Epigenetic Plasticity Drives Carcinogenesis and Multi-Therapy Resistance in Multiple Myeloma.

We demonstrate that carcinogenesis and multi-therapy resistance in multiple myeloma (MM)-a treatable yet incurable plasma cell malignancy-are driven by epigenetic dysregulation. In this new paradigm, genomic and cytogenetic events unlock epigenetic plasticity, reshaping MM cell biology to evade tumor microenvironment constraints and therapeutic pressure. These conclusions are derived from a newly assembled cohort of nearly 1,000 patients, spanning premalignant to late-stage refractory MM, comprehensively characterized at molecular and clinical levels. Our findings provide a unifying framework to explain inter-patient genomic heterogeneity and the emergence of therapy resistance in sequential samples without new genomic alterations. In conclusion, we propose targeting epigenetic plasticity-mediated plasma cell evasion as a promising therapeutic strategy in MM.