Integrated Genomic and Epigenomic Analysis Reveals Epigenetic Plasticity in Disease Progression and Multidrug Resistance in Multiple Myeloma

Multiple myeloma (MM) is marked by recurrent cytogenetic abnormalities and mutations that accumulate as the disease progresses. Here, we sought to elucidate the transitions driving tumorigenesis and therapy resistance in MM using a unique cohort of nearly 900 patients spanning premalignant to late-stage refractory MM, comprehensively characterized at molecular and clinical levels. Waves of epigenetic dysregulation drove these critical transitions. In this paradigm, genomic and cytogenetic events unlocked epigenetic plasticity, reshaping MM cell biology to evade tumor microenvironment constraints and therapeutic pressures. Functional perturbation studies in an isogenic proteasome inhibitor-resistant cell line model demonstrated enhanced reliance on transcriptional cofactors, supporting a mechanistic link between chromatin plasticity and therapy adaptation. Collectively, these findings support a unifying framework in which genomic heterogeneity unlocks gene regulatory plasticity, enabling plasma cells to evade microenvironmental constraints and therapeutic pressure. These results provide a mechanistic explanation for sequential relapse without new genomic alterations and nominate epigenetic plasticity-mediated plasma cell adaptation as a therapeutic vulnerability in the heterogeneous genetic background of MM.