Introducing CELMoDs into the Multiple Myeloma Treatment Paradigm

At the Miami Cancer Institute’s Seventh Annual Immunotherapies Summit for Hematologic Malignancies, Paul G. Richardson, MD, discussed the evolving role of cereblon E3 ligase modulators (CELMoDs) in treating multiple myeloma. With their potency already established as monotherapy and in combinations, pivotal phase 3 studies are ongoing, and Richardson and his colleagues are beginning to consider the key roles these agents will fill in clinical practice, particularly in patients who have relapsed disease after chimeric antigen receptor (CAR) T-cell therapy and bispecific therapies, and in the place of immunomodulatory imide drugs (IMiDs).

He emphasized that these agents are not merely updated versions of existing immunomodulatory drugs (IMiDs) like lenalidomide (Revlimid) but are distinct molecules with unique characteristics. By engaging the cereblon E3 ligase complex more profoundly, CELMoDs demonstrate superior potency. This structural advantage allows them to overcome resistance to earlier therapies and stimulate the immune system to combat the disease.

“We can see for our patients these oral agents becoming true backbones in terms of the therapeutic armamentarium,” Richardson, director of Clinical Research and Clinical Program Leader at the Jerome Lipper Multiple Myeloma Center, the Dana-Farber Cancer Institute and RJ Corman Professor of Medicine, Harvard Medical School, said in an interview with Targeted Oncology.

In the interview, Richardson highlighted their versatility as potential backbone therapies in both early and advanced disease settings. Iberdomide is emerging as a favorable option for early relapse and frontline maintenance due to its remarkable tolerability and low off-target effects. Meanwhile, mezigdomide has shown impressive activity in highly refractory populations, including those with extramedullary disease or prior exposure to CAR T and bispecific therapies. As pivotal phase 3 trials progress, Richardson anticipates that these oral agents will provide a convenient, powerful platform that can be partnered with various existing treatments to significantly improve patient outcomes.

Targeted Oncology: What did your presentation at the Immunotherapies Summit cover?

Paul Richardson, MD: This is a really good research meeting annually now that's held and led by the Miami Cancer Institute group, and in particular, Dr Guenther Koehne. The remit was to talk about the integration of CELMoDs into the treatment paradigm in myeloma. The important thing to start with is that these are not…glorified IMiDs. They are distinct in their own characteristics and their own medicinal chemistry. As a result of that, they engage the cereblon E3 ligase complex far more profoundly than do the IMiDs. Most importantly, their closure of that cerebral E3 ligase complex is dramatic. If you can get into [the cereblon E3 ligase complex] and shut it down, the whole thing falls apart.

The other thing CELMoDs do so effectively is they marshal…the immune system to come in and finish off the job. If you think of it like that, lenalidomide and pomalidomide [Pomalyst] close that complex to about 15 to 20%, tops. Iberdomide closes it by 50%, and then mezigdomide comes in at 100% closure. The potency of mezigdomide in this setting is quite striking, and that translates into a whole array of pharmacodynamic effects which are very impressive, as does iberdomide. But the key point is they are substantially more potent from a structural point of view. Their engagement of the cereblon E3 ligase pocket is like a lock and key, whereas…the smaller…ring structures that constitute lenalidomide and pomalidomide, their engagement in that pocket is fractional. As a result of it, they're distinctly different, and I think that's reflected in what we see clinically.

What are the defining features of iberdomide and mezigdomide?

Iberdomide showed us the ability to override lenalidomide and pomalidomide resistance, and an ability also to be extremely favorable in terms of tolerability [with a] remarkably benign [adverse event (AE)] profile. The other piece that's so interesting is that they don't carry this off-target effect on C1Kα, which is an off-target effect that lenalidomide has that promotes second cancers, in short, and that same mechanism doesn't exist with iberdomide or mezigdomide.

Mezigdomide, in the same way as iberdomide does, overcomes lenalidomide and pomalidomide resistance impressively, but more so because it's that much more powerful. Its [AE] profile is a little more challenging, and that really centers around neutropenia, but off-target effects are minimal. It doesn't have any cardiac toxicity. We do not see neuropathy, which is remarkable. We also can see a little bit of fatigue and occasionally some mild dysgeusia, which just means you just have a funny taste in your mouth; nothing like that we see with other drugs in this space, such as talquetamab [Talvey], not even comparable, but just those kind of mild [AEs] that are manageable with appropriate supportive care.

Mezigdomide, in a nutshell, showed us that it could generate about a 40% to 50% response rate in a highly refractory population just as a combination with dexamethasone.¹ We were able to overcome the impact of extramedullary disease. We saw remarkable responses in extramedullary disease, which the molecule was designed to do by tissue penetration. When we combined it with other agents, the response rates were impressive. For example, if you combine mezigdomide with bortezomib [Velcade], the response rates go to 90%. With carfilzomib [Kyprolis], they're in the region of 80%, even in patients who've been previously exposed to those proteasome inhibitors.

Iberdomide is similarly synergistic, but not quite the same degree. The response rates in similar populations are around 25 to 30% for iberdomide/dexamethasone alone. If you combine it with other agents such as bortezomib and daratumumab [Darzalex], for example, the response rates are very impressive, but not quite as remarkable as we see with mezigdomide. What that does is position them both really well. You can think of iberdomide going into early relapse and then being used up front, and you can think of mezigdomide coming in [similarly to] pomalidomide to be the real agent of choice in a relapsed/refractory setting, and then that's how we've been developing the drugs going forward.

How does your presentation discuss how these are being integrated into different combination settings?

This is an immunotherapy summit; the goal was to share with the audience how I saw the ability to put mezigdomide into the space with CAR T therapy and also with bispecifics, and, for that matter, also with antibody-drug conjugates. In all spaces, it has a place. The most important thing about mezigdomide is that it reinvigorates the immune system. It activates it, it regenerates it, it gets it back to where it needs to be if there's immune T cell exhaustion.

I was able to share some data of our own in which we've combined mezigdomide with selinexor [Xpovio] as part of a clinical trial led by my colleague, Clifton Mo, [MD] and we've seen their remarkable evidence of, essentially, a reversal of T-cell exhaustion by combining those 2 agents in patients in whom [B-cell maturation antigen (BCMA)-targeted)] therapies have unfortunately failed them and at the same time do so in a way that's both tolerable and then sets…the patient up to then receive further immune therapy….²

The other area we've seen real benefit is in patients [who have had] both CAR T and bispecifics fail them, and they've got extramedullary disease and so forth. In this area, mezigdomide in combination has shown remarkable results. One of the most interesting combinations, in my view, has been what we call the Novel-Novel study [CA057-003 (NCT05372354)], where we've combined mezigdomide with other small molecule inhibitors, specifically trametinib [Mekinist] and tazemetostat [Tazverik], both separately. This has been a real privilege…working with Luciano Costa, [MD, PhD] as the [principal investigator] and I as the senior investigator, we've been able to show response rates of over 50% when we combine mezigdomide with tazemetostat and over 75% combined with trametinib in patients who have been refractory to both CAR T and bispecific therapy.³ The promise of these oral agents and their convenience for patients is remarkable in that setting. We're really encouraged by this. We feel that mezigdomide is providing us with an oral agent of choice in this very difficult space.

But then…how about putting mezigdomide with a CAR T in the sense of a maintenance strategy? How about doing that with a bispecific? It's very exciting. We are also combining belantamab mafodotin [Blenrep] with iberdomide as part of an Alliance trial that's currently ongoing. Similarly, belantamab being combined with mezigdomide is now planned as the next step in a future direction.

What should be understood about the role of CELMoDs?

We're thinking [mezigdomide] is providing a critical sort of…lubricant to keeping everything moving. But it's a bit more than that. It's not just a fill-in. It's a backbone agent, potentially, in my opinion. Because of that, we can think of it in a much more pivotal role, as opposed to just an adjunct. As a single agent, it's probably the most impressive oral therapy I've worked with in this context, and in combination, it's fulfilling its potential.

Iberdomide going up front and being thought of as a maintenance strategy is very exciting. Iberdomide has proved its mettle in maintenance and in combination already, and especially in upfront disease, it's quite amazing…how well it's tolerated and how active it is. Mezigdomide is capturing the relapsed/refractory space, as I've outlined.

One important thing to share is that this space of degraders is not just unique to the CELMoDs alone. There are other degraders under study, and they're coming through the pipeline. They're a little bit behind, but they have a different molecular structure, and so they may have the promise of working when these other agents have stopped.

The data with cemsidomide…has been encouraging in that the cemsidomide/dexamethasone platform, of just the 2 drugs, has generated a response rate of around 30% so far, with a favorable tolerability profile.⁴ …I think it remains to be seen how they'll all match up. But my own personal feelings in this field and bias is that it's not one vs the other. We'll need all of them because at the end of the day our patients are extraordinarily heterogeneous…and most importantly, these drugs all have different characteristics, so they may be better suited for a patient at the particular time, and then there's another time in a different context. The whole oral therapy degrader space is really attractive and very exciting.

What are the CELMoD regimens that are the biggest priorities now?

A few years ago, we had such great data from mezigdomide/dexamethasone, particularly during the COVID era, where an oral therapy was very advantageous, and we had very low rates of infection, and we had very low rates of zero COVID mortality. I think that really made us feel that these agents would have a very important place, even a few years ago. Having recognized that in that context, the FDA [was] very clear that we would have to bring in pivotal phase 3 trials to answer the question.

First, EXCALIBER-RRMM [NCT04975997] has come in to show this by meeting its primary end point of [minimal residual disease (MRD)] improvement that's been released to the public.⁴ The data will be coming later this year, but I'm hopeful that they'll show exactly that, that there is a substantial MRD gain when you compare the combination of iberdomide, daratumumab, and dexamethasone compared [with] a very active control, which is bortezomib, daratumumab, and dexamethasone, and at the same time, we'll see a [progression-free survival (PFS)] benefit that will be adequate to show clinical superiority to the iberdomide, daratumumab, dexamethasone combination. We'll have to see what that shows, but I'm cautiously hopeful.

We will have data on SUCCESSOR-2 [NCT05552976], which is this very well-done phase 3 trial, which did a dose optimization phase as [stage] 1 and then moved into [stage] 2, which was the randomized comparison taking [the] best dose established in the dose-optimization phase. It is the first trial of its kind to reflect in results so far this dose-optimization strategy followed by phase 3 comparison. Why that's so valuable is because obviously we're confident about the dose and schedule, which is no. 1. No. 2, we provide the FDA with a strategy or a framework for which they can feel very comfortable approving this approach and improving the therapy for patients. I'm very optimistic that we'll see an approval for the CELMoDs broadly, and it may be led by iberdomide as early as this year, [but]…one way or another, within the next year or so, we'll see the CELMoDs have FDA approval.

What is the foremost takeaway from the potential of CELMoDs?

…Mezigdomide…essentially provides a very strong and powerful immunotherapeutic platform in an oral therapy, which has all those advantages of accessibility for patients. At the same time, what I'm so struck by is that it's an excellent dance partner with all of our drugs, be [they] proteasome inhibitors, monoclonal antibodies, other small molecule inhibitors, bispecifics, and CAR Ts, recognizing these are all areas of active study. Iberdomide, although it's less potent, is well tolerated, so it has potential for outstanding performance upfront as induction and then as maintenance that's very safe. I'm very hopeful we will see low second cancer risk, excellent tolerability, and above all, efficacy in terms of activity. We can see for our patients these oral agents becoming true backbones in terms of the therapeutic armamentarium. I'm very hopeful that's what we'll see. I think the early-phase data suggest that, and the phase 3 data, I believe will support that. Then it opens the door for us to rationally partner these classes of drugs with all the available options we have to improve patient outcomes.

REFERENCES

1. van de Donk NWCJ, Bahlis NJ, Pawlyn C, et al. The role of CELMoD agents in multiple myeloma. Onco Targets Ther. 2025;18:921-933. doi:10.2147/OTT.S398118

2. Mo C, Gasperetto C, Costa C, et al. Selinexor, mezigdomide, and dexamethasone in patients with Relapsed/Refractory multiple myeloma who relapsed or are ineligible for T-cell–redirecting therapy: Stomp Phase 1 results. Blood. 2025;146(suppl 1):4010. doi:10.1182/blood-2025-4010

3. Costa LJ, Schjesvold F, Popat R, et al. Mezigdomide (MEZI) in novel-novel combinations for relapsed or refractory multiple myeloma (RRMM): Preliminary results from the CA057-003 trial. Blood. 2024;144(suppl 1):677. doi:10.1182/blood-2024-198403

4. Dhakal B, Yee AJ, Richardson PG, et al. Updated results of a phase 1 first-in-human study of cemsidomide (CFT7455), a novel MonoDAC® degrader, with dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: 22^nd Annual Myeloma Society Meeting; September 17–20, 2025; Toronto, Canada.