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The identification of novel MM-specific molecular markers could ameliorate risk-stratification tools and accurately identify high-risk patients towards personalized prognosis and therapy. miRNA-seq analysis of CD138+\u2009plasma cells (n\u2009=\u200924) unveiled miR-221-3p and miR-222-3p (miR-221\/222 cluster) as the most downregulated miRNAs in R-ISS III compared to R-ISS I\/II patients. Subsequently, miR-221\/222 levels were quantified by RT-qPCR in CD138+\u2009plasma cells of our screening cohort (n\u2009=\u2009141), assessing patients\u2019 mortality and disease progression as clinical endpoints. Internal validation was performed by bootstrap analysis, while clinical benefit was estimated by decision curve analysis. Kryukov et al. (n\u2009=\u2009149) and Aass et al. (n\u2009=\u200986) served as institutional-independent validation cohorts. Loss of miR-221\/222 cluster was strongly associated with patients\u2019 short-term progression and poor overall survival, which was confirmed by Kryukov et al. and Aass et al. validation cohorts. Intriguingly, miR-221\/222-fitted multivariate models offered superior risk-stratification within R-ISS staging and risk-based cytogenetics. Moreover, miR-221\/222 loss could effectively discriminate optimal 1st-line treatment responders with inferior treatment outcome. Our study identified the loss of miR-221\/222 cluster as a powerful independent predictor of patients\u2019 post-treatment progression, ameliorating prognosis and supporting precision medicine in MM.<\/jats:p>","DOI":"10.1038\/s41408-025-01248-2","type":"journal-article","created":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T12:31:22Z","timestamp":1742041882000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Refining precision prognostics in multiple myeloma: loss of miR-221\/222 cluster in CD138+ plasma cells results in short-term progression and worse treatment outcome"],"prefix":"10.1038","volume":"15","author":[{"given":"Konstantinos","family":"Soureas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis","family":"Malandrakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Alexandra","family":"Papadimitriou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Minopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Ntanasis-Stathopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine-Ivy","family":"Liacos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gavriatopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efstathios","family":"Kastritis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8990-3254","authenticated-orcid":false,"given":"Meletios-Athanasios","family":"Dimopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Scorilas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaritis","family":"Avgeris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5133-1422","authenticated-orcid":false,"given":"Evangelos","family":"Terpos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,15]]},"reference":[{"key":"1248_CR1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A. 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