LAUSR

Significance Multiple myeloma (MM) is a lethal malignancy arising from plasma cells. MM cells experience endoplasmic reticulum (ER) stress due to immunoglobulin hyperproduction. The ER-resident sensor IRE1α mitigates ER stress by expanding protein-folding and secretion capacity, while supporting proteasomal degradation of ER misfolded proteins. IRE1α elaborates these functions by deploying a cytoplasmic kinase–RNase module to activate the transcription factor XBP1s. Although IRE1α has been implicated in MM, its validity as a potential therapeutic target—particularly as a kinase—has been unclear. Using genetic and pharmacologic disruption, we demonstrate that the IRE1α–XBP1s pathway is critical for MM tumor growth. We further show that the kinase domain of IRE1α is an effective and safe potential small-molecule target for MM therapy. Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase–endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α–XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138− cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.