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.

The persistence of high relapse rates and therapy resistance continues to challenge the effective management of multiple myeloma (MM). 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+ plasma cells (n = 24) 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+ plasma cells of our screening cohort (n = 141), assessing patients' 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 = 149) and Aass et al. (n = 86) served as institutional-independent validation cohorts. Loss of miR-221/222 cluster was strongly associated with patients' 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' post-treatment progression, ameliorating prognosis and supporting precision medicine in MM.