Multiple Myeloma Subtyping That Associates Normal B-Cell Subset Phenotypes, do Correlate to Disease Stage and Prognosis - Indication of Reversible Phenotypic Plasticity as a Hallmark

e48 p1⁄40.0005). To further validate this signature, we generated 500 randomly computed re-sampling of the data sets. The three-miRNA signature was consistently significant with a p-value < 0.05 in more than 78% and < 0.10 in 86% of the 500 randomizations. In a multivariable Cox regression model, the circulating exosomal miRNA signature was an independent prognostic marker after adjusting for cytogenetics and ISS. In a receiver operating characteristic (ROC) analysis, a combination of this signature together with International Staging System (ISS) and cytogenetics had a better prognostic value than ISS and cytogenetics alone in the training set (2 years area under the ROC curve 0.64 [95% CI 0.560.72] vs. 0.60 [95% CI 0.52-0.69]) and the validation set (0.67 [0.59-0.75] vs. 0.58 [0.50-0.66]). Interpretation: This study demonstrates unprecedented evidence of the prognostic significance of exosomal miRNAs in patients with MM. We identified a threemiRNA signature in circulating exosomes that adds prognostic value to ISS and cytogenetic status and helps improve prognostic identification of newly diagnosed MM patients.