Clinical, cytogenetic, and germline genetic determinants of arterial thromboembolism in IMiD-treated multiple myeloma

Abstract Immunomodulatory drugs (IMiDs) are associated with an increased risk of arterial thromboembolism (ATE) in multiple myeloma (MM), but determinants and mechanisms remain poorly defined. We evaluated incidence, timing, and clinical risk factors in 4287 patients with newly diagnosed MM from the Myeloma-XI-trial; all received IMiD-based induction and 1412 were randomised to Lenalidomide (Len) maintenance. Associations with tumour and inherited genetics, the latter through a genome-wide association study (GWAS), were interrogated in subsets of 1800 patients each. ATE occurred in 92 patients (2.1%), predominantly as ischaemic stroke (>80%). At MM diagnosis, higher leucocyte count, lower serum albumin, and Len-based-induction in elderly were independent risk factors. Older age was the predominant determinant for maintenance-related ATE. Among tumour genetics, del(17p) (HR 3.5, P = 0.001) was strongly associated with ATE risk. Finally, GWAS identified a germline locus at 6q15 independently linked to ATE risk (OR 4.8, P = 3.9 × 10 −8 ). Functional annotation implicates vascular enhancer activity and regulation of MAP3K7 and BACH2 . Together, these findings demonstrate distinct temporal patterns of IMiD-associated ATE risk across treatment phases. In addition to clinical risk factors, inherited variation at 6q15 may contribute to individual susceptibility. These results are hypothesis-generating and require validation in independent cohorts but may ultimately inform individualised prevention strategies.