Novel Non-Immunologic Agents for Relapsed and Refractory Multiple Myeloma: A Review Article

Simple Summary: Immunotherapy-based treatments have brought many new options in the treatment of multiple myeloma; still, the disease will inevitably relapse as it remains incurable. The development of non-immunologic drugs is therefore still needed, particularly for patients with advanced myeloma who become refractory to most of the drugs available, including immunotherapy. Non-immunologic agents have proven effective in the field for the past 20 years, notably with the advent of cytotoxic drugs and, subsequently, targeted therapy. In this review, we summarize the information currently available on novel generations of non-immunologic agents:proteasome inhibitors, immunomodulatory agents, anti-BCL-2/MCL-1, anti-XPO1, peptide-drug conjugates, and targeted drugs in early-stage development.Novel treatments are needed to address the lack of options for patients with relapsed or refractory multiple myeloma. Even though immunotherapy-based treatments have revolutionized the field in recent years, offering new opportunities for patients, there is still no curative therapy. Thus, non-immunologic agents, which have proven effective for decades, are still central to the treatment of multiple myeloma, especially for advanced disease. Building on their efficacy in myeloma, the development of proteasome inhibitors and immunomodulatory drugs has been pursued, and has led to the emergence of a novel generation of agents (e.g., carfilzomib, ixazomib, pomalidomide). The use of alkylating agents is decreasing in most treatment regimens, but melflufen, a peptide-conjugated alkylator with a completely new mechanism of action, offers interesting opportunities. Moreover, with the identification of novel targets, new drug classes have entered the myeloma armamentarium, such as XPO1 inhibitors (selinexor), HDAC inhibitors (panobinostat), and anti-BCL-2 agents (venetoclax). New pathways are still being explored, especially the possibility of a mutation-driven strategy, as biomarkers and targeted treatments are increasing. Though multiple myeloma is still considered incurable, the treatment options are expanding and are progressively becoming more diverse, largely because of the continuous development of non-immunologic agents.