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.