Histone methyltransferase NSD2 (MMSET) overexpression in multiple myeloma (MM) patients plays an important role in the development of this disease subtype. Through the expansion of transcriptional activating H3K36me2 and the suppression of repressive H3K27me3 marks, NSD2 activates an aberrant set of genes that contribute to myeloma growth, adhesive and invasive activities. NSD2 transcriptional activity also depends on its non-catalytic domains, which facilitate its recruitment to chromatin through histone binding. In this study, using NMR, ITC and molecular dynamics simulations, we show that the tandem PHD domain of NSD2 (PHD_VC5HCH_NSD2) is a combinatorial reader of unmodified histone H3K4 and tri-methylated H3K27 (H3K27me3). This is the first PHD tandem cassette known to decode the methylation status of H3K27. Importantly, in a NSD2-dependent MM cellular model, we show that expression of NSD2 mutants, engineered to disrupt the interaction between H3K27me3 and PHD_VC5HCH, display in comparison to wild-type NSD2: incomplete loss of H3K27 methylation throughout the genome, decreased activation of adhesive properties and cell adhesion genes, and a decrease of the corresponding H3K27ac signal at promoters. Collectively, these data suggest that the PHD_VC5HCH domain of NSD2 plays an important role in modulating gene expression and chromatin modification, providing new opportunities for pharmacological intervention.