The cytotoxicity of proteasome inhibitor, one of the first-line therapies for transplant-ineligible MM patients, is primarily attributable to amino acid deprivation, ERAD blockade and activation of PERK- and ATF6-mediated UPR pathways, which result in lethal ER stress and cytosolic oxidative damage due to mitochondrial dysregulation [51, 87, 237, 238]. This evidence concerns the gene ATF6 and Miyoshi myopathy.