CELMoDs in multiple myeloma

By Dylan Barrett, Jen Wyatt Green, Louise Niven

Learning objective: After reading this article, learners will be able to describe the mechanism of action, latest clinical data, and applications for CELMoDs in multiple myeloma.

Many treatment options are now available for multiple myeloma (MM), with immunomodulatory agents such as lenalidomide and pomalidomide commonly used in combination regimens in both newly diagnosed (ND) and relapsed/refractory (RR) settings.1 Lenalidomide and pomalidomide modulate cereblon within an E3 ubiquitin ligase complex to promote the proteasomal degradation of MM-related proteins.1 However, resistance remains a challenge and necessitates the development of novel agents to improve patient outcomes and treat relapsed disease.1

Novel next-generation cereblon E3 ligase modulatory drugs (CELMoDs) currently under clinical development are designed to improve potency and selectivity toward proteins targeted for degradation by cereblon, with greater antimyeloma and immune-stimulating activity compared with classic immunomodulatory agents.2

Two CELMoDs are in clinical development for MM, iberdomide and mezigdomide. Here, we provide a review of their mechanism of action and an overview of phase III clinical trials currently investigating these agents in RRMM.

Mechanism of action

Advancements in our understanding of the pathogenesis of MM have identified the ubiquitin-proteasome system as a therapeutic target. In healthy cells, this system regulates intracellular protein synthesis and degradation; however, in MM cells, this system is dysregulated and promotes cell growth and survival by increasing the degradation of pro-apoptotic and tumor suppressor proteins. Cereblon is part of the cullin 4a-cereblon cullin-RING ligase (CRL4CRBN) E3 ubiquitin ligase complex, which is crucial for the ubiquitination of specific target proteins. Modulating cereblon has proven to be an effective mechanism for antimyeloma activity.

Iberdomide and mezigdomide alter the conformation of cereblon within the E3 ligase substrate receptor, switching it from an ‘open’ to ‘closed’ state. This causes the CRL4CRBN E3 ligase to recruit neosubstrates for degradation, including two critical lymphoid transcription factors, Ikaros and Aiolos (Figure 1). Ikaros and Aiolos have an essential role in the development and differentiation of hematopoietic cells and in the survival of MM cells.

The downregulation of Ikaros and Aiolos results in enhanced cytotoxic effects in myeloma cells in vitro, while stimulating T-cell activity, enhancing interleukin-2 and interferon-γ production and increasing natural killer cell proliferation (Figure 2). The antimyeloma activity of CELMoDs has been observed in cells that are resistant to lenalidomide and pomalidomide.

Figure 1. Mechanism of action of CELMoDs*

Figure 2. Immunomodulatory effects of IMiDs and CELMoDs in MM*

Efficacy and safety

Iberdomide

The phase I/II CC-220-MM-001 trial ( NCT02773030) assessed the safety and efficacy of iberdomide plus dexamethasone in adult patients with RRMM. Among patients who received iberdomide plus dexamethasone, in the dose-escalation cohort, patients received oral iberdomide at doses ranging from 0.3 mg to 1.6 mg on Days 1–21 plus oral dexamethasone at 40 mg and 20 mg for patients aged ≤75 years and ≥75 years, respectively, on Days 1, 8, 15, and 22 of each 28-day cycle. The overall response rate (ORR) was 32% in the dose-escalation cohort. The median time to response and median duration of response (DoR) were 8.1 weeks and 10.4 months, respectively.

Mezigdomide

The phase I/II CC-92480-MM-001 trial ( NCT03374085) evaluated multiple doses and schedules of mezigdomide plus dexamethasone in heavily pretreated patients with RRMM. In the dose-escalation cohort, the RP2D was determined to be 1.0 mg of mezigdomide plus dexamethasone once daily in a 21-day schedule. In the dose-expansion cohort, the ORR was 41% and the median DoR was 7.6 months.

Phase III trials

Several phase III trials are currently evaluating the safety and efficacy of CELMoDs in patients with RRMM ( Figure 10). The phase III EXCALIBER-RRMM trial ( NCT04975997) will assess the efficacy and safety of IberDd vs daratumumab plus bortezomib and dexamethasone (DVd) in patients aged ≥18 years with RRMM and 1–2 prior lines of therapy. The trial will include two stages: the first will randomize 200 patients to receive various doses of iberdomide, while the second will randomize 664 additional patients for efficacy analysis.

The phase III SUCCESSOR-1 ( NCT05519085) trial will compare the safety and efficacy of mezigdomide vs pomalidomide in patients aged ≥18 years with RRMM.

Conclusion

CELMoD therapies have demonstrated promising clinical activity and a tolerable safety profile for the treatment of patients with RRMM. Based on the clinical data available, CELMoDs could be an effective treatment option for patients who are refractory to immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies.