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CELMoDs for MM
How Do CELMoDs Work for Multiple Myeloma?

Released: August 13, 2025

Michele Cavo
Michele Cavo, MD
Sagar Lonial
Sagar Lonial, MD, FACP
Charlotte Pawlyn
Charlotte Pawlyn, MB BChir, PhD
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Key Takeaways
  • CELMoDs (including iberdomide and mezigdomide) are novel protein degraders and immune modulators.
  • These agents are being studied in ongoing phase III trials in the maintenance and relapsed/refractory settings.

Cereblon E3 ligase modulatory drugs (CELMoDs) are currently being investigated in phase III trials for the treatment of multiple myeloma (MM) in several disease settings. In this commentary derived from a live symposium at the European Hematology Association 2025 Congress, experts discuss the mechanism of action of CELMoDs in MM and possible use in the clinic. 

How do CELMoDs work?

Charlotte Pawlyn, MB BChir, PhD:
Most are now familiar with the development of immunomodulatory drugs (IMiDs) that are or have been used in clinical practice to treat MM. These include lenalidomide, pomalidomide, and thalidomide. IMiDs target the ubiquitin–proteasome system (UPS), which normally functions to tag proteins with ubiquitin, thereby marking them for degradation. IMiDs act as “molecular glues” and bring ligase and target proteins into proximity to begin protein degradation by the UPS. Specifically, IMiDs bind to cereblon, an E3 ligase that is part of the UPS, allowing proteins that previously could not bind to the UPS to bind and be tagged for degradation. These include Ikaros and Aiolos, which are transcription factors important to the survival of MM cells and repression of T-cell activation.

CELMoDs (including iberdomide and mezigdomide) are also molecular glues. However, CELMoDs differ from IMiDs in several key ways. One is that classical IMiDs present as a mixture of the S and R isomers (different forms of the same compound), but CELMoDs are present as 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 use the remaining cereblon and potentially overcome some of those other mechanisms of resistance. 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 that we see increased efficacy in protein degradation.

I think that the novel CELMoDs are some of the most exciting new drugs for treating MM because they harness this unique way of targeting proteins and signaling pathways within MM cells. 

How do you think CELMoDs might be used in treating MM if they are approved?

Michele Cavo, MD:
Let me start by noting that no CELMoD is approved for treating MM as of August 2025. 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 daratumamab, bortezomib, and dexamethasone 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 and the EMN26 study, which demonstrated the activity of iberdomide in the R/R and maintenance settings. 

Mezigdomide is currently being assessed in 2 phase III studies: SUCCESSOR-1 (mezigdomide plus bortezomib and dexamethasone vs pomalidomide, bortezomib, and dexamethasone 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 carfilzomib and dexamethasone for R/R MM with 1 or more prior line of therapy including prior lenalidomide and an anti-CD38 antibody with PD; NCT05552976). These trials are supported by data from the phase I/II CC-92480-MM-001 and CC-92480-MM-002 trials, which demonstrated the activity of iberdomide in the R/R and maintenance settings.

Sagar Lonial, MD, FACP:
Looking at iberdomide and mezigdomide, both are oral agents and both have demonstrated activity in MM, including in combination with other standard-of-care agents. Both agents clearly have activity in IMiD-exposed and IMiD-resistant patients. 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 potentially lower rates of neutropenia, a hallmark adverse event associated with CELMoD therapy. Iberdomide currently has ongoing phase III trials in the maintenance and R/R settings, and mezigdomide has ongoing phase III trials in the R/R setting. One of the unique aspects of mezigdomide is its ability to be effective in extramedullary disease. If you measure mezigdomide or the metabolites of mezigdomide in plasmacytomas, the drug actually gets into the plasmacytoma, which is a major problem for the IMiD class of drugs.

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