Phase 1 Study of Anitocabtagene Autoleucel for the Treatment of Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM): Efficacy and Safety with 34-Month Median Follow-up

Introduction: Anitocabtagene autoleucel (anito-cel, previously CART-ddBCMA) is an autologous D-Domain BCMA-directed chimeric antigen receptor (CAR) T-cell therapy being studied in patients (pts) with RRMM. Previously reported at a median follow-up of 26.5 months, pts had 100% overall response rate (ORR), ≥CR rate of 76%, and 24-month progression-free survival (PFS) rate of 56% (Frigault et al., ASH 2023). Additional pt population details and longer-term efficacy and safety outcomes for this Phase 1 first-in-human clinical trial are reported. Methods: Pts with RRMM who had received ≥3 prior lines of therapy (LoT) were enrolled and received a single infusion of anito-cel following lymphodepletion chemotherapy (fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 daily for 3 days). Two dose levels (DL1 and DL2, respectively) of 100 & 300 (±20%) × 106 CAR+ T cells were evaluated. The primary endpoints included incidence of adverse events and dose-limiting toxicities. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed by ASTCT consensus grading. Additional endpoints included depth and duration of clinical response assessed according to the IMWG Uniform Response Criteria for MM, evaluation of minimal residual disease (MRD), progression-free (PFS), and overall survival (OS). Results: As of May 31, 2024, 40 pts were enrolled; 38 pts (95%) received anito-cel (32, DL1; 6, DL2) and were evaluable for safety and clinical response. Two pts were not eligible for anito-cel infusion due to medical complications despite successful manufacturing. Median age was 66 years (range, 44-76), median time from MM diagnosis was 6.5 years (range, 1.5-14.9), and median prior LoT was 4 (range, 3-16). Racial distribution was 32 (84%) White, 4 (11%) Black or African American, 1 (3%) Asian, and 1 (3%) Other. All pts (n=38, 100%) were triple-class refractory, 26 (68%) were penta-drug refractory, 20 (53%) were ≥65 years of age, 13 (34%) had extramedullary disease (EMD), 11 (29%) had high-risk cytogenetics, and 9 (24%) had high tumor burden with ≥60% bone marrow plasma cells (BMPCs). Twenty-six pts (68%) received bridging therapy between apheresis and anito-cel infusion; bridging agents were limited only to those previously received. For pts in DL1 (the recommended Phase 2 dose), the median CAR+ T cell dose was 115 x 106 (range, 112-120). Median follow-up after anito-cel infusion was 34 months (range, 21-52 months). CRS occurred in 36 pts (95%) with 18 (47%) Grade (Gr) 1, 17 (45%) Gr2, and 1 (3%) Gr3 at the higher DL2. ICANS occurred in 7 pts (18%) with 3 (8%) Gr1, 2 (5%) Gr2, and 1 Gr3 case in each DL. All cases of CRS & ICANS resolved without further sequalae. No delayed neurotoxicity events or Parkinsonian-like symptoms have been observed. All 38 pts demonstrated investigator-assessed clinical response per 2016 IMWG criteria (ORR, 100%) with 30 CR/sCR (≥CR rate, 79%), 5 VGPR (≥VGPR rate, 92%), and 3 PR. Conversions to sCR occurred from 1 to ≥12 months. Median time to first response, best response, and complete response or better was 1 month (range, 0.85-1.9), 2.8 months (range, 0.9 -19.4), and 2.7 months (range, 0.9 - 19.4), respectively. Of those evaluable for MRD testing (n=28), 25 (89%) achieved MRD negativity at 10-5. Median time to reach MRD negativity at 10-5 was 1.0 month (range, 0.9-5.6). The Kaplan-Meier estimated PFS rates for 9, 18, and 27 months were 92%, 65%, and 52% and for OS rates were 97%, 82%, and 78%, respectively. Pts with high-risk features (EMD, BMPC ≥60%, or B2M ≥5.5, n=24) demonstrated durable responses comparable to the overall population, with PFS rates of 92%, 66%, and 55% for 9, 18, and 27 months. Conclusions: At a longer median follow-up of 34 months, a single anito-cel infusion led to early, deep, and durable responses in heavily pre-treated pts with RRMM, with the ≥CR rate deepening to 79%. The safety profile is manageable with no cranial nerve palsies, no Guillain-Barre syndrome, and no Parkinsonian-like events. Follow-up is continuing and updated data will be presented. Further investigations of anito-cel are ongoing in 4L+ RRMM (iMMagine-1, NCT05396885) and in earlier lines (iMMagine-3, NCT06413498).