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

Abstract

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.

Keywords: HDAC inhibitors; IMiDs; XPO1 inhibitors; anti BCL-2; anti MCL-1; multiple myeloma; non-immunologic agents; peptide–drug conjugates; proteasome inhibitors; relapsed or refractory.

Figure 1

Overview of the mechanisms of action of the most innovative non-immunologic drugs currently in development for multiple myeloma: CELMoDs, BCL-2 inhibitors, peptide–drug conjugates, and XPO-1 inhibitors. (1) CELMoDs bind with high affinity to cereblon—part of the cereblon E3 ubiquitin ligase complex, which modulates the activity of the complex and increases the polyubiquitination of the transcription factors (TFs) Ikaros and Aiolos (zinc finger TFs of the Ikaros family), which are involved in MM cells’ survival and, therefore, their proteasome-dependent degradation. (2) Venetoclax binds to the BH3 domain of BCL-2 and, therefore, frees the pro-apoptotic proteins Bax and Bak that would be inhibited by BCL-2. Bax/Bak activation leads to their mitochondrial outer membrane permeabilization and initiates caspase-mediated apoptosis. (3) Melflufen is a peptide-conjugated alkylator that is rapidly internalized into cells due to its high lipophilicity. As a prodrug, it is metabolized by aminopeptidases, which are increased in MM cells, and selectively releases alkylating agent into tumor cells to exert its cytotoxic activity. (4) Selinexor targets XPO1, which is overexpressed in MM and performs the nuclear export of tumor-suppressor proteins (TSPs). Thus, blocking the action of XPO1 leads to the reactivation of TSPs, and then induces tumor cell apoptosis.