median follow-up of 16.1 months, ORR was 87% (complete response rate, 53%), median duration of response was 18.0 months, median PFS was 18.3 months (95% confidence interval, 11.8-21.9; n = 79), and 1-year OS rate was 90% (N = 84). Arlo-cel showed a manageable safety profile and deep, durable responses, with promising PFS and OS in heavily pretreated RRMM, supportive of future clinical research. This trial was registered at www.clinicaltrials.gov as NCT04674813.