CELMoDs Could Address T-Cell Fitness Needs in Multiple Myeloma Management

With the use of CAR T-cell therapies and bispecific antibodies expanding across the multiple myeloma treatment paradigm, a novel class of agents known as CELMoDs could help promote T-cell fitness for patients, along with delivering other antimyeloma effects, according to Gurbakhash Kaur, MD.

“There is definitely a need in the myeloma space, where we need novel agents that are going to help us deal with the T-cell exhaustion aspects of [other treatments and the disease],” Kaur said in an interview with OncLive^®. “There is certainly a need for these [CELMoDs]. I'm looking forward to seeing how these studies are going to read out and what the regulatory pathway is going to be for these drugs.”

In the interview, Kaur explained what sets CELMoDs apart from earlier-generation immunomodulatory drugs (IMiDs), explained where this class of agents could fit into the multiple myeloma treatment paradigm, and provided insight on potential clinical trial enrollment in studies evaluating these agents.

Kaur s an assistant professor of medicine, hematology, and medical oncology at Mount Sinai in New York, New York.

OncLive: Looking at CELMoDs as a whole, what differentiates this class of agents from existing IMiDs?

Kaur: CELMoDs are cereblon E3 ligase modulators. Some people like to think of them as next-generation of IMiDs; however, they are different. They bind to cereblon, change its substrate specificity, and promote protein degradation via the transcription factors Ikaros and Aiolos. That's their main mechanism of action.

They are different from IMiDs in the sense that their binding to cereblon is much stronger, and CELMoDs tend to have activity in patients who have IMiD-refractory disease. We think that they're more potent than IMiDs, as well. There are two [CELMoDs currently being evaluated]: iberdomide [CC-220] and mezigdomide [CC-92480]. Both of them are very potent and have been tested in preclinical and clinical studies, and they are currently in development in clinical trials.

Although these agents are still being evaluated in clinical trials, how could you ultimately see CELMoDs affecting the multiple myeloma treatment paradigm?

More than ever, there is a need for novel agents—especially agents that can capture or rescue patients post–CAR T-cell therapy or post–bispecific antibody failure. We know that CAR T-cell therapy is approved [as early as] the second line,² so more and more patients are quad-exposed and quad-refractory [after earlier lines of therapy].

One exciting thing about CELMoDs is that they are able to restore immune fitness. We're going on from one immune cell therapy, whether it's CAR T-cell therapy or a bispecific, we think that there is a factor of T-cell exhaustion. We know that in general, IMiDs tend to promote T-cell fitness, and I think that the data are even stronger to believe that for iberdomide and mezigdomide [promote T-cell fitness]. The clinical efficacy data for both are impressive. It was a small number of patients, but mezigdomide [has shown efficacy] in [patients with] extramedullary disease, which is an unmet need right now when we see post–bispecific antibody and post–CAR T-cell therapy.

Another area where you could potentially think about the use of CELMoDs is either pre–CAR T-cell therapy or pre–bispecific antibodies as a sort of priming mechanism. There's an ongoing interest in exploring that, or even maintenance strategies. In patients who are getting CAR T-cell therapy or bispecifics, but have high-risk disease, disease that relapses rather quickly, or a depth of response that isn't what you want it to be, CELMoDS could help promote ongoing response in that [setting].

What has been shown regarding the safety of CELMoDs? How have efficacy and safety data supported their evaluation as a part of combination regimens?

Historically, myeloma drugs have been studied as a single agent, and if there is single-agent activity, that is probably the strongest indicator that these drugs are going to be effective. That gives the basis to do combination therapy, which is done with most myeloma drugs because they can work synergistically with each other. That's why you have the ongoing trials like [phase 3] SUCCESSOR-1 [NCT05519085] and SUCCESSOR-2 [NCT05552976] studies when it comes to [mezigdomide].^2,3

The safety profile is very much predictable [with CELMoDs]. The biggest concern is most likely cytopenias when it comes CELMoDs.

With standard-of-care treatment options available across the multiple myeloma paradigm, how do you weigh clinical trial enrollment for a study evaluating a CELMoD-based treatment vs treatment with a standard-of-care approach?

The standard of care in myeloma is changing [almost] every day. CAR T-cell therapy [is approved in the] second line, and now you have data for bispecific antibodies, which [are approved as] fifth-line agents, and now they're [potentially moving to earlier lines of therapy]. That goes to show the progress we're making in the field, and that's one of the reasons why we enroll patients in clinical trials.

The single-agent efficacy [of CELMoDs] is quite remarkable. [Clinical trial enrollment] may depend on which line of therapy you are considering; when you're trying to enroll patients in a first- or second-line trial, where the standard of care has such a high benchmark, the recruitment does have to focus both on efficacy and safety. The further along [a patient's] myeloma courses, and depending on where and when their disease is relapsing, that's what drives the conversation when it comes to CELMoDs. We are definitely dealing with-T cell exhaustion, and in between immune therapies is a very great place to study [CELMoDs]. They [could also be studied] pre–CAR T-cell therapy or pre–immune therapy because we know that there's a T-cell fitness aspect to it.

There are so many factors that play into an individual patient's decision [to participate in a clinical trial], but [CELMoDs] are also oral agents. Both bispecifics and CAR T-cell therapy, are high-maintenance therapies. We have to give intravenous immunoglobulin, we have to check cytomegalovirus [status], and we have to give pneumocystis pneumonia prophylaxis. Therefore, not everybody may [be in the right situation] to be able to get these [cellular] therapies right away. [CELMoDs] offer an alternative.

In my opinion, most myeloma agents get used at some point [during the course of treatment]. It's not necessarily yes or no [about receiving a class of drug]; it's when. For patients who need time to determine the timing of CAR T-cell therapy or immune therapy, or if caregiver support is questionable, it's not necessarily just the medical aspect of it. The social aspect of the care is equally complicated and needs to be implemented. [CELMoDs] offer great alternatives.

References

1. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at lease one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed February 25, 2025. https://www.jnj.com/media-center/press-releases/carvykti-is-the-first-and-only-bcma-targeted-treatment-approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractory-multiple-myeloma-who-have-received-at-least-one-prior-line-of-therapy
2. A study to evaluate mezigdomide, bortezomib and dexamethasone (MEZIVd) versus pomalidomide, bortezomib and dexamethasone (PVd) in participants with relapsed or refractory multiple myeloma (RRMM) (SUCCESSOR-1). ClinicalTrials.gov. Updated February 23, 2026. Accessed February 25, 2026. https://clinicaltrials.gov/study/NCT05519085
3. A study to evaluate mezigdomide in combination with carfilzomib and dexamethasone (MeziKD) versus carfilzomib and dexamethasone (Kd) in participants with relapsed or refractory multiple myeloma (SUCCESSOR-2). ClinicalTrials.gov. Updated February 11, 2026. Accessed February 25, 2026. https://clinicaltrials.gov/study/NCT05552976