Abstract Introduction: The CAR-T therapies ide-cel and cilta-cel are approved for patients (pts) with relapsed/refractory multiple myeloma (RRMM). The aim of this study was to determine the incidence, subtypes, and associated risk factors for subsequent primary malignancies (SPMs) in MM pts treated with CAR-T therapy in the real-world setting. Methods: A retrospective, multicenter observational cohort study was conducted of pts who received CAR-T therapy between May 2021 and Dec 2024 at 15 centers within the US Multiple Myeloma Immunotherapy Consortium. Logistic models were used for univariable analyses of invasive SPMs (excluding non-melanoma skin cancers). Variables significant at p < 0.10 were included as candidate variables in the multivariable analysis. Time to event endpoints were analyzed using Kaplan-Meier curves. Results: Of n=1460 CAR-T recipients, median follow-up from the time of CAR-T infusion for the entire cohort, ide-cel, and cilta-cel pts was 13.1, 16.9, and 10 months, respectively. A total of 55 invasive SPMs were noted in 53 pts (SPM incidence 3.6%). The incidence rate of SPMs was 4.55 per 1,000 person-years, based on 53 SPMs occurring over 11,646.14 person-years (calculated from CAR-T to the SPM diagnosis, death, or last follow-up). Baseline characteristics were similar for pts with no SPM versus SPM including: age at CAR-T (median 67 vs 65), female (36% vs 43%), Black (13% vs 16%), prior autologous transplant (87% vs 80%), lenalidomide for ≥2 years (31% vs 27%), high risk cytogenetics (23% vs 29%), and known clonal hematopoiesis (7.5% vs 9.9%). Differences were observed in baseline characteristics among pts with SPM versus no SPM for ≥2 prior alkylator lines of therapy (LOT) (82% vs 60%, p=0.002) and median prior LOT (6 vs 5, p=0.008). There was a trend for more patients with SPMs being age ≥70 (35% vs 37%, p=0.074). Of the 53 SPMs, 26 (49%) were myeloid (MDS or AML), 19 (35.8%) were solid, 7 (13.2%) were of T-cell origin, and 1 was a B-cell lymphoma. Of the T-cell SPMs, three were of T-LGL, though one of the T-LGL pts later developed an invasive CNS T-cell lymphoma (CAR-negative). There were four cases of confirmed CAR-positive T-cell SPMs (all pts treated with cilta-cel), of which two were indolent T-cell lymphoma of the GI tract and two were cutaneous PTCL. There was no difference in total incidence of SPMs among pts who received ide-cel (total=4.4%; myeloid=2.2%, T-cell=0.04%) versus cilta-cel (total=3%; myeloid=1.4%; T-cell=0.5%) (p=0.21). Median OS from the time of CAR-T therapy was 40.8 months for pts without SPM compared to 27.6 months for pts with SPM (p=0.4). Median OS did not differ by myeloid, solid, and T-cell subgroup: 26.4, 37.2, and 24 months, respectively (p=0.21). Median time from CAR-T cell to SPM was 12 months overall, and by subtypes of myeloid, solid, and T-cell was 13.2, 9.6, and 9.6 months, respectively (p=0.74). There was no difference in time to any SPM among pts receiving ide-cel versus cilta-cel (p=0.61). An earlier time to diagnosis of myeloid SPM was observed for cilta-cel versus ide-cel (4.8 vs 20.4 months; p=0.003). Median OS from the time of diagnosis of any SPM, myeloid, solid, or T-cell SPM was 9.6, 7.2, 15.6, and not reached in months, respectively (p=0.006), demonstrating that pts diagnosed with myeloid subtype SPM had inferior OS from the time of their SPM diagnosis compared to other subtypes. The cause of death of 4/11 myeloid SPM pts was the myeloid SPM itself. In univariable analysis for the entire cohort, age ≥70 (p=0.079), ≥5 prior LOT (p=0.012), and ≥2 prior alkylator LOT (p<0.001) were associated with higher risk for SPM. In multivariable analysis, ≥2 LOT containing alkylators was associated with higher risk of SPM (p=0.005). For the univariable analysis of the myeloid subgroup, ≥2 prior alkylator LOT (p=0.016) and ≥2 years of lenalidomide maintenance (p=0.063) were associated with higher risk of SPM. In multivariable analysis, ≥2 years of lenalidomide (p=0.065) was associated with a trend toward increased risk of myeloid SPM. Conclusions: With a median follow up of 13.1 months, the incidence of developing a SPM following CAR-T in pts with RRMM was 3.6%, of which approximately half were myeloid malignancies. There was no difference in SPM incidence when comparing the two CAR-T products. Pts treated with ≥2 alkylator LOT had a higher risk of SPM in multivariable analysis and may warrant additional monitoring for SPM development.