The role of immunomodulatory drugs (IMiDs) has been engrained in the multiple myeloma treatment paradigm, with agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) already approved for select patients. Now, a novel class of agents known as cereblon E3 ligase modulatory drugs (CELMoDs) could represent the next wave of treatment aiming to build on the efficacy of IMiDs, according to Joshua Richter, MD.

“In many ways, [CELMoDs] are far more potent agents [than IMiDs], and because they both have antimyeloma effects and immunostimulatory/immunomodulatory effects, we can use this new class in many of the classical ways and in some exciting new ways,” Richter said.

, Richter delved into how CELMoDs differ from their IMiD predecessors, provided background on 2 CELMoDs—iberdomide [CC-220] and mezigdomide [CC-92480]—that are currently being evaluated in clinical trials, and detailed where these agents could fit into the multiple myeloma treatment paradigm.

Richter is an associate professor of medicine at The Tisch Cancer Institute and director of Multiple Myeloma at the Blavatnik Family Chelsea Medical Center at Mount Sinai in New York, New York.

: How do CELMoDs differ from existing IMiDs used within the multiple myeloma paradigm right now?

: CELMoDs are a new class of drugs. However, in many ways, we think about them as super IMiDs. We started off with thalidomide, then we got lenalidomide [Revlimid] and pomalidomide [Pomalyst]. Now we have iberdomide and mezigdomide—these are the newer, oral immunomodulatory agents that we call CELMoDs.

These are effective drugs, and they exert their antimyeloma effect in a number of ways. One of them has to do with direct plasma cell killing, and the other has to do with immune modulation and the enhancement of natural killer T-cell activity. One of the ways we can evaluate this is their involvement with this conformation of cereblon. Even though lenalidomide and pomalidomide only lead to approximately 10% to 20% conformational change, we get 50% [conformational change] with iberdomide and 100% with mezigdomide.

Although CELMoDs remain in clinical development, where could these agents fit into the multiple myeloma treatment paradigm?

There are a couple of ways that [iberdomide and mezigdomide could] involve themselves in the new paradigm. [When I] think about iberdomide and mezigdomide, I think of iberdomide as a better-tolerated drug long term. It’s similar to lenalidomide, but it has a better myelotoxicity profile, so it’s a great drug to use as a maintenance therapy, [such as] post-autologous stem cell transplant [ASCT] or post-CAR T-cell therapy. For example, some of the more recent data from the [phase 2] EMN 26 trial [NCT04564703], which looked at iberdomide as a maintenance therapy post ASCT, [showed] minimal residual disease [MRD] conversion rates. With some of the best data with lenalidomide, we only see maybe 10% to 20% MRD-negativity conversion. With some of the cohorts [with iberdomide], we saw 30% to 50% conversion. Right now, we’re looking at dual maintenance studies with drugs like lenalidomide and daratumumab [Darzalex]. We’re starting to see similar data with one drug: iberdomide. Iberdomide is going to be a great maintenance therapy.

Mezigdomide is a more potent drug, and one of the areas that we’re seeing extreme effectiveness is in [patients with] extramedullary disease [EMD]. EMD has been one of the hardest diseases to control in the myeloma world, with some of the best data coming from the [phase 1/2] RedirecTT-1 study [NCT04586426] combining teclistamab-cqyv [Tecvayli] and talquetamab-tgvs [Talvey]. [This combination] is highly effective but is a relatively difficult regimen to get through [for patients]. However, we have seen some great data, 

which has been presented by Paul G. Richardson, MD

, [of Dana-Farber Cancer Institute in Boston, Massachusetts], about giving just mezigdomide and dexamethasone—an all oral doublet—and achieving some deep remissions in patients with EMD.

 [Potentially], mezigdomide is going to be for the really bad stuff, [such as EMD], and iberdomide may be a great long-term maintenance strategy.

What should hematologists know when considering a potential clinical trial evaluating a CELMoD for patients with multiple myeloma?

The best way to think about CELMoDs is that they’re similar to IMiDs. They’re more potent and have different effects on the immune system, but these are similar concepts. [Patients] are taking a pill once a day for 3 weeks on and 1 week off. We need to keep in mind the concept of thromboprophylaxis, either with low-dose aspirin or an oral anticoagulant.

In my mind, I go back to that funny, old definition of insanity, which is doing the same thing over and over again and expecting different results. By that, I mean if [a patient] didn’t do well with lenalidomide or pomalidomide, I wouldn’t go to a CELMoD as my next choice [of therapy]. However, if [a patient] had a long duration of remission on lenalidomide and/or pomalidomide, to me, an obvious next step is to consider someone for an iberdomide- or mezigdomide-based trial.

van de Donk NWCJ, Touzeau C, Terpos E, et al. Iberdomide maintenance after autologous stem-cell transplantation in newly diagnosed MM: first results of the phase 2 EMN26 study. 

. 2023;142(suppl 1):208. doi:10.1182/blood-2023-177564

Mezigdomide plus dexamethasone elicits responses with acceptable safety in R/R myeloma. OncLive.com. Updated December 15, 2023. Accessed November 20, 2025. https://www.onclive.com/oncclub/mezigdomide-plus-dexamethasone-elicits-responses-with-acceptable-safety-in-r-r-myeloma

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