Arlocabtagene autoleucel-a GPRC5D-targeted CAR T-cell therapy in heavily pretreated relapsed/refractory multiple myeloma

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 (NCT04674813) enrolled adult patients with RRMM and ≥3 prior antimyeloma treatment regimens, including an immunomodulatory drug (IMiD), a proteasome inhibitor, and an anti-CD38 antibody. At baseline, patients (N=84) had a median of 5 prior regimens and 49% had previously received BCMA-targeted therapy, of whom 38% received CAR T-cell therapy. Arlo-cel was administered as a one-time intravenous infusion of 25×106-450×106 CAR T cells. Primary endpoints were safety and maximum tolerated dose (MTD); secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Data cutoff was 23August2024. 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 highest dose level. On-target/off-tumor skin (30%), nail (19%), and oral (32%) adverse events were transient, grade 1/2; most resolved without intervention. MTD was not reached. With median follow-up of 16.1 months, ORR=87% (complete response rate=53%), median duration of response=18.0 months, and median PFS=18.3 months (95% CI, 11.8-21.9) (n=79). The 1-year OS rate was 90% (N=84). In conclusion, arlo-cel had a safety profile supportive of future study and demonstrated deep and durable responses, with promising PFS and OS in patients with heavily pretreated RRMM.