Endoplasmic reticulum stress in multiple myeloma: adaptive mechanisms, therapy resistance, and emerging therapeutic opportunities

Multiple myeloma (MM), a hematological malignancy of antibody-producing plasma cells is one of the most common hematological malignancies alongside leukemia and lymphoma. Despite a significant number of therapeutic advances in immunotherapy, proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, bispecific antibodies, and CAR T Cell therapies, it remains incurable hematologic cancer, mostly due to acquired resistance during therapy. Disease relapse and therapeutic resistance continue to be major clinical challenges. High rate of immunoglobulin production in MM cells, imposes chronic endoplasmic reticulum (ER) stress and renders myeloma cells highly dependent on adaptive protein quality control mechanisms particularly, unfolded protein response (UPR). The three principal UPR signaling include inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6) coordinate cellular adaptation by restoring proteostasis, promoting cell survival, and enabling resistance to therapeutic stress. Increasing evidence indicates that dysregulation of ER stress pathways is interconnected with several other cellular stress pathways such as oxidative stress, the integrated stress response (ISR), mitochondrial dysfunction autophagy, and metabolic reprogramming, collectively supporting myeloma cell survival and disease progression. In this review we highlighted the importance of ER stress-associated pathway and emerging novel molecular targets with translational potential in MM. Relevant literature was selected based on its focus on ER stress, drug resistance and their molecular mechanisms in myeloma, were critically reviewed and interpreted. A comprehensive understanding of these mechanisms is important for the development of innovative therapeutic strategies to combat drug resistance and improve patient outcomes in MM.