Though previous studies have exploited UPR pathway markers (IRE1-XBP1/PERK-eIF2α) as a treatment target in MM both in vitro and in vivo, our findings on the EZH2 mediated regulation of UPR pathway have uncovered two additional EZH2 regulated genes, FOXO3 and ZFP36, that activate UPR pathway via PLUM-EZH2 interaction to drive the therapeutic resistance of MM. This evidence concerns the gene FOXO3 and Miyoshi myopathy.