Background: CARTITUDE-4 is a global, phase 3, randomized, controlled trial (NCT04181827) of ciltacabtagene autoleucel (cilta-cel), a dual-binding, BCMA-targeting CAR-T cell therapy, vs standard of care (SOC; pomalidomide, bortezomib, and dexamethasone [PVd] or daratumumab, pomalidomide, and dexamethasone [DPd]) in lenalidomide (len)-refractory patients (pts). Methods: Eligible pts had 1–3 prior lines of therapy (LOT), including PI and IMiD, and were len-refractory. After apheresis, pts randomized to cilta-cel received PVd or DPd (physician’s choice) bridging therapy, then 1 cilta-cel infusion 5–7 days after lymphodepletion. In the SOC arm, pts received PVd or DPd until progression. Primary endpoint was progression-free survival (PFS) in the intent-to-treat (randomized) population. Results: 419 pts were randomized (cilta-cel, n=208; SOC, n=211 [PVd, n=28; DPd, n=183]). 176 pts received cilta-cel as study treatment (tx), 20 more received it after PD on bridging therapy, and 208 received SOC. There were no manufacturing failures. Baseline characteristics were balanced (cilta-cel vs SOC: 59% vs 63% cytogenetic high risk [including gain/amp 1q]; 50% vs 46% PI refractory; 24% vs 22% anti-CD38 refractory; 33% vs 32% had 1 prior LOT). Median dose was 0.71×10⁶ CAR+ viable T cells/kg. At Nov 1, 2022, data cut-off, median follow-up was 16 mo (range, 0.1–27). Primary endpoint was met; cilta-cel reduced risk of progression/death by 74% (HR=0.26; P<0.0001). Cilta-cel vs SOC significantly improved ORR, rate of ≥CR, and overall MRD negativity rate (Table), with a positive trend in OS (HR, 0.78; 95% CI, 0.5–1.2). 97% and 94% of pts treated in the cilta-cel or SOC arms, respectively, had grade (gr) 3/4 AEs, including infections (27% vs 25%) and cytopenias (94% vs 86%). In the cilta-cel and SOC arms, respectively, 39 and 46 pts died (14 and 30 due to PD). In pts who received cilta-cel as study tx (n=176), 76% had CRS (1% gr 3; no gr 4/5) and 5% had ICANS (all gr 1/2). 1 pt had a gr 1 movement/neurocognitive TEAE. Conclusions: A single cilta-cel infusion significantly improved PFS vs SOC in len-refractory pts with 1–3 prior LOT, with a favorable benefit/risk profile across pt populations. The 74% reduction in progression/death and high rates of CR and MRD negativity highlight the potential for cilta-cel to become a key therapy for pts with MM after first relapse. Clinical trial information: NCT04181827.

^aPer computerized algorithm by constant piecewise weighted log-rank test. ^bIn 176 pts who received cilta-cel as study tx: ORR, 175 (99%); ≥CR, 152 (86%). ^cFor MRD-evaluable pts: cilta-cel, 88% (126/144); SOC, 33% (33/101).