7535 Background: The phase 2 multicohort CARTITUDE-2 study is evaluating ciltacabtagene autoleucel (cilta-cel) in patients (pts) with MM across multiple settings. Cohort A is examining cilta-cel in earlier lines of treatment (tx; LOT) in pts with lenalidomide (len)-refractory multiple myeloma (MM). Initial results for cohort A (N=20; median follow-up, 30 mo) showed cilta-cel led to minimal residual disease negativity (MRD neg) at 10 –5 in 100% of pts with evaluable samples (n=17). ORR was 95% (19/20), median DOR was not reached (NR), and the 24-mo PFS rate was 75%. We report protocol-specified results for the expansion subgroup. Methods: Pts with len-refractory MM after 1–3 LOT, including a PI and IMiD, and no anti-BCMA tx were enrolled. A single cilta-cel infusion (target dose, 0.75×10 6 range, 0.5–1.0×10 6 CAR+ viable T cells/kg) was given 5–7 d after the start of lymphodepletion. Cohort A initially evaluated cilta-cel manufactured by clinical trial processes and later expanded to evaluate cilta-cel manufactured by commercial processes. Primary endpoint was MRD neg at 10 –5 . Efficacy is reported for pts who received cilta-cel at target dose; demographics, baseline disease characteristics, and safety are reported for all treated pts in the expansion subgroup. Results: As of Sept 5, 2023, median follow-up was 16 mo. Of 24 pts enrolled, 23 received cilta-cel infusion (22 at target dose). Median age was 63 y, 52% were male, and 61% were triple-class exposed. Of 16 MRD-evaluable pts, 100% achieved MRD neg at 10 –5 ; median time to MRD neg was 2 mo (range, 1–12). ORR was 91% (20/22). Median DOR was NR; 79% of responders remained in response at 12 mo. Median (range) time to first and best responses were 1 mo (1–10) and 6 mo (1–19), respectively. 12-mo PFS and OS rates were 77% and 91%, respectively. All pts had TEAEs (grade gr 3/4, n=22; gr 5, n=1). Hematologic TEAEs included neutropenia (96%), leukopenia (65%), lymphopenia (65%), anemia (57%), and thrombocytopenia (57%). Infections occurred in 8 (35%) pts (gr 3/4, n=1; gr 5, n=1 due to sepsis). CRS occurred in 23 (100%) pts (gr 1/2, n=23); median time to onset was 8 d and recovery was 4 d. ICANS occurred in 4 (17%) pts (gr 1, n=3; gr 4, n=1); median time to onset was 10 d and recovery was 2 d. No other neurotoxicities or MNTs/parkinsonism occurred. 2 pts had secondary malignancies (SM); 1 pt had separate SM of gr 2 basal cell carcinoma and gr 2 squamous cell carcinoma and 1 pt had MDS diagnosed on d 846 that later transformed to AML. Per investigator assessment, SM were not tx-related. Conclusions: In the expansion subgroup of cohort A, cilta-cel led to deep and durable responses in pts with len-refractory MM as early as after first relapse; safety was consistent with the known mechanism of action of CAR-T tx. Results in the expansion and initial subgroups are comparable. Data for CARTITUDE-2 cohort A underscore observations in CARTITUDE-4 which enrolled a similar pt population. Clinical trial information: NCT04133636 .