miRNA-seq identification and clinical validation of CD138+ and circulating miR-25 in treatment response of multiple myeloma

Abstract

Background Despite significant advancements in multiple myeloma (MM) therapy, the highly heterogenous treatment response hinders reliable prognosis and tailored therapeutics. Herein, we have studied the clinical utility of miRNAs in ameliorating patients’ management. Methods miRNA-seq was performed in bone marrow CD138+ plasma cells (PCs) of 24 MM and smoldering MM (sMM) patients to analyze miRNAs profile. CD138+ and circulating miR-25 levels were quantified using in house RT-qPCR assays in our screening MM/sMM cohort (CD138+ plasma cells n = 167; subcohort of MM peripheral plasma samples n = 69). Two external datasets (Kryukov et al. cohort n = 149; MMRF CoMMpass study n = 760) served as institutional-independent validation cohorts. Patients’ mortality and disease progression were assessed as clinical endpoints. Internal validation was performed by bootstrap analysis. Clinical benefit was estimated by decision curve analysis. Results miRNA-seq highlighted miR-25 of CD138+ plasma cells to be upregulated in MM vs. sMM, R-ISS II/III vs. R-ISS I, and in progressed compared to progression-free patients. The analysis of our screening cohort highlighted that CD138+ miR-25 levels were correlated with short-term progression (HR = 2.729; p = 0.009) and poor survival (HR = 4.581; p = 0.004) of the patients; which was confirmed by Kryukov et al. cohort (HR = 1.878; p = 0.005) and MMRF CoMMpass study (HR = 1.414; p = 0.039) validation cohorts. Moreover, multivariate miR-25-fitted models contributed to superior risk-stratification and clinical benefit in MM prognostication. Finally, elevated miR-25 circulating levels were correlated with poor survival of MM patients (HR = 5.435; p = 0.021), serving as a potent non-invasive molecular prognostic tool. Conclusions Our study identified miR-25 overexpression as a powerful independent predictor of poor treatment outcome and post-treatment progression, aiding towards modern non-invasive disease prognosis and personalized treatment decisions.

Role of Non-Coding RNAs in Diagnosis, Prediction and Prognosis of Multiple Myeloma

“…This was confirmed by multivariate analysis (HR = 4.1, 95%CI = 0.79–21.32). A similar relationship was not observed for PFS [ 58 ]. The described miR-25-3p belongs to the miR-106b-25 cluster, which directly targets TP53 , inhibiting its expression, and activates the PI3K/Akt signaling pathway, inducing PTEN expression, resulting in inhibition of apoptosis and cell aging [ 59 ].…”

TAZ upregulates MIR‐224 to inhibit oxidative stress response in multiple myeloma

“…Recent reports suggest that miRNA and oxidative stress programs are interconnected in many diseases, including cancer 18,19 . In line with these findings, several studies have shown dysregulated miRNA expression in myeloma cells 20–23 . Despite these reports, the molecular mechanisms underlying oxidative stress response in MM are still poorly defined; no study has examined the relationship between TAZ and miRNA or oxidative stress in MM.…”