<p>Multiple myeloma (MM) is characterized by the clonal proliferation of plasma cells in the bone marrow. Although the precise molecular mechanisms differentiating men and women in MM are not fully understood, uncovering these differences is crucial for improving personalized therapeutic approaches. Here, we show sex-specific dysregulation of exosomal non-coding RNAs (ncRNAs) in MM. We conducted an in-depth analysis of dysregulated ncRNAs in male and female patients, as well as MM cell lines, revealing distinct expression signatures across multiple clinical contexts, including newly diagnosed, relapse, progression, Hyperdiploid, non-Hyperdiploid, and treatment exposure. Our findings highlight the pivotal roles of lncRNAs and miRNAs in MM pathogenesis, detecting alterations in enriched pathways that influence key biological processes such as cellular proliferation, apoptosis, and gene regulation. We established a panel of ncRNAs with distinct sex-specific expression patterns, significant effects on mRNA regulation, and involvement in MM-associated biological pathways. Our results demonstrate that exosomes provide enhanced analytical resolution for detecting non-coding RNAs, enabling more sensitive and precise identification of transcriptomic alterations. These results suggest that sex-specific dysregulation of ncRNAs may contribute to differences in MM progression and therapy response. Ultimately, this study underscores the importance of exosomal ncRNA profiling in designing sex-tailored therapeutic strategies targeting dysregulated ncRNAs, paving the way for personalized medicine in MM.</p>