Venous thromboembolism in multiple myeloma patients treated with BCMA-directed CAR T-cell therapy: A systematic review and meta-analysis Free

Background. Multiple myeloma (MM) ia associated with a 7–9-fold higher risk of venous thromboembolism (VTE) than the general population. IMiD-based regimens historically reported VTE rates up to 26% during induction and >50% in some combinations. The MELISSE study found a 15.5% incidence while they were on thromboprophylaxis with aspirin. In modern care, thromboprophylaxis with LMWH or specific direct factor Xa inhibitors (apixaban or rivaroxaban) has led to a dramatic reduction in MM-associated thrombosis in more recent cohorts.

Aims. To determine whether B-cell maturation antigen (BCMA)-directed CAR T-cell therapy (ide-cel, or cilta-cel) is associated with an increased incidence of VTE in patients with MM.

Methods We performed a PRISMA-guided systematic review and meta-analysis (PROSPERO CRD420251105194). Searches of PubMed, Embase, and Scopus (January 2015–July 2025) identified 311 records; following blinded screening and eligibility assessment, 18 studies were included. We extracted study data and VTE events, and calculated incidence, Fisher's exact tests, and odds ratios (ORs) with 95% CIs. Zero-event RWE series precluded formal heterogeneity estimation. Where available, comparisons with standard-of-care (SOC) treatments are also presented. Information on thromboprophylaxis use was obtained from the published articles or, when not reported, by directly contacting the principal investigators.

Results Across 2,886 patients (median 5.35 prior lines; 60.0% triple-refractory and 23.6% penta-refractory), VTE events were infrequent. Among 1,605 ide-cel recipients, 5 VTE events were reported (0.3%), while 5 events (0.5%) occurred in 938 cilta-cel recipients. Additionally, seven real-world cohorts including over 900 patients documented no VTE episodes.

Direct comparison revealed no significant difference in VTE risk between ide-cel and cilta-cel (OR 0.58; 95% CI 0.17–2.02; p = 0.51). Compared with standard-of-care (SOC)—predominantly pomalidomide-based regimens—both ide-cel (OR 0.11; 95% CI 0.03–0.35; p = 0.0006) and cilta-cel (OR 0.18; 95% CI 0.06–0.61; p = 0.0073) were associated with significantly lower odds of VTE.

In trial-only analyses, VTE incidence was 1.0% for ide-cel and 2.8% for cilta-cel. In CARTITUDE-4, cilta-cel was associated with a VTE rate of 0.5% compared with 2.8% in SOC (OR = 0.17; p = 0.12). In KarMMa-3, VTE incidence was 1.2% (3/254) with ide-cel versus 0% (0/132) with SOC. LMWH or direct specific fator Xa inhibitors were used for thromboprophylaxis.

Discussion Across clinical trials and real-world series, BCMA-directed CAR T-cell therapy was associated with a low risk of VTE. No significant differences were observed between the two therapeutic regimens. Moreover, the VTE risk in patients receiving BCMA CAR T-cell therapy was comparable to that seen with IMiD-based SOC. The low incidence of VTE observed in recent BCMA CAR T trials, as well as in modern IMiD-based regimens, contrasts sharply with the historically higher VTE burden reported when aspirin alone was used for thromboprophylaxis. This underscores the major progress achieved with current prophylaxis strategies using LMWH or direct factor Xa inhibitors.

The very low VTE rates seen in patients trearted with BCMA-directed CAR T-cell therapy may also reflect intrinsic features of this treatment, including the absence of prolonged corticosteroid use, rapid disease control, and resolution of cytokine release syndrome (CRS)-associated inflammation. Furthermore, this meta-analysis suggests that any potential prothrombotic effects of CRS are effectively mitigated by appropriate pharmacological thromboprophylaxis.

Conclusions BCMA-directed CAR T-cell therapies (ide-cel, cilta-cel) are not associated with an increased risk of VTE in relapsed/refractory MM. Absolute event rates were very low across 18 studies, and CAR T arms demonstrated equal or lower VTE incidence compared with SOC. In an era where prophylaxis has substantially reduced MM-associated thrombosis, CAR T-cell therapy offers potent antimyeloma efficacy without added thrombotic risk.