iberdomide (CC-220)

We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion.

P1, N=16, Terminated, iTeos Therapeutics | Phase classification: P1/2 --> P1

P1, N=174, Recruiting, Celgene | Trial primary completion date: Sep 2024 --> Dec 2024

P1, N=24, Recruiting, Icahn School of Medicine at Mount Sinai | Enrolling by invitation --> Recruiting | Trial completion date: Aug 2027 --> Jun 2026 | Trial primary completion date: Aug 2024 --> Jun 2025

P2, N=42, Recruiting, University of Nebraska | Withdrawn --> Recruiting

P1, N=121, Recruiting, Hoffmann-La Roche | Trial completion date: Mar 2029 --> Jul 2028 | Trial primary completion date: Mar 2027 --> Jul 2026

Iber-Dd and Iber-DKd are safe combinations and able to eliminate MRD persistent after modern induction therapy and ASCT in NDMM. This study is ongoing, complete safety and efficacy results from part 1 and updated results from part 2 will be presented at the meeting.

P1, N=125, Recruiting, Hoffmann-La Roche | Trial completion date: Jul 2028 --> Mar 2029 | Trial primary completion date: Jul 2026 --> Mar 2027

P2, N=0, Withdrawn, University of Nebraska | N=38 --> 0 | Recruiting --> Withdrawn

P2, N=68, Recruiting, Emory University | Trial primary completion date: Aug 2024 --> Sep 2025

P3, N=1216, Recruiting, Bristol-Myers Squibb | Active, not recruiting --> Recruiting

P1/2, N=66, Recruiting, Hackensack Meridian Health | Suspended --> Recruiting

Using a literature search methodology comprising searches of PubMed (unlimited time-frame) and international hematology/oncology conference abstracts (2019-2023) for terms including IKZF1, IKZF3, Ikaros, Aiolos, CELMoD, IMiD, iberdomide, mezigdomide, and MM, this paper reviews the importance of Ikaros and Aiolos in MM, the mechanism of action of the IMiDs and CELMoD agents and their relative potency for targeting Ikaros and Aiolos, and preclinical and clinical data on iberdomide and mezigdomide. Emerging data suggest iberdomide and mezigdomide have promising activity, including in IMiD-resistant settings, and, pending phase 3 findings, may provide additional treatment options for patients with MM.

P1/2, N=49, Not yet recruiting, Omar Nadeem, MD

In addition, pomalidomide only overcomes lenalidomide refractoriness in a subset of patients. We will discuss the biological aspects of these agents, including their mechanisms of action, efficacy, and toxicity profile, and provide a comprehensive review of current literature. Special attention will be paid to ongoing and future clinical trials that provide insights into the potential of these novel therapies in the management of MM.

P3, N=1216, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P1, N=100, Recruiting, Pfizer | Trial completion date: Mar 2028 --> Jul 2028 | Trial primary completion date: Apr 2027 --> Aug 2027

P1/2, N=88, Not yet recruiting, Alliance for Clinical Trials in Oncology | Initiation date: Mar 2024 --> Aug 2024

Iberdomide treatment promotes a cyclical pattern of immune stimulation without causing exhaustion, inducing a functional shift in T cells toward an activated/effector memory phenotype, including in triple-class refractory patients and those receiving IMiDs as a last line of therapy. This analysis demonstrates that iberdomide's clinical mechanisms of action are driven by both its cell-autonomous effects overcoming CRBN dysregulation in MM cells, and potent immune stimulation that augments anti-tumor immunity.

This suggests that iberdomide broadly induces innate and adaptive immune activation in the TME, contributing to its antitumor efficacy. Our approach establishes a strategy to study treatment-induced changes in the TME of patients with MM and, more broadly, patients with cancer and establishes rational combination strategies for iberdomide with immune-enhancing therapies to treat MM.

P2, N=60, Active, not recruiting, Amsterdam UMC, location VUmc | Trial completion date: Nov 2023 --> Dec 2024 | Trial primary completion date: Nov 2023 --> Dec 2024

P2, N=78, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Apr 2024 --> Dec 2024

Importantly, combining IMiD treatment and BRD9 targeting, which leads to the downregulation of MYC protein and upregulation of CRBN protein, was able to override IMiD resistance of cells exposed to iberdomide in long-term culture. Taken together, our results support the notion that combination therapy based on agents targeting BRD9 and IKZF3, two established dependencies in MM, represents a promising novel therapeutic strategy for MM and IMiD-resistant disease.

P3, N=411, Recruiting, University of Heidelberg Medical Center | Not yet recruiting --> Recruiting

P1, N=38, Not yet recruiting, Thomas Martin, MD

P1/2, N=16, Terminated, iTeos Belgium SA | N=162 --> 16 | Trial completion date: Dec 2025 --> Nov 2023 | Recruiting --> Terminated; Company operational decision. Decision to stop study is not due to safety or efficacy concerns

Biotransformation of iberdomide in humans included multiple oxidations of the morpholino moiety as well as glutarimide ring hydrolysis of parent and oxidized metabolites and a combination of these pathways. Iberdomide was the predominant component in human plasma, with metabolite M12 being the most prominent circulating metabolite. In excreta, similar iberdomide-derived radioactivity was found in urine and feces.

Multi-agent regimens incorporating immunomodulatory (IMiD®) agents such as thalidomide, lenalidomide, and pomalidomide have become the preferred standard of care for the treatment of patients with multiple myeloma (MM), resulting in improved survival outcomes. Here, we discuss AEs associated with pomalidomide and present five clinically relevant hypothetical case studies in patients with RRMM to provide scenario-driven guidance regarding treatment selection and AE prevention and management in the clinical setting. Lastly, as new treatment approaches continue to be explored in MM, we also discuss novel cereblon E3 ligase modulator (CELMoD™) agents including iberdomide (CC-220) and mezigdomide (CC-92480).

P1/2, N=66, Suspended, Hackensack Meridian Health | Recruiting --> Suspended

P2, N=160, Active, not recruiting, Stichting European Myeloma Network | Trial primary completion date: Dec 2023 --> Jul 2023

P1, N=100, Recruiting, Pfizer | Not yet recruiting --> Recruiting | Trial completion date: Jun 2028 --> Mar 2028 | Trial primary completion date: Aug 2026 --> Apr 2027

P1/2, N=532, Active, not recruiting, Celgene | Phase classification: P1b/2a --> P1/2 | Trial completion date: Oct 2029 --> Feb 2028 | Trial primary completion date: Oct 2029 --> Mar 2024

Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL.

P1, N=111, Recruiting, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company | Not yet recruiting --> Recruiting

Cereblon-targeting degraders, including immunomodulatory imide drugs lenalidomide and pomalidomide alongside cereblon E3 ligase modulators like iberdomide and mezigdomide, have demonstrated significant anti-myeloma effects...Despite their evident efficacy, approximately 5% to 10% of MM patients exhibit primary resistance to lenalidomide, and resistance commonly develops over time. Understanding the intricate mechanisms of action and resistance to this drug class becomes imperative for refining and advancing novel therapeutic combinations.

P1/2, N=88, Not yet recruiting, Alliance for Clinical Trials in Oncology

P1, N=100, Not yet recruiting, Pfizer

P3, N=411, Not yet recruiting, University of Heidelberg Medical Center

P1, N=6, Enrolling by invitation, Icahn School of Medicine at Mount Sinai | Recruiting --> Enrolling by invitation | N=31 --> 6 | Trial completion date: Aug 2025 --> Aug 2027 | Trial primary completion date: Dec 2023 --> Aug 2024

Venetoclax is a B-cell lymphoma 2 (Bcl-2) inhibitor with activity in patients with t(11;14) and/or Bcl-2 expression. Iberdomide and mezigdomide are cereblon E3 ligase modulators with higher potency, immunomodulatory, and antiproliferative activity compared with lenalidomide and pomalidomide...Modakafusp alfa is an immunocytokine that targets interferons to CD38+ cells. It has demonstrated single agent activity in relapsed/refractory MM in the phase 1 setting.

P1, N=31, Recruiting, Icahn School of Medicine at Mount Sinai

P2, N=38, Recruiting, University of Nebraska