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CELMoDs in Multiple Myeloma
CELMoDs in Multiple Myeloma

Released: July 28, 2025

Expiration: January 27, 2026

Jesus Berdeja
Jesus Berdeja, MD
Amrita Krishnan
Amrita Krishnan, MD, FACP
Sagar Lonial
Sagar Lonial, MD, FACP
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Key Takeaways
  • CELMoDs (including iberdomide and mezigdomide) are novel protein degraders and immune modulators being studied in ongoing phase III trials in the maintenance and relapsed/refractory settings.
  • CELMoDs are active in IMiD-resistant multiple myeloma.
  • CELMoDs are associated with grade 3/4 neutropenia and possibly lower rates of nonhematologic adverse events than IMiDs.

Cereblon E3 ligase modulatory drugs (CELMoDs), are an emerging class of investigational therapeutics currently being assessed in several hematologic malignancies, including multiple myeloma (MM). In this commentary derived from a symposium at ASCO 2025, experts discuss CELMoD therapy for MM, including mechanism of action, available clinical data, ongoing trials, and potential future implications.

What is the mechanism of action of CELMoDs, and how do they differ from immunomodulatory imide drugs (IMiDs)?
Amrita Krishnan, MD, FACP: CELMoDs (including iberdomide and mezigdomide) are novel protein degraders, bringing ligase and target proteins into proximity to begin protein degradation by the ubiquitin-proteasome system. Specifically, CELMoDs co-opt cereblon to enable enhanced degradation of target proteins, including Ikaros and Aiolos (transcription factors with increased levels in malignant plasma cells).

Sagar Lonial, MD, FACP: A real added value of the CELMoD class is the ability of these agents to make the immune system better. CELMoDs are associated with T-cell activation and NK cell proliferation and activation. I like to think of these agents as cappuccino for T-cells. You can take an exhausted T-cell and wake it up. That is important when we think about CAR T-cell collection, post–CAR T-cell infusion, or T-cell engagers enhancement by combining with the CELMoD class of agents.

Amrita Krishnan, MD, FACP: There are a few things that make the CELMoDs different than the original IMiDs. One is that classical IMiDs present as a mixture of the S and R isomers, so different forms of the same compound, but the CELMoDs are a single S isomer, which is more effective in terms of cereblon binding affinity. This is important because if you have lower levels of cereblon in the cell, for example, because of resistance acquired from previous exposure to IMiDs, you need a much more potent drug to be able to utilize the remaining cereblon and potentially overcome some of those other mechanisms of resistance as well. In clinical studies, CELMoDs have been shown to be active in IMiD-resistant MM.

In addition, there are differences in the conformational change that we see when CELMoDs or IMiDs bind to cereblon. IMiDs or CELMoDs bind to cereblon and change the binding pocket to enable different proteins to bind. We know that the closed conformation is where those proteins can bind and be degraded, and that closed conformation is formed much more potently by iberdomide and mezigdomide compared with lenalidomide and pomalidomide. This is one of the reasons we see increased efficacy in protein degradation.

In what disease settings are CELMoDs being investigated in ongoing phase III trials?
Jesus Berdeja, MD: Both iberdomide and mezigdomide are being assessed in ongoing phase III trials. Iberdomide is being compared with lenalidomide as maintenance therapy for patients with MM who have achieved at least partial response with primary therapy in the EXCALIBER Maintenance trial (NCT05827016). It is also being assessed in the EXCALIBER RRMM trial in combination with daratumumab and dexamethasone vs DVd as treatment for relapsed/refractory (R/R) MM in patients with 1-2 prior lines of therapy with progressive disease (PD) who are not refractory to bortezomib or anti-CD38 therapy (NCT04975997).

These trials are supported by data from the phase Ib/IIa CC-220-MM-001 trial, a multicohort study that assessed iberdomide as monotherapy and in combination with standard of care treatments. Looking at patients with R/R MM and 2 or more prior therapies, iberdomide plus dexamethasone was associated with an overall response rate (ORR) of 26% and iberdomide plus dexamethasone plus daratumumab with an ORR of 46%. Iberdomide monotherapy was also shown to be active as maintenance therapy in patients with newly diagnosed MM with at least partial response after induction with a proteasome inhibitor, IMiD, and autologous stem cell transplant (with or without consolidation) in the EMN26 study.

Mezigdomide, another CELMoD, is currently being assessed in 2 phase III studies: SUCCESSOR-1 (mezigdomide plus bortezomib and dexamethasone vs PVd for R/R MM with 1-3 prior lines of therapy including prior lenalidomide with PD; NCT05519085) and SUCCESSOR-2 (mezigdomide plus carfilzomib plus dexamethasone vs Kd for R/R MM with 1 or more prior line of therapy including prior lenalidomide and an anti-CD38 antibody with PD; NCT05552976).

Mezigdomide has been assessed in combination with dexamethasone in the phase I/II CC-92480-MM-001 study in R/R MM with 3 or more prior therapies, demonstrating activity in the dose expansion phase of this trial with an ORR of 41%. The phase I/II CC-92480-MM-002 trial assessed mezigdomide in combination with dexamethasone and other agents for R/R MM; mezi-Kd and mezi-Vd were associated with ORRs of about 85% across doses.

What are key adverse events (AEs) associated with CELMoD treatment?
Considering AEs with the CELMoD class, something we should expect is neutropenia as a byproduct of their mechanism of action. With iberdomide plus dexamethasone in CC-220-MM-001, approximately 45% of patients experienced grade 3/4 neutropenia; when adding daratumumab or bortezomib to this regimen, grade 3/4 events were observed in approximately 66% and 28%, respectively. Similarly, with mezigdomide plus dexamethasone in CC-92480-MM-001, approximately 76% of patients experienced grade 3/4 neutropenia; when daratumumab or bortezomib was added, grade 3/4 events were observed in approximately 54% to 78% of patients.

I think it is interesting that when looking at the nonhematologic toxicities, we appear to see lower rates than what we are used to with the IMiDs. For example, for those of you who have treated patients with lenalidomide maintenance, you know that many patients complain of fatigue or develop diarrhea. With iberdomide and mezigdomide, grade 3/4 events with these side effects are seen infrequently. I think this is something that we would expect since CELMoDs are so specific for cereblon, with 1 isomer only with activity, whereas IMiDs are present as 2 isomers, the second isomer presumably being the 1 that is associated with off-target effects.

How do you think CELMoDs might be used in treating MM if they are approved?
Sagar Lonial, MD, FACP: Let me start by noting that no CELMoD is approved for treating MM as of July 2025. That said, both agents clearly have activity in IMiD-exposed and IMiD-resistant patients. Looking at iberdomide and mezigdomide, both are oral and both have demonstrated activity in MM, including in combination with other standard of care agents. Mezigdomide has greater cereblon-binding potency, and as such has a better and longer impact on downstream effects. Iberdomide, however, may be a little bit more tolerable, with lower rates of severe neutropenia. Iberdomide currently has ongoing phase III trials in the maintenance and R/R settings, while mezigdomide has ongoing phase III trials in the R/R setting.

Jesus Berdeja, MD: I think mezigdomide may be the more potent of the 2, but it appears that it may also be associated with higher rates of grade 3/4 neutropenia. I see mezigdomide as the 1 that is going to be used in combination, when you are trying to get a patient into remission.

I like iberdomide because it is still a very powerful drug, but it does have a potentially improved toxicity profile. I think this agent may be considered in combination pre CAR T-cell therapy. We know that CAR T-cell therapy works very well, and we know that the toxicity with this therapy is less when you have good control of disease. So if you are trying to not only get your disease under control, but then use a drug that also may potentiate your T-cells, then this might be an ideal space where iberdomide in a combination could do that.

Sagar Lonial, MD, FACP: For me, the fewer nonheme AEs with iberdomide make it a potential partner for many of our induction regimens. The maintenance setting also makes a lot of sense to me. For mezigdomide, use in the context of high-risk cytogenetics, for heavily pretreated advanced disease, is an exciting concept.

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