Background Cancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective. Results Here, we combined the notions of epipolymorphism and epiallele switching to analyze DNA methylation heterogeneity in MM patients. We show that MM is characterized by the continuous accumulation of stochastic methylation at the promoters of development-related genes. High entropy change is associated with poor outcomes and depends predominantly on partially methylated domains (PMDs). These PMDs, which represent the major source of inter- and intrapatient DNA methylation heterogeneity in MM, are linked to other key epigenetic aberrations, such as CpG island (CGI)/transcription start site (TSS) hypermethylation and H3K27me3 redistribution as well as 3D organization alterations. In addition, transcriptome analysis revealed that intratumor methylation heterogeneity was associated with low-level expression and high variability. Conclusion We propose that disordered methylation in MM is responsible for high epigenetic and transcriptomic instability allowing tumor cells to adapt to environmental changes by tapping into a pool of evolutionary trajectories. ### Competing Interest Statement The authors have declared no competing interest. * MM : Multiple myeloma PMDs : Partially methylated domains CGI : CpG island TSS : Transcription start site PCs : Plasma cells NPCs : Normal plasma cells WGBS : Whole genome bisulfite sequencing eRRBS : Enhanced reduced representation bisulfite sequencing SMM : Smoldering multiple myeloma PDR : Proportion of discordant reads eloci : Epigenetic loci EPM : Eloci per million loci covered ESCs : embryonic stem cells FPM : mapped read counts per million of mapped fragments OR : Odd ratio CLL : Chronic lymphocytic leukemia TAD : Topological associated domain LAD : lamina-associated domain KEGG : Kyoto encyclopedia of genes and genomes 3D : Three-dimensional IFM : Intergroupe francophone du myélome MGUS : Gammopathy of undetermined significance RRBS : Reduced representation bisulfite sequencing SNPs : Single-nucleotide polymorphism RNA-seq : RNA sequencing ICED : Iterative correction and eigenvector decomposition TTS : Transcription termination site FDR : False discovery rate DAVID : Database for annotation, visualization and integrated discovery RFS : Relapse-free survival

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