Background Chimeric antigen receptor T-cell (CAR-T) therapy has transformed outcomes in relapsed/refractory multiple myeloma (MM) but may increase risks of early venous thromboembolism (VTE), stroke, and myocardial infarction (MI) through cytokine-driven endothelial injury. Although MM and several of its treatments are known to be associated with hypercoagulability, the real-world incidence of these events post–CAR-T remains unclear. This study aims to compare the 90-day risk of VTE, stroke, and MI in MM patients receiving CAR-T versus matched non–CAR-T controls using a large multi-institutional database.

Methods We conducted a retrospective, real-world cohort study using the TriNetX US Collaborative Network, which included electronic health records from 69 healthcare organizations. Adults (≥18 years) with MM diagnosed between January 1, 2017, and December 31, 2024, were identified. The study includes two cohorts of patients with confirmed MM identified using the ICD-10 diagnosis code C90.0. The CAR-T cohort consists of patients who received CAR-T (n=1,393), defined by the procedure code “CAR-T Administration”. The non-CAR-T cohort includes patients who did not receive CAR-T therapy (n=118,370). Outcomes of interest were analyzed as a composite outcome: VTE, stroke, MI, and acute limb ischemia (ALI) within 90 days of the CAR-T administration or matched MM diagnosis. Propensity score matching (1:1) was performed across key demographics, comorbidities, baseline cardiovascular risk factors, and the use of antiplatelet or anticoagulant before CAR-T cell therapy which yielded two balanced cohorts of 1,389 patients each. Risk ratios, odds ratios, and Kaplan–Meier survival analyses were generated, with statistical significance set at p<0.05.

Results Following propensity score matching, 1,389 patients were included in each cohort, ensuring balance across demographics and comorbidities. Within 90 days of the index event, VTE occurred in 171 CAR-T recipients compared with 126 in the non–CAR-T control group, corresponding to an absolute risk increase of 3.2% (12.3% vs. 9.1%), a 36% relative risk increase (RR 1.36, 95% CI 1.09–1.69, p=0.006), and a hazard ratio of 1.32 (95% CI 1.04–1.66, p=0.018). Kaplan–Meier curves demonstrated increased occurrence of VTE in the CAR-T group, with sustained higher VTE incidence in the CAR-T group throughout follow-up. Stroke risk was numerically increased but did not reach statistical significance, occurring in 37 CAR-T patients versus 32 controls (2.7% vs. 2.3%; RR 1.16, 95% CI 0.73–1.85, p=0.54; HR 1.12, 95% CI 0.70–1.80, p=0.63). Myocardial infarction rates were similar between groups (1.9% vs. 2.1%; RR 0.91, 95% CI 0.53–1.55, p=0.72), as were ALI events (0.6% vs. 0.5%; RR 1.20, 95% CI 0.45–3.21, p=0.71), though both outcomes were rare.

Conclusion In this large, propensity-matched analysis of real-world data, CAR-T therapy for MM was associated with a significantly increased 90-day risk of VTE, with a higher event burden per affected patient, compared with non–CAR-T controls. On the other hand, rates of stroke, MI, and ALI were low and were not significantly different between the two cohort groups. Closer clinical monitoring, early patient mobilization, and use of thromboprophylaxis may help with early detection and prevention of VTE.

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2025
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