Risk of thrombosis in multiple myeloma patients treated with carfilzomib-based regimens: A systematic review and meta-analysis of clinical trials

Abstract Background: Carfilzomib is a second-generation, irreversible proteasome inhibitor approved for treatment of multiple myeloma (MM). It is commonly used in combination with immunomodulatory drugs (IMIDs), anti-CD38 monoclonal antibodies, cytotoxic agents and steroids. Carfilzomib is the only proteosome inhibitor with an increased risk of venous thrombosis for which thromboprophylaxis is recommended. However, the incidence of thrombosis in prospective clinical trials has not been systematically quantified. We conducted a systematic review and meta-analysis to evaluate the incidence of thrombotic events in MM patients receiving carfilzomib-based combinations in phase 2 and 3 trials. Methods We conducted a comprehensive search of four databases; PubMed, Embase, Web of Science and ClinicalTrials.gov for phase 2 and 3 clinical trials reporting on carfilzomib-based therapy in adults with multiple myeloma, published from inception to March 2025. Only studies reporting thrombotic adverse events and follow up period were included. Two reviewers independently screened studies and extracted data. The primary outcome was the event rate of venous and arterial thrombotic events (VTE, ATE). Secondary outcomes included subtype of thrombosis and bleeding. A random-effects model was used to estimate the thrombosis event rate per 100 patient-months across all studies, and to calculate pooled relative risk of thrombosis in randomized trials. Heterogeneity was assessed using the I² statistic. Results Our search resulted in 1317 studies for screening of which 51 studies (16 randomized and 35 non-randomized trials) were included for data extraction. A total of 11190 patients were included of which 6457 had newly diagnosed MM (NDMM) and 4733 had relapsed/refractory MM (RRMM). 4342 patients were treated with carfilzomib-IMID combinations. The median age was 62 (range 56-75) years. Thromboprophylaxis recommendation was reported in only 58% of studies, most commonly with aspirin. The VTE event rate was 0.19 per 100 patient-months (95% CI 0.14 – 0.26; I2 79.3%). The event rate for deep vein thrombosis and pulmonary embolism was 0.16 (95% CI 0.10 - 0.27; I2 70.8%) and 0.09 (95% CI 0.06 – 0.14; I2 49.6%) per 100 patient-months, respectively; ATE was noted at 0.05 (95% CI 0.04 - 0.07; I2 24.5%) per 100 patient-months. Incidence of VTE was higher in carfilzomib-IMID combinations compared to carfilzomib-non-IMID combinations (0.25 vs 0.13 per 100 patient-months, p 0.036; I2 79.3%). There were no significant differences in VTE incidence in NDMM vs RRMM (0.17 vs 0.25 per 100 patient-months; p 0.17; I2 79.3%) or dosing schedule (weekly vs twice weekly; 0.20 vs 0.21 per 100 patient-months; p 0.53; I2 79.6%). ATE events were higher in RRMM compared to NDMM with carfilzomib combinations (0.08 vs 0.04 per 100 patient-months; p 0.01; I2 24.5%). Among 7 randomized trials including 5151patients that included a non-carfilzomib control arm (n=2571), the pooled relative risk for VTE was 1.72 (95% CI 1.04-2.84; p 0.03; I2 61.9%) for carfilzomib as compared to non-carfilzomib combinations, whereas the pooled relative risk for DVT was 1.73 (95% CI 0.85-3.55; p 0.13; I2 67.5%), and for PE was 1.47 (95% CI 0.62- 3.64; p 0.38; I2 57.6%). Bleeding events were not consistently reported across studies and were not meta-analyzed. Conclusions Thrombotic events are a clinically significant complication of carfilzomib-based therapy, particularly when used in combination with IMIDs. In our meta-analysis of randomized control trials, we report increased risk of VTE with carfilzomib-based combinations as compared to non-carfilzomib-based combinations, supporting the use of thromboprophylaxis with carfilzomib treatment. However, while some studies cited general recommendations for thromboprophylaxis, data on the thrombotic risk stratification, regimen prescribed, adherence, and bleeding complications were inconsistently reported. These findings highlight the need for standardized thromboprophylaxis strategies and consistent reporting of thrombotic and bleeding events in trials of carfilzomib-based therapies for multiple myeloma.