Circulating extracellular vesicle isomiR signatures predict therapy response in patients with multiple myeloma Gómez Martín, Cristina Drees, Esther E. E. Van Eijndhoven, Monique A. J. Groenewegen, Nils Wang, Steven Verkuijlen, Sandra AWM Van Weering, Jan R. T. Aparicio-Puerta, Ernesto Bosch, Leontien Frerichs, Kris A. Verkleij, Christie P. M. Kersten, Marie J. Zijlstra, Josée M. De Jong, Daphne Groothuis-Oudshoorn, Catharina G. M. Hackenberg, Michael Pegtel, D. Michiel multiple myeloma liquid biopsy extracellular vesicles miRNAs isomiR modelling response prediction personalized therapy This work was supported by Stichting Cancer Center Amsterdam (CCA2021-9-77, CCA2023-9-93) to C.G.-M., Spanish Government (AGL2017-88702-C2-2-R) to M.H., multiple grants awarded to D.M.P., including NWO Perspectief Cancer-ID, TKI-health Holland AQrate, and Stichting NEXTGEN HIGHTECH Program (Biomed02). Multiple myeloma (MM) is a plasma cell neoplasm characterized by high inter- and intra-patient clonal heterogeneity, leading to high variability in therapeutic responses. Minimally invasive biomarkers that predict response may help personalize treatment decisions. IsoSeek, a single-nucleotide resolution small RNA sequencing method can profile thousands of microRNAs (miRNAs) and their variants (isomiRs) from patient plasma-purified extracellular vesicles (EVs). Machine learning-generated miRNA/isomiR classifiers accurately predict therapeutic response in relapsed/refractory MM (RRMM) patients receiving daratumumab-containing regimens, achieving an area-under-the-curve of 0.98 (95% confidence interval [CI]:0.94–1.00). A classifier signature with the plasma cell-selective miR-148-3p, predicts durable response (≥6 months), progression-free (hazard ratio [HR]: 33.09, 95% CI: 4.2–262, p < 0.001), and overall survival (HR: 3.81, 95% CI: 1.05–13.99, p < 0.05). Targetome analysis connects the prognostic classifier to established MM drug targets BCL2 and MYC suggesting biological relevance. Thus, EV-isomiR sequencing in MM patients offers a tumor-naïve alternative to an invasive bone-marrow biopsy for predicting treatment outcome. 2026-01-26T12:50:46Z 2026-01-26T12:50:46Z 2025-10-21 journal article Gómez Martín, Cristina et al. Circulating extracellular vesicle isomiR signatures predict therapy response in patients with multiple myeloma. Cell Reports Medicine Volume 6, Issue 10, 21 October 2025, 102358. https://doi.org/10.1016/j.xcrm.2025.102358 https://hdl.handle.net/10481/110283 10.1016/j.xcrm.2025.102358 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier