miRNA-seq analysis of CD138+ plasma cells revealed miR-221-3p and miR-222-3p (miR-221/222) as the most downregulated miRNAs in R-ISS III compared to R-ISS I/II patients, prompting us to further evaluate for the first time the clinical potential of miR-221/222 cluster loss in MM treatment outcome, using a screening MM cohort (n = 141 patients) and two external institutional-independent validation cohorts, the Kryukov et al. (n = 149) [19] and the Aass et al. (n = 86) [20] cohorts. The gene discussed is SDC1; the disease is Miyoshi myopathy.