Nonselective proteasome inhibitors in multiple myeloma and future perspectives

Introduction : The ubiquitination system is the most important cascade of protein degradation independently of lysosomal function. The proteasome system is actively involved in cell cycle regulation. Therefore, proteasome inhibition can lead to inhibition of tumor cell proliferation, and therefore it constitutes a potential therapeutic anticancer approach especially in the therapeutic algorithm of patients with multiple myeloma. Areas covered Three different proteasome inhibitors are currently approved, bortezomib, carfilzomib and ixazomib, and they have been investigated in multiple myeloma and other hematological malignancies. Multiple myeloma cells are extremely sensitive to this inhibition which leads to accumulation of proteins and endoplasmic reticulum stress, leading finally to apoptosis. However, these agents lack specificity, since they target both the constitutive proteasome and the immunoproteasome. Targeting the constitutive proteasome is the main reason for side toxicity due to the effect on normal tissues. In contrary, immunoproteasome inhibition may reduce the adverse events while maintaining the therapeutic efficacy. In this review the authors present the role of the available proteasome inhibitors in myeloma therapeutics and future perspectives of both selective and non-selective proteasome inhibitors. Expert opinion The available non-selective proteasome inhibitors have changed the therapeutics of multiple myeloma the last 10 years and have significantly improved the clinical outcomes of the patients. Furthermore, selective proteasome inhibitors are now under preclinical investigation and there is hope that their optimization will come with an improved safety profile with at least comparable efficacy.