Experts Discuss CELMoD Agents for Multiple Myeloma

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Dr. Mateos: Hello to everyone and welcome to this podcast, in which we will have the opportunity to discuss about CELMoD agents for multiple myeloma. My name is María-Victoria Mateos, and I work as a pathologist at the University Hospital of Salamanca in Spain. Professor Dimopoulos will join me in this podcast today. Thanos, do you want to introduce yourself?

Dr. Thanos Dimopoulos (University of Athens): Hello. Thank you for the opportunity to participate in this podcast. I am Thanos Dimopoulos. I work at the Department of Clinical Therapeutics, University of Athens in Athens, Greece. I just want to ask Dr. Mateos, since we have so many agents for the treatment of myeloma, and we have seen that the outcome of patients has improved Dramatically, is there a need to have a new class of agents?

Dr. Mateos: Thank you very much, Thanos. I think that your question is very appropriate because when we plan what are the therapeutic needs in multiple myeloma? Maybe today we do not need more active drugs, but what we have to plan and for me, this is the most important medical need we have in myeloma is to deliver the right therapy to the right patient at the right time. Because the evolution of the main objectives we have today for multiple myeloma is to achieve disease control, but to reach deep responses, sustain the minimal residual disease negativity, treatment free remissions, and potential cure.

It is true that the classical proteasome inhibitors immunomodulatory drugs and an anti-CD38, monoclonal antibodies are basically taking part of the first line of therapy. Majority of the patients are going to be triple class exposure, and it is true that not all patients are going to be refractory to all these compounds at the moment of the first relapse. Definitely, although the progression free survival is becoming longer and longer after the first line of therapy.

We have, at the end of the day patients at the moment of the first relapse, and we have to deal with these patients, and we have to incorporate the novel T-cell redirecting therapies that basically these novel therapeutic approaches has clearly changed the treatment landscape for patients with multiple myeloma. The landscape is quite crowded in terms of T cell redirecting therapies, and CAR Ts bispecific monoclonal antibodies do utilize the T cells.

The importance of the immune system makes sense in order to incorporate why not novel compounds, and we are going to discuss it today about CELMoDs. Because of their mechanism of action, we know that they are going to enhance the immune system. This is going to be crucial in order to try to offer excellent outcomes for myeloma patients, maybe after the first two or three lines of therapy. This is what I consider.

In the future, majority of the patients will receive maybe no more than two or three lines of therapy. Based on this, of course, we will continue having unmet needs in patients with high risk and ultra-high risk disease. We have to try to improve the access of patients to all these novel therapeutic approaches. We have to try to reduce the treatment burden. Myeloma patients are going to arrive at the relapsed setting more elderly, sometimes a frail population.

We have to try to deliver safer and very effective combinations also to these patients. I think that these are basically what I consider the therapeutic needs in multiple myeloma. If we focus on the CELMoDs, Professor Dimopoulos, so what are CELMoD agents and what is the mechanism of action and how these CELMoD agents differentiate from the classical immunomodulatory drugs that we have been using for the last 20 or 25 years in myeloma?

Dr. Dimopoulos: Yes. You are right, María-Victoria. I agree with you that despite the progress that we have made, we still need agents that have a different mechanism of action. CELMoDs are not really IMiDs. Iberdomide and mezigdomide are the two CELMoDs that are in clinical development. They bind to cereblon within the CRL4 ubiquitin ligase complex. This binding is much more effective than the one that we are seeing with IMiDs.

They enhance recruitment and ubiquitination of the transcription factor Ikaros and Aiolos, and this polyubiquitinated substrate are subsequently degraded by the proteasome. This results in suppression of the IL-4 MiC dependent survival pathways, and they promote downstream immunomodulatory effects, including augmenting T-cell activation and NK cell expansion and myeloma activity. As you pointed out, T-cell exhaustion is a key factor not only because it is associated with increased risk of severe infection, but also because it is considered to represent a mechanism of resistance to T-cell redirecting therapies.

There are data both in vitro and in vivo, which indicate that mezigdomide, for example, stimulates T cell activation and reduces T cell exhaustion markers both clinically and preclinically.

Dr. Mateos: Yes. Thank you very much, Thanos. The most common CELMoD agents that we have today are iberdomide, mezigdomide. Do you have any feedback about other CELMoDs like mezigdomide or another one so that definitely they are different because they are only in clinical research?

Dr. Dimopoulos: Yes, you are right. Especially we are very excited because very recently, actually a couple of days ago, we had the approval by FDA of the combination of iberdomide with daratumumab and dexamethasone based on the EXCALIBER-RRMM study. How do you see this approval affecting the treatment of multiple myeloma, María-Victoria?

Dr. Mateos: I think that this is great because the information we have so far about these new CELMoDs in patients with multiple myeloma is good. It is true that we have to wait until EXCALIBER-RRMM for the approval of iberdomide, the first CELMoD so far approved in relapsed refractory myeloma in combination with daratumumab and dexamethasone. We know that the mezigdomide will be maybe also approved in combination with carfilzomib and dexamethasone, based on the SUCCESSOR-2 study that it was presented at ASCO and as well as EHA this year in June.

If we go back, I think that we have a phase 1, 2 clinical studies in which we had the opportunity to see how iberdomide plus dexamethasone-mezigdomide plus dexamethasone were indeed effective in the unmet medical need population we had some years ago, the triple class exposure and the triple class refractory population. I would like just to remark some important concepts because we have seen how mezigdomide and dexamethasone was also evaluated in a group of patients previously exposed to BCMA targeted therapy.

We had the opportunity to see how mezigdomide was effective in this population, but both CELMoDs iberdomide and mezigdomide demonstrated it to be efficacy in patients previously refractory to lenalidomide and pomalidomide what is important. Also the extramedullary disease subgroup of patients, we know that they are an unmet medical need population and the mezigdomide and dexamethasone in the phase 2 clinical study showed to be also effective in this population.

Now we have I think that excellent news because we have, as you pointed out, iberdomide, daratumumab, and dexamethasone in this EXCALIBER-RRMM trial so far approved by FDA. There is another important information. This is the first phase 3 clinical study that has been approved based on the new endpoint and minimal residual disease and complete response. We know that iberdomide data basically duplicated the MRD negativity rate, as we have seen in the press release and the PFS will be coming.

Definitely this is the first time the authorities are considering minimal residual disease and CR as the primary endpoint for the approval of a new combination. As I previously said, the mezigdomide and carfilzomib and dexamethasone, based on the excellent data reported in the SUCCESSOR-2 clinical study, we will have the opportunity to have these two new combinations based on CELMoDs based combination in earlier lines of therapy.

That from my point of view, this is the excellent place in order to use the CELMoDs today, although we have also clinical studies and some data about iberdomide in combination with bortezomib in combination with daratumumab as part of the first line of therapy. You know that there is indeed a phase 3 clinical study ongoing evaluating iberdomide as maintenance therapy after autologous stem cell transplantation.

Dr. Dimopoulos: I think this is a great point that since we have now the approval of an iberdomide based combination, we are looking forward to large randomized studies that are evaluating iberdomide head to head comparison with lenalidomide may be replacing lenalidomide in the future in the frontline setting. Also an important study comparing iberdomide and lenalidomide as maintenance. One may envision that in the future, iberdomide will be used in the front line in the consolidation and as maintenance.

Whereas mezigdomide may have a major role later in the course of the disease, probably as a bridging therapy between T cell-directed therapies. However, there are some concerns regarding the safety of these drugs, which is the major side effect of iberdomide and mezigdomide based on your evaluation of the data that are available.

Dr. Mateos: Do you want to comment something about the key safety data of these CELMoDs?

Dr. Dimopoulos: Yeah. I think a non-target effect is the neutropenia that we see frequently with mezigdomide. In SUCCESSOR-2 study, we had a significantly higher rate of neutropenia. However, this neutropenia is predictable. It is short lived. It is not associated with a high risk of infection. One practical approach that we used in this study, and in the use of mezigdomide outside the clinical trials is as soon as we see grade 3 or 4 neutropenia, we continue the treatment by using G-CSF on a regular basis.

In my mind, this is the major complication of the drug. I have been also pleasantly surprised to see in the randomized maintenance study that the use of iberdomide as maintenance is associated with a much lower frequency of diarrhea, which is a major obstacle in the long term use of lenalidomide. I do not know what is your experience with these two agents as far as safety is concerned.

Dr. Mateos: Yeah, exactly what you said. I think that the management is quite easy, but we have to take care of neutropenia because it is the most frequent adverse event. It is grade 3, 4 in majority of the patients. We should pay attention in order to be very proactive with the use of G-CSF. I would say that the incidence of grade 3, 4 neutropenia is even more pronounced with mezigdomide than iberdomide. Indeed I have now several patients included in clinical trials with novel combinations based on mezigdomide novel compounds. We have to plan the primary prophylaxis with G-CSF.

It is true that with this approach, neutrophils counts usually are recovered and patients are able to initiate every cycle. This is important. The second important consideration is what you said. In spite of the high frequency of neutropenia, febrile neutropenia is not very frequent as well as severe infections. It is extremely important to see how some other adverse events like asthenia, fatigue, diarrhea, are not present with these new CELMoDs because of the conformation.

Because of the structure of these CELMoDs is different in comparison with lenalidomide and pomalidomide, it is true that in the clinical practice we do not see these non-hematological adverse events. Thanos, correct me. We have to continue using the thromboprophylaxis with these new CELMoDs, right?

Dr. Dimopoulos: Yes. The rate, of course, of deep vein thrombosis in SUCCESSOR-2 was quite low. However, it is something that we have to keep in mind. In the majority of our patients, I believe that we can use low dose aspirin, but there are patients that may need heparin or DOAC. María-Victoria, let me ask you when the combination of mezigdomide with carfilzomib dexamethasone will be approved and hopefully this will happen in the next few months, where do you see this combination being used today? What type of clinical setting?

Dr. Mateos: I have to say that for me, SUCCESSOR-2, especially mezigdomide, carfilzomib and dexamethasone was evaluated in a truly unmet need population after just one or two prior lines of therapy, because the majority of the patients were not only refractory to lenalidomide, but also refractory to anti-CD38 monoclonal antibodies. When we evaluated the efficacy of the control arm in this study, carfilzomib and dexamethasone median PFS eight months.

We have seen how mezigdomide plus KD resulted in a median PFS of one and a half year. I think that in this population, this is the ideal place to use. For me, it is true that the key point is how to deal with mezi-KD maybe in the context of the T cell redirecting therapy. It is true that the only data we have in a similar population to the population included in SUCCESSOR-2 is teclistamab monotherapy, included in the MajesTEC-9 clinical study.

In MajesTEC-9, the PFS has not been reached yet, but I cannot envision a very, very different progression free survival. I think that maybe we do not have to select one or another. Both are available and even it is possible to sequence one after the other. I think that this is one of the main advantages of the CELMoDs, because they are going to enhance the immune system. They do not need, in principle the T cells, as this is the case for bispecific monoclonal antibodies.

I think that the mezigdomide KD, but the same is applicable to either dara-dex complement very well the treatment landscape in earlier lines of therapy complemented with either CAR Ts. You pointed out before about the role of bridging therapy, but also in order to sequence this T cell redirecting therapy.

Dr. Dimopoulos: No, I agree with you. I would like also to make the point that although bispecifics are very active, they are associated with severe hypogammaglobulinemia. They are associated with sometimes severe infections that can be unpredictable. There are several practicing physicians, especially in smaller centers in community setups that are skeptical about this potential complication.

Whereas the combinations that include iberdomide and mezigdomide can be given in all clinical settings. The main issue is neutropenia. Hematologists know how to deal with neutropenia. The rate of hypogammaglobulinemia, the SUCCESSOR-2 study was very low, was about 10%. The need for immunoglobulin administration was 20%, 25%. Whereas we know that with specifics, essentially all patients need to take immunoglobulin.

There is the activity, but also there is the issue of safety and the ease of administration. These regiments, these oral drugs can be given easily to outpatient settings in all type of practices, not only in academic centers, but also in smaller community clinical practices. I think this is an important issue sometimes to select therapies.

Dr. Mateos: Yes, of course. Even just to add that we are evaluating different new combinations based on the bispecific monoclonal antibodies plus the CELMoDs. We have some data based on the combination of iberdomide plus elranatamab, the BCMA, bispecific monoclonal antibody, and the data are preliminary and were presented at ASCO 2025.

The overall response rate for this majority of the patients, triple class exposed and triple class refractory was over 90%. I think that there is another possibility for combining CELMoDs with the T cell redirecting therapy like a bispecific monoclonal antibodies. As we have previously discussed, I think that the CELMoDs are going to be very valid in order to sequence CAR T cell therapy, bispecific monoclonal antibodies and why not to incorporate also belantamab mafodotin that it will be another potential combination. Belantamab in combination with either a iberdomide or mezigdomide.

Dr. Dimopoulos: Absolutely. We made the point, but it is important to repeat it that mezigdomide-based combinations, they seem to have activity in plasmacytomas, para skeletal, extramedullary plasmacytomas. There are some data regarding activity in CNS involvement of myeloma of the combination. These are important issues, especially when we are dealing with patients that have advanced refractory disease.

Dr. Mateos: Yes. Of course, I do not know if you visualize any potential barrier to the near future CELMoD agents integration into the treatment landscape for patients with multiple myeloma.

Dr. Dimopoulos: Yeah. I think, as you said at the beginning, we have many active combinations, and it is important to find a way to sequence them in the best appropriate manner so that a given patient can take advantage of all these new therapies. In my mind, I see in the future iberdomide replacing lenalidomide in the quadruples or in the triplets and also in the maintenance, a single agent in the future in combination with daratumumab or anti-CD38.

There is a Spanish trial which is evaluating this approach, a very important study. Mezigdomide probably playing the role of pomalidomide in the more advanced setting as a bridging therapy second line when there is some skepticism about the potential use of a bispecific history of infection, distance from a major hospital center as a bridging therapy in combination.

As you said, there are studies with both iberdomide and mezigdomide in combination with bispecifics to enhance their activity, to reduce T cell exhaustion, which is a factor of resistance to bispecific. I believe that these agents, as they are becoming available through the approval of several studies, they will provide an additional way to prolong the life of our patients with myeloma and to have the prospect of cure in more patients than we have today.

Dr. Mateos: Yes, I completely agree. If you allow me just to add something in which maybe we have to educate to the medical doctors, because some clinicians may initially consider if my patient is already pomalidomide refractory, why would I use another cereblon targeting agent? I think that the biological and clinical distinction more potent and rapid Ikaros and Aiolos degradation and activity despite IMID refractoriness needs to be clearly understood. We should emphasize this amongst the clinicians because these CELMoDs are not better IMiDs, are different agents, and you explained very well their mechanism of action, and they are more potent.

Dr. Dimopoulos: We have clinical data from SUCCESSOR-2, where up to one-third of patients were pomalidomide resistant. They had a significant benefit from the combination of carfilzomib with mezigdomide and dexamethasone.

Dr. Mateos: Exactly. Thank you very much, Thanos. It has been great pleasure for me to have this podcast about the CELMoDs.

Dr. Dimopoulos: I am looking forward to see data from other studies, as you mentioned from EXCALIBER-RRMM, the PFS data and also the overall survival data from SUCCESSOR-2. By the end of the year, we will have the data from SUCCESSOR-1. Hopefully this is a journey that is starting for CELMoDs, and it will be a very positive one.

Dr. Mateos: Absolutely. Thank you very much.