Targeting ikaros and Aiolos: reviewing novel protein degraders for the treatment of multiple myeloma, with a focus on iberdomide and mezigdomide

ABSTRACT

Introduction

The treatment of multiple myeloma (MM) is evolving rapidly. We have seen quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies emerge as standard-of-care options for newly diagnosed MM, and numerous novel therapies approved for relapsed/refractory MM. However, there remains an ongoing need for novel treatment options in multiple treatment settings, including refractoriness to frontline standards of care.

Areas covered

Targeting degradation of the lymphoid transcription factors IKZF1 and IKZF3 – Ikaros and Aiolos – through modulation of cereblon, an E3 ligase substrate recruiter/receptor, is a key mechanism of action of the IMiDs and the more recent class of compounds known as the CELMoD agents. Two CELMoD agents, iberdomide and mezigdomide, have demonstrated substantial preclinical and clinical activity in MM and have entered phase 3 investigation. 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.

Expert opinion

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.

KEYWORDS:

• Aiolos
• CELMoD agents
• cereblon
• iberdomide
• Ikaros
• mezigdomide
• multiple myeloma
• relapsed
• refractory
• ubiquitin–proteasome system

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Article highlights

• Novel treatment options are needed for patients with multiple myeloma (MM) in the context of the evolving treatment algorithm and the development of disease that is refractory to established standards of care.

• The key mechanism of action of the immunomodulatory drugs (IMiDs) in MM is that of cereblon modulation mediating selective degradation of the neo-substrates IKZF1 and IKZF3, also known as Ikaros and Aiolos; the CELMoD compounds iberdomide and mezigdomide are next-generation agents with enhanced potency for targeting Ikaros and Aiolos degradation.

• Ikaros and Aiolos are overexpressed in MM cells versus normal plasma cells, contributing to MM pathogenesis and to proliferative and antiapoptotic activity via a positive-feedback relationships with MM oncogenes c-Myc and IRF4.

• Through their mechanism of action, IMiDs and CELMoD agents have direct apoptotic and anti-proliferative effects on MM cells, disrupt supportive MM cell–bone marrow microenvironment interactions, and also promote an antitumor immune response, with superior antimyeloma and immunomodulatory effects demonstrated with CELMoD agents compared with the IMiDs.

• As seen with the IMiDs, iberdomide and mezigdomide have demonstrated enhanced activity in preclinical studies in combination with standard-of-care agents including the CD38 monoclonal antibody daratumumab, the proteasome inhibitor bortezomib, and bispecific antibodies, with notable activity seen in lenalidomide- and pomalidomide-resistant cells and models.

• The efficacy of IMiD-based regimens in patients with newly diagnosed (NDMM) or relapsed/refractory MM (RRMM) is well established from multiple phase 3 trials, and promising clinical activity has been seen in early-phase studies of iberdomide- and mezigdomide-based therapy in the RRMM setting, including in triple-class refractory patients.

• The common grade ≥3 toxicities of the IMiDs and CELMoD agents are hematologic, with the high rates of grade ≥3 neutropenia reflecting a class effect associated with the impact of Ikaros and Aiolos degradation on normal hematopoietic differentiation; infections are generally the second most common grade ≥3 toxicity with the IMiDs and CELMoD agents.

• Six phase 3 trials of iberdomide and mezigdomide are currently ongoing in the NDMM and RRMM settings to help elucidate their future roles in the MM treatment algorithm.

Declaration of interest

CC Mo has acted on the advisory boards for AbbVie, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda, has acted as a consultant for AbbVie, Janssen, Karyopharm, and Sanofi. MA Hartley-Brown has acted on the advisory boards for Abbvie, BMS, Celgene, GSK, Janssen, Karyopharm, and Sanofi, and has received research funding from BMS/Celgene, GSK, and Sanofi. AS Sperling has acted as a consultant for Novartis and Roche. S Midha has acted as a consultant for Pfizer. AJ Yee has acted as a consultant for AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Pfizer, Prothena, Regeneron, Sanofi, Sebia, Takeda, and has received research funding from Amgen, BMS, Janssen. O Nadeem has acted on the advisory boards for BMS, Janssen, GSK, Sanofi, and GPCR Therapeutics, and has received research funding from Takeda and Janssen. PG Richardson has received grants to their institution for clinical trials from Karyopharm and Oncopeptides, and has acted on the advisory committees for Bristol Myers Squibb/Celgene, GSK, Karyopharm, Oncopeptides, Regeneron, Sanofi, and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A peer reviewer has received honoraria and travel support from Janssen.

Acknowledgements

The authors gratefully acknowledge Steve Hill of Ashfield MedComms, an Inizio company, for medical writing and editing support, funded by the Dana-Farber Cancer Institute and the RJ Corman Multiple Myeloma Research Fund.

ASCT, autologous stem cell transplantation; CELMoD, cereblon E3 ligase modulator; dex, dexamethasone; EMA, European Medicines Agency; FDA, United States Food and Drug Administration; IMiD, immunomodulatory drug; MM, multiple myeloma; MP, melphalan-prednisone; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed/refractory multiple myeloma.

Table 1. Preclinical studies of iberdomide and mezigdomide in combination with other antimyeloma agents providing the rationale for synergy in combination regimens in the clinic.

Table 2. Clinical efficacy in NDMM and RRMM reported with the CELMoD agents iberdomide and mezigdomide and the MonoDAC CFT7455.

Table 3. Safety data from key studies in NDMM and RRMM with the IMiDs, the CELMoD agents, and the MonoDAC CFT7455.

Table 4. Ongoing studies of iberdomide and mezigdomide in novel combinations in NDMM and RRMM (ClinicalTrials.gov, March 21, 2024).

Additional information

Funding

This paper was not funded.