The Impact of Multiple Myeloma and Carfilzomib on the Endothelium

Abstract

Background: Multiple myeloma (MM) is associated with one of the highest rates of venous thromboembolism among malignancies, yet the vascular mechanisms underlying this risk remain incompletely defined. This thesis tests the hypothesis that MM drives a coordinated program of endothelial activation encompassing thrombosis and angiogenesis, and evaluates whether the proteasome inhibitor carfilzomib (CFZ) counteracts this program at the molecular and functional levels. Methods: Plasma from MM patients and matched controls was analysed for Weibel–Palade body (WPB)–derived proteins, including von Willebrand factor (VWF), angiopoietin-2, osteoprotegerin, and IL- 8, alongside VWF multimer structure and angiogenic activity. Endothelial cells were exposed to MM cell line–derived conditioned media, with functional assessment by ELISA, shear-dependent VWF–platelet string assays, Matrigel tube formation, and RNA sequencing. Transcriptomic analysis combined curated endothelial gene panels, differential expression, gene set enrichment, and GO/Reactome pathway analysis to define network-level responses. CFZ was assessed for its ability to modulate MM- induced endothelial activation. Results: MM patient plasma exhibited elevated WPB- derived proteins, enrichment of high-molecular-weight VWF multimers, and increased angiogenic potential, indicating systemic endothelial activation. MM-conditioned media induced VWF secretion, platelet-decorated VWF strings under flow, and robust endothelial sprouting. Transcriptomic profiling revealed coherent endothelial programs enriched for angiogenesis, coagulation, inflammatory signalling, extracellular matrix remodelling, and metabolic reprogramming. In contrast, CFZ consistently suppressed MM-associated angiogenic and inflammatory gene networks while inducing proteostatic and protein quality-control pathways. GO and Reactome analyses confirmed a shift toward endothelial quiescence, characterised by enhanced ubiquitin–proteasome regulation and attenuation of vascular activation modules. Conclusion: MM induces a coordinated pro-thrombotic and pro-angiogenic endothelial state through network-level transcriptional reprogramming. CFZ exerts a robust counter-regulatory effect by suppressing pathological vascular activation and reinforcing endothelial homeostasis, positioning endothelial signalling pathways as key therapeutic targets in mitigating MM- associated vascular complications.