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COMy: Protein Degradation Modulators
Recent Advances, Future Directions, and Ideas on Integrating CELMoDs Into The Care Of Patients With Myeloma

Released: July 01, 2026

Sagar Lonial
Sagar Lonial, MD, FACP, FASCO
Mohamad Mohty
Mohamad Mohty, MD, PhD
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Listen in to learn from Sagar Lonial, MD, and Mohamad Mohty MD, PhD, about the advantages and future implications of the next-generation protein degradation modulator based therapy and find out how to integrate their use into your practice.

This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.

Dr. Sagar Lonial (Winship Cancer Institute): Hello. I am Dr. Sagar Lonial, from the Winship Cancer Institute at Emory University in Atlanta. I am joined by my colleague, Prof. Mohamad Mohty, from the Department of Saint-Antoine Hospital and Sorbonne University in Paris, France. We were together at COMy and talked about a number of different important topics in the context of multiple myeloma. Welcome, Mohamad.

Prof. Mohamad Mohty (Saint-Antoine Hospital and Sorbonne University): Thank you very much, Sagar. It is a great pleasure to be with you today.

Dr. Lonial: One of the things we wanted to talk a little bit about today was some of the exciting data on CELMoDs. I will just get us started with a little bit differentiating CELMoDs from their previous cousins, the IMIDs, and then let you tell us a little bit about your perceptions as well.

We know that the two CELMoDs that are furthest along in myeloma, which are mezigdomide and iberdomide, are structurally different and, really, in my mind, have three nice differentiating points from lenalidomide, pomalidomide, or even thalidomide. The first is much higher binding affinity, which allows you to actually induce cytotoxicity as opposed to cytostasis when you treat myeloma cells with them. The second is a better adverse event profile. The third has to do with immune activation. These, to me, represent three nice differences between the CELMoDs as well as their previous predecessors, lenalidomide and pomalidomide.

Tell me your thoughts about this and how you think it plays in clinical practice.

Prof. Mohty: You nailed it very nicely, Sagar. We all know that the IMIDs, starting with the grandfather thalidomide, then lenalidomide, the father, the son pomalidomide, represented a huge revolution in the field of multiple myeloma. They were transformative, whether in newly diagnosed multiple myeloma, but also in the relapsed/refractory setting.

I am very excited about this new generation of IMIDs, the so-called CELMoDs, which represent an evolution beyond actually classical IMIDs because, as you summarized it nicely, they combine direct anti-tumor activity with profound immunomodulatory effects. They may restore sensitivity in heavily pre-treated patients. Due to their mechanism of action, they are the next-generation cereblon e3 ligase modulators. You insisted on the enhanced cereblon binding, and obviously, this will lead to potent degradation of Ikaros, Aiolos, immune activation, and, obviously, overcoming resistance. Actually, from a mechanistic perspective, we are clearly here performing a cereblon pathway optimization with a stronger substrate degradation and immune activation. This will lead, I believe, into synergy with some of the most active antibodies we use in myeloma.

Dr. Lonial: You have hit on a number of really important topics. From a clinical perspective, a question that I often get is, are they really more potent than lenalidomide and pomalidomide? While the best head-to-head comparison of lenalidomide and iberdomide is ongoing in the EXCALIBER-Maintenance trial, certainly the preliminary efficacy that Niels van de Donk has presented suggests that they are more likely to induce CRS and MRD negativity than what we had seen with lenalidomide before, to me, the indirect comparison, particularly in newly diagnosed myeloma, when we look at the iberdomide + daratumumab + dexamethasone combination as opposed to MAIA, which was lenalidomide + daratumumab + dexamethasone, the CR rate and MRD negativity rate is double in the iberdomide + daratumumab + dexamethasone.

These are not head-to-head randomized trials, but certainly, that suggests that the potency you have hit upon that we have seen in preclinical data may actually bear out in clinical practice.

Prof. Mohty: I fully agree with you. Actually, although we are missing or we will never have these so-called head-to-head comparisons, we do have some strong indicators suggesting that the CELMoDs are probably, from a clinical standpoint, stronger and more potent than the classical IMIDs because we have seen responses even in very difficult-to-treat populations. The activity seen in post-BCMA settings is very important. We have seen strong activity in the triple class refractory with durable responses. The corollary for this, in my opinion, is that if we bring them into earlier lines and even into frontline - and you mentioned the daratumumab + iberdomide + dexamethasone combination - obviously, one would see even better responses. You alluded in your introduction to the improved safety profile. Actually, improving the outcome of a given patient is about improving the efficacy, but also improving the safety and the overall balance would be very positive. This is why I am very optimistic about the positioning of these new CELMoDs, not only in the advanced stage relapsed refractory setting, where clearly, we need them after failure of bispecific antibodies after CAR T-cells, but also into earlier lines, especially in combination, for instance, maintenance after CAR T-cells or as a backbone for combinations in the sequencing strategies.

Dr. Lonial: Yes. Really nice points. I fully agree with you. A lot of what you are describing now, we have seen hints of in data we did not have at COMy. That is data from the SUCCESSOR-2 trial that we have seen at least preliminary data in the abstracts that were released from ASCO already. It is really, really exciting. Tell me your thoughts about what we know so far about the SUCCESSOR-2 data. That is a slightly different agent. It does have even more potency than iberdomide. What I am really intrigued by is the activity in high-risk myeloma, as well as the potential for activity in extramedullary disease that we have seen. Tell me your thoughts because I know that that is a challenge for all of us dealing with those subsets of patients.

Prof. Mohty: Exactly. These are the hard-to-treat patients. Based on the abstract you are alluding to - and I am very excited to listen to the presentation during the next ASCO 2026 annual meeting - we do have a clear, potent signal about the efficacy in the hard-to-treat patients, namely the high-risk cytogenetics, but also, for instance, the extramedullary disease. In my opinion, we owe this to the immune synergy that one can see between IMIDs and, for instance, proteasome inhibitors, but also probably the capacity of these agents to potentiate T cell redirecting approaches. At the end of the day, when you look to the full sequence of treatment, probably patients are going to do better.

Dr. Lonial: Yes. Whether it is a SUCCESSOR-2 or SUCCESSOR-1 with mezigdomide or EXCALIBER relapse, which is iberdomide + daratumumab + dexamethasone versus DVd, we know that that trial hit its primary endpoint, and we are hopeful for an FDA approval. These agents, in all the clinical situations you described, are going to be really important, not only for directly attacking myeloma but potentially for resetting immune function, particularly in the context of repeated bouts of immune therapy. We know that T cell exhaustion and other issues may limit the efficacy of many of our immune therapies. These drugs, the CELMoDs, give us a way to perhaps rejuvenate the immune system in that context.

Prof. Mohty: I would like to add here, Sagar, something very important about the safety profile because this is always a matter of concern, and we have seen, for instance, with the T cell engagers bispecific antibodies, that opportunistic infections are clearly a big concern. Here, we are talking mainly about hematologic toxicity and cytopenia, which is, I would say, the core business of hematologists, something that we relatively easily manage. The infectious risk is relatively mild, so we do not need the monitoring, the immunoglobulin systemic administration. The tolerance in general is very good.

Last but not least, I would add that the adoption by the community is going to be very quick because experience accumulated from the historical IMIDs will help clinicians to adopt very quickly these new CELMoDs and navigate their toxicity management. I am quite optimistic about the advent of these CELMoDs, which will become central components of our anti-myeloma strategies.

Dr. Lonial: We have hit on a lot of the clinical data that we have available to us now from phase II trials, emerging phase III trials that we hope to have more granular data on. What I want to shift our focus to in these last couple of moments is really talking about the future, the forward-thinking approaches. We have seen preliminary data combining T cell engagers with iberdomide, combining T cell engagers with mezigdomide. There are already data looking at T cell engagers with lenalidomide and pomalidomide in earlier lines of therapy. To me, a big question is, is a T cell engager/CELMoD combination as good or better than a CD38/T cell engager combination? This is the next big question that we need to answer in our field, right?

Prof. Mohty: I fully agree. Actually, you are alluding to what I would personally call the next-generation immunotherapy platforms. We do have already some strong in vitro and animal data suggesting, for instance, that mezigdomide can allow for immune restoration. This is clearly needed when you are speaking about immunotherapy. These CELMoDs will become central components of any future immune-based strategies because they illustrate how modulation of the tumor microenvironment is becoming increasingly important. I would say the field, thanks to CELMoDs and other innovations, is moving toward a biology-driven combination than just rather sequential adding drugs one after each other.

Dr. Lonial: Yes. We have spent a lot of time talking about T cell engagers and the ability to potentiate efficacy by combining with CELMoDs. Let us get even a little closer to what is near and dear to your heart, which is cell therapy. Do you see a role for these in the context of CARs, whether they are in vivo or they are ex vivo, improving the quality of the apheresis product, improving the innate quality of the T cells before or after? Tell me what you see as the potential opportunities.

Prof. Mohty: Absolutely. I would say they can be useful at the different stages of any T cell therapy. Before apheresis or before administration of CAR T-cells, they can be helpful in terms of bridging. We know that they will have a positive impact on the T cell fitness that we will use to manufacture the CAR T-cells. I believe, although we like, all of us, the single-shot treatment with CAR T-cells, we need to acknowledge that we will not be able to cure every single patient with a single shot CAR T-cell. In many situations, especially the high-risk situations, but also the situations where your CAR T-cell construct is maybe weaker - because not all the CAR-T constructs are equal - definitely using the CELMoDs after CAR T-cells to promote or to continue to trigger the immune reactivation and improve the efficacy of CAR T-cells is going to be crucial.

Dr. Lonial: If you poll those of us who use a lot of CARs, very few of us are doing no maintenance after a CAR. Whether it is switching targets or whether it is using an IMID, hopefully in the future, a CELMoD, at least for a limited duration with the intent of trying to improve persistence. To me, that is a big difference between lymphoma CARs or ALL CARs versus myeloma CARs. The persistence is just so much longer in lymphoma and ALL, at least from my interpretation of the literature. That may be a challenge when we are using a myeloma CAR.

Prof. Mohty: I can only agree with these statements because clearly, with CELMoDs, we are not simply talking about stronger IMIDs. They are clearly the backbone of a new platform for immune modulation and reactivation in myeloma. Obviously, they will become, in my opinion, mandatory as partners with all the other different immune therapies, which are very promising and which we are using more and more routinely.

Dr. Lonial: Yes. Fully agree. Our field is moving so fast, there is already new data coming out at ASCO and at EHA, as well as at IMS and ASH. It is such an exciting time in a field that for so long had laid dormant. Every innovation is making a big difference for patients. Thank you again for your time, Prof. Mohty. Again, thank you for hosting us at your meeting. Absolutely delightful as always. I appreciate everybody listening to this really nice summary of the current, the present, and the future of CELMoD therapy in myeloma. Thank you.

Prof. Mohty: Thank you very much, Prof. Lonial, for the insightful discussion. You are all very welcome to COMy 2027.

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