Comprehensive epigenomic studies in multiple myeloma (MM) that unravel the connections between major epigenetic regulators, their intertwined collaboration and the potential of combinatorial targeting remain limited. Utilizing ChIP-seq, ATAC-seq, RNA-seq, and DNA methylation (DNAme) data, we generated whole-genome chromatin annotations from normal plasma cells and MM patients, revealing epigenomic re-configuration affecting downstream genes involved in tumour growth and survival. Primary MM samples showed global DNA hypomethylation but site-specific hypermethylation was observed at transcription start sites, promoters, and enhancers. Moreover, increased deposition of H3K27me3 was observed in clinically relevant functional chromatin clusters. Combined EZH2 and DNMTs inhibition resulted in extensive epigenomic alterations activating apoptosis and cell cycle genes, leading to increased G2/M arrest and apoptosis in MM cell lines. Our findings provide novel insights into the role of epigenetic gene silencing in MM tumorigenesis and the interplay between the Polycomb repressive complex 2 and DNAme.