Ubiquitination and Ubiquitin-Like Modifications in Multiple Myeloma: Biology and Therapy

SIMPLE SUMMARY: Multiple myeloma is a cancer of plasma cells causing bone fractures, anemia, renal insufficiency and hypercalcemia. Despite the introduction of new drugs in the past years, it still remains incurable and most patients die from the disease. Multiple myeloma cells are characterized by the production of high amounts of monoclonal antibodies. Therefore, maintaining protein homeostasis from synthesis through folding to degradation is crucial for multiple myeloma cells. While protein ubiquitination and organized degradation are typically considered critical for cellular health, an emerging strategy is to block these processes to induce cell death in disease-state cells characterized by protein over-production. Recent development of compounds that alter the ubiquitin proteasome pathway and drugs that affect ubiquitin-like modifications appear promising in both preclinically and in clinical trials. This review summarizes the impact of protein modifications such as ubiquitination and ubiquitin-like modifications in the biology of multiple myeloma and how it can be exploited to develop new effective therapies for multiple myeloma. ABSTRACT: Multiple myeloma is a genetically heterogeneous plasma cell malignancy characterized by organ damage and a massive production of (in-)complete monoclonal antibodies. Coping with protein homeostasis and post-translational regulation is therefore essential for multiple myeloma cells to survive. Furthermore, post-translational modifications such as ubiquitination and SUMOylation play key roles in essential pathways in multiple myeloma, including NFκB signaling, epigenetic regulation, as well as DNA damage repair. Drugs modulating the ubiquitin–proteasome system, such as proteasome inhibitors and thalidomide analogs, are approved and highly effective drugs in multiple myeloma. In this review, we focus on ubiquitin and ubiquitin-like modifications in the biology and current developments of new treatments for multiple myeloma.