Pulmonary embolism associated with CRBN-targeting immunomodulatory drugs: a FAERS-based pharmacovigilance and...

CRBN-targeting immunomodulatory drugs (IMiDs), including lenalidomide and pomalidomide, are widely used in hematologic malignancies but are associated with an elevated risk of venous thromboembolism (VTE). However, real-world risk patterns and the potential biological mechanisms underlying pulmonary embolism (PE) remain incompletely characterized. We conducted a comprehensive pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS) from 2004 to Q3 2025. Disproportionality analyses (ROR, PRR, BCPNN, MGPS) and Weibull distribution modeling were employed to assess signal strength and time-to-onset (TTO). Systems biology tools, including network pharmacology and enrichment analyses (GO, KEGG), were used to uncover shared and drug-specific pathogenic pathways. Bibliometric mapping of core literature further validated mechanistic insights and policy relevance. A total of 2,428 and 372 PE cases were identified for lenalidomide and pomalidomide, respectively. Both drugs exhibited an "early failure" risk profile (β < 1), with a shorter median TTO for lenalidomide (81.5 days) compared to pomalidomide (134 days). High-risk subgroups included males, elderly patients (65-85 years), and individuals with obesity (> 100 kg). The PI3K-Akt pathway emerged as a central mechanism for endothelial dysfunction and thrombogenesis. Pomalidomide showed additional enrichment in fluid shear stress and TNF signaling pathways. Literature analysis confirmed alignment with core topics such as thrombotic events, platelet function, and prophylactic anticoagulation. Our findings highlight an urgent need to shift from empirical anticoagulation to precision-based thromboprophylaxis in patients treated with CRBN-targeting IMiDs. Early-onset PE risk is mechanistically linked to vascular endothelial injury and inflammatory signaling, supporting the use of dynamic risk stratification tools (e.g., IMPEDE-VTE score) and early DOAC intervention. Public health policy should integrate molecular insights with real-world surveillance to optimize clinical safety frameworks for oncology patients.