Developing next generation immunomodulatory drugs and their combinations in multiple myeloma.

Anjan Thakurta,Michael D Amatangelo,Amit Agarwal,Erin Flynt,William E Pierceall

doi:10.18632/oncotarget.27973

Anjan Thakurta, Michael D Amatangelo + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.27973

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Journal: Oncotarget	Publication Date: Jul 20, 2021
Citations: 26	License type: cc-by

Affiliation: Bristol-Myers Squibb (United States)

Abstract

Multiple Myeloma (MM) is an incurable malignancy with current treatment choices primarily comprising combination regimens implemented with a risk-adapted approach. Cereblon (CRBN)-targeting immunomodulatory agents (IMiDs®) lenalidomide (LEN) and pomalidomide (POM) play a central role in combination regimens due to their pleiotropic antitumor/immunomodulatory mechanisms that synergize with many anti-myeloma approved or developmental agents. Currently, more potent next generation cereblon E3 ligase modulators (CELMoDs®) - iberdomide (IBER) and CC-92480 are in clinical development. With an expanding number of active agents/therapeutic modalities and a myriad of combinatorial possibilities, physicians and drug developers share an opportunity and challenge to combine and sequence therapies to maximize long-term patient benefit. Understanding drug mechanisms and their application in combination settings as well as the unique disease biology considerations from newly diagnosed (NDMM), relapsed/refractory (RRMM), and maintenance settings will be vital to guide the development of future MM therapies centered on a backbone of IMiD or CELMoD agents. Key aspects of drug activity are critical to consider while evaluating potential combinations: direct antitumor effects, indirect antitumor cytotoxicity, immune surveillance, and adverse side effects. In addition, the treatment journey from NDMM to early and late MM relapses are connected to genomic and immune changes associated with disease progression and acquisition of resistance mechanisms. Based on the types of combinations used and the goals of therapy, insights into mechanisms of drug activity and resistance may inform treatment decisions for patients with MM. Here we focus on the evolving understanding of the molecular mechanisms of CRBN-binding drugs and how they can be differentiated and suggest a strategic framework to optimize efficacy and safety of combinations using these agents.

Highlights

IMiD and CELMoD agents have shared as well as unique substrates; their downstream cellular effects may be differentiated by the presence, abundance of, and relative preference for these key substrate proteins of functional consequence (Figure 1)
Preclinical models showed enhanced immune costimulatory activities of IBER when compared to LEN and POM, including increased IL-2 secretion and granzyme-B degranulation in stimulated peripheral blood mononuclear cells (PBMCs) and enhanced immune-mediated killing of MM cells [6, 20]
In combination studies, IBER treatment increased the activity of daratumumab (DARA) more than IMiD compounds, and enhanced the anti-tumor activity of CAR-T based therapies [21,22,23]

Summary

Introduction

IMiD and CELMoD agents have shared as well as unique substrates; their downstream cellular effects may be differentiated by the presence, abundance of, and relative preference for these key substrate proteins of functional consequence (Figure 1). IBER and CC-92480 bind CRBN with ~10-20-fold higher affinity and induce more potent and efficient degradation of Ikaros and Aiolos as compared to LEN/POM [4, 5]. The rate of degradation of Ikaros and Aiolos and subsequent downregulation of IRF4 and c-MYC expression correlates with downstream pharmacological effects of IMiD and CELMoD compounds in MM cell lines [7, 11,12,13].

Results

Conclusion