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Extracellular vesicles (EV) are cell\u2010derived, lipid bilayer\u2013enclosed particles that mediate intercellular communication and circulate in body fluids, making them promising biomarkers. This study compares the proteome of MM\u2010derived EV with parental cells and evaluates whether EV represent a superior source of MM\u2010specific biomarkers. We used high\u2010resolution mass spectrometry to analyze MM cell lines and their EV. Cell line\u2013derived EV offer a cleaner, tumor\u2010specific protein profile, minimizing background from nonmalignant cells and improving biomarker accuracy. MS datasets were subjected to bioinformatic analysis, followed by functional enrichment using gene set libraries such as Gene Ontology, Jensen Compartments, TRRUST and DisGeNET, to extend interpretation beyond limited protein databases. Compared to cellular proteins, the EV proteome was enriched in functions related to oncogenic signaling, transcriptional regulation and MM pathophysiology, strengthening its potential as a cancer\u2010related biomarker source. DisGeNET identified cancer\u2010related proteins that were further evaluated to identify MM\u2010specific candidates analyzing MM patients' gene expression databases containing clinical data. This led to the identification of macrophage migration inhibitory factor (MIF) and prohibitin. ELISA on plasma from MM patients detected significantly increased MIF levels in smoldering and active MM compared with healthy donors. Approximately half of circulating MIF was EV\u2010associated in MM patients, indicating that MIF is distributed between vesicular and soluble plasma fractions and underscoring its potential as a noninvasive biomarker for MM early detection and patient monitoring.<\/jats:p>","DOI":"10.1111\/cas.70473","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:29:02Z","timestamp":1784194142000},"page":"2877-2890","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protein Profile of Multiple Myeloma\u2010Derived Extracellular Vesicles for the Discovery of Novel Myeloma\u2010Related Biomarkers"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1300-8565","authenticated-orcid":false,"given":"Natalia","family":"Platonova","sequence":"first","affiliation":[{"name":"Department of Health Sciences University of Milan  Milan 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