Background: High-risk (R-ISS stage III) newly diagnosed multiple myeloma (NDMM) has a poor prognosis (median PFS, 29 mo), highlighting the need for novel disease-targeting approaches (Palumbo A, et al. J Clin Oncol 2015;33:2863-2869). Ide-cel, a BCMA-directed CAR T cell therapy, demonstrated deep, durable responses in heavily pretreated patients (pts) with relapsed and refractory MM (RRMM; Raje N, et al. N Engl J Med 2019;380:1726-1737; Munshi NC, et al. J Clin Oncol 2020;38[suppl 15]. Abstract 8503), including those with high-risk (R-ISS stage III) RRMM. In this population, earlier use of ide cel—when there may be more bone marrow reserve, more healthy peripheral blood mononuclear cells, a less compromised immune status, and less extensive disease to debulk before cell therapy—may result in improved outcomes vs standard therapies and offer an opportunity to replace transplant with CAR T cell therapy. Methods: KarMMa-4 (NCT04196491), a multicenter, open-label, phase 1, single-arm study, is currently evaluating ide-cel in pts with high-risk NDMM, defined as R-ISS stage III (ISS stage III [serum ß₂ microglobulin ≥ 5.5 mg/L] and cytogenetic abnormalities t(4;14), del(17p), and/or t(14;16) by interphase FISH; or ISS stage III and serum LDH > ULN). Pts must have received ≤ 3 cycles of the induction regimens listed below, be aged ≥ 18 years, and have ECOG PS 0-1. Nonsecretory MM and CNS involvement are exclusion criteria. Pts can enroll between induction cycles 1 and 3. Permitted cycle 1 regimens are carfilzomib + lenalidomide (LEN) + dexamethasone (DEX) ± daratumumab (DARA; KRd ± DARA), LEN + bortezomib (BOR) + DEX ± DARA (RVd ± DARA), or cyclophosphamide + BOR + DEX (CyBorD). Induction cycles 2-4 are limited to KRd or RVd, with DEX omitted during cycle 3. Pts will undergo T cell collection via leukapheresis after cycle 3, and ide-cel will be manufactured during cycle 4. Stem cell collection for future use may be conducted after cycle 3 (following leukapheresis) or 4 (before lymphodepletion). Ide-cel is infused after 2 days of rest following lymphodepletion with 3 days of fludarabine 30 mg/m² + cyclophosphamide 300 mg/m². LEN-based maintenance may be provided upon bone marrow recovery or 90 days after ide-cel infusion, whichever is later. Dose-limiting toxicity and safety are the primary endpoints. Secondary endpoints include complete response (CR) rate and overall response rate, duration of response, time to CR, time to start of maintenance, feasibility of initiating maintenance, PFS, overall survival, and pharmacokinetics. Exploratory endpoints include LEN maintenance safety, minimal residual disease, immunogenicity and biomarkers. The starting ide-cel target dose is 450 × 10⁶ CAR+ T cells, with dose escalation/de-escalation (150, 300, and 800 × 10⁶ CAR+ T cells). Upon determination of optimal target dose, 12 pts will be enrolled in the dose-expansion phase. Clinical trial information: NCT04196491