Hello and welcome to the Decera Clinical Education Oncology Podcast I’m your host, Ryan Topping. Today’s episode features Dr. Jesus Berdeja from Tennessee Oncology in Nashville, Tennessee; Dr. Amrita Krishnan from City of Hope in Irvine, California; and Dr. Niels van de Donk from Amsterdam UMC in Amsterdam, Netherlands as they address key questions on CELMoD agent therapy for multiple myeloma, including combination strategies, adverse event management, and where CELMoD agents may best fit within current and future treatment strategies.

This episode is part of a larger educational program titled, “Myeloma Myth Busters: Investigating the Now, Soon, and Future Clinical Implications of CELMoD Agents.” For more information, along with a link to the larger education program, please visit the show notes for this episode.

Now let’s get started and hear what our experts have to say about this important topic.

Could CELMoD agents enhance immune activation in combination with CAR T-cell therapy or bispecifics? And I know that both of you are involved in an interesting clinical trial.

You with Mezi and you with Iber, I think, after CAR T. So maybe, Amrita, you can comment on this.

Dr. Krishnan: The data you so nicely showed in terms of its effects on T-cells clearly suggests it has a role both with bispecifics and as well in the post-CAR T setting. I think we also already have data combining bispecifics with immunomodulatory agents that we are also going to see further at this meeting. So this is sort of the next generation of those trials.

Dr. Jesus Berdeja (Tennessee Oncology): Yes, no, I agree. I do not think it is a debate. The question for me is, when do we incorporate them? Do we treat with them before you collect the T-cells to get a fitter T-cell as part of your CAR T? Do you bring it on as maintenance after the CAR T, hoping to continue that activation and maybe suppressing and leading to longer durations of responses without activating or increasing toxicity? Because ultimately, that is the problem. So at some point, we may do too well, and do you really want those T-cells to live forever and then have this long-term toxicity? So those are the questions that come up. Sometimes a little can be too much.

But I think from all our experience, our little experience that we have in trials, these seem to be really good agents to combine with CAR Ts and with bispecifics as well.

Dr. Krishnan: I was going to ask you a question then, Niels. But would you give, to your point about when do you do it, would you give a bispecific combination, and then would you stop one of them and continue a CELMoD agent, for example?

Dr. van de Donk: Yes, I think that is a very important question because now the bispecifics are given until progression. And the big issue is, of course, with the BCMA bispecifics is that you continue to have zero B-cells, zero normal plasma cells, no humoral immunity. So I think now that bispecifics are coming to the early relapse setting, are coming to the newly diagnosed setting, I think we have to think about fixed duration so that patients can experience B-cell reconstitution, normal plasma cell reconstitution, so that you can stop IVIG, and it can sometimes take several months before humoral immunity is recovered.

So I think it would be very interesting to explore fixed-duration bispecific, maybe followed by a certain duration of a CELMoD agent to maintain the remission. Maybe it is not needed, so it would be interesting to explore both fixed-duration and CELMoD as a maintenance strategy. Because we know that we induce a very high rate of MRD negativity, especially when you start combining bispecifics with other drugs.

Dr. Berdeja: The other thing, again, we all have very limited experience incorporating these agents, but especially in the post-CAR T space is, as you will see, the main toxicity of these agents, by definition, is neutropenia. And so, trying to navigate sort of the immunosuppression that can result from the agents, having to stop, how much do you need? And I do not think you need that much. I think you can do a very short amount of treatment and actually stop, and it actually does induce prolonged responses.

Dr. van de Donk: Maybe one question for my clinic. Last week, two weeks ago, I had a patient that got a CAR T-cell product. He had massive expansion. And in this trial, we had to start with lenalidomide maintenance at day 28, but he had a lymphocyte count of 50. So I did not do it. I wanted to wait until the whole peak was a little bit down, because during the expansion, he also had transaminitis, high LDH. So I wanted to wait a little bit with the immune activation by an IMiD.

When do you think is the best moment to start CELMoD or IMiD maintenance after CAR T? What is your practice or is your trial saying?

Dr. Berdeja: Yes, no, that is a good question. I agree. I would not start it then either, not because we know what will happen, but just because of the potential of inducing, again, these later toxicities. But I think, in general, it is when you get a hematopoietic reconstitution. That is usually when, again, because of the toxicity or the potential side effects of these drugs, that is usually the window where you start. So it is usually about 30-60 days after the CAR T in general.

Dr. van de Donk: Yes, and I think you should also wait until all the toxicities, the lab toxicities, the neurological toxicities. Maybe not while they are having CRS or neurotoxicity now.

Dr. Krishnan: So here is my question, because you mentioned you have the Iber post-CAR, we have Mezi. Do you think there is one that is better than the other post-CAR?

Dr. Berdeja: Yes. Oh. I do not know.

Dr. Krishnan: Niels, you can be the tiebreaker.

Dr. van de Donk: You do Mezi and you do Iber.

Dr. Berdeja: I do not know which one is better. Again, in this setting, we are not using them for their anti-tumor effect. We are using for the immune modulating effects. And I think the better toxicity profile is with Iber over Mezi. I, personally, would think Iber makes more sense.

Dr. van de Donk: I think I would also favor Iber, although I do not have clinical experience in the post-CAR T setting with Iber. But given the lower rate of neutropenia, I think Iber is a very good maintenance drug, also in the post-CAR T setting. I only have experience with Len maintenance after CAR T at this moment.

I am actually going to pick one of the other questions to ask them, because I think it is important. So we see a lot of neutropenia with these agents. So I am curious how you guys manage the neutropenia. You have a patient in front of you, and you are expecting to get neutropenia. So what do you do as Dr. Krishnan? You are shaking your head, so I am going to ask you first.

Dr. Krishnan: Well, I see a research nurse actually sitting in the back. We have a patient on trial with Mezi right now, and that is very much a significant issue. It is fairly profound neutropenia, and this is fairly advanced relapsed disease post-CAR T. And so it is that challenge of we do not really want to have to hold drug for long periods of time. We have been basically now giving just scheduled growth factor to try and maintain dose.

Dr. Berdeja: Do you agree?

Dr. van de Donk: We also give growth factors, and at a certain time point, of course, also dose reductions, both to keep the patient on treatment, on therapy, because we think that that will result in a longer duration of the response. So both growth factor support, modulated GCSF, I think is easier than GCSF, or dose reductions after a while.

Dr. Krishnan: I think that one good thing, though, is the thrombocytopenia does not seem as prominent. As Niels said, the neutropenia is manageable.

Dr. Berdeja: So I am curious. You have a patient in cycle one and become neutropenic. Do you do immediate dose reductions, or do you try GCSF and see if you can maintain the dose intensity?

Dr. van de Donk: First, I try GCSF. If you continue to need GCSF, while tumor burden has substantially decreased, the patient is in a deep remission, I tend to go down in the dose.

Dr. Krishnan: Yes, I take that same approach, too.

Dr. Berdeja: But I think that is important, because obviously we are taught by insurances that you should not give your growth factor while you are giving chemo. And so I think we need to kind of dissociate that from these agents, that it is safe to give growth factors during, and really to try and maintain the patient on there, especially initially when they may have disease in the marrow that is complicating this further. So I agree with you.

But I think it is hard. I think it is ingrained in us, right? It is like, oh, my God, they are neutropenic. We need to stop. But yes, I agree.

Dr. van de Donk: And the important thing, maybe, neutropenic fever is very rare with the CELMoDs. Also with mezigdomide, that is a rare type of infection.

Dr. Krishnan: I think the other thing, and maybe you will talk about this in your maintenance study, because I was happy to see that the quality of life was included in terms of much less diarrhea.

Dr. van de Donk: Yes. I think that is one of the assets that you also mentioned, that with Iber, but also with Mezi, other than infections, grade 3 or higher adverse events are very uncommon. So I enrolled many patients in the maintenance study, EMN26, European Myeloma Network Study 26, and none of my patients on Iber needed, for diarrhea management, cholestyramine or Questran or cholesterol gel, drugs that you typically have to give to patients that receive lenalidomide maintenance.

So in terms of quality of life, diarrhea, there is really a difference. Fatigue, incidence of neuropathy, very different side effect profile.

Dr. Berdeja: Yes, that is a great point. I am just going to go back, we are not saying that if a patient has neutropenia and a fever or an infection, that you should continue therapy. But if it is truly just neutropenia, then, again, I think it is worthwhile to use the growth factors and not immediately hold or dose reduction.

Now, would you feel the same way if a patient is doing well on treatment and in cycle six they become neutropenic?

Dr. Krishnan: Yes, I think that I agree with Niels, too, because then it also depends how many dose reductions you have done. And that is where you are going to weigh that. If you have not dose-reduce at all, then sure, I am going to dose reduce and maybe see if I can get away with a little less growth factor then.

Dr. van de Donk: Do you agree?

Dr. Berdeja: Yes, so I agree. I think, again, at the initial first two cycles where we may have tumor burden, I think you are more tolerant of neutropenia and really pushing and doing growth factors. But if the patient is now in remission and now they are still becoming neutropenic at that point, you definitely probably should dose adjust.

All right. Anything else? Any final thoughts?

Dr. Krishnan: I guess I have a question, too. Do you think a PI is a better partner or a CD38 antibody for a CELMoD agent?

Dr. van de Donk: When you look at the mode of action, you would never have tried to combine CELMoDs with proteasome inhibitors, right? Because you need the degradation of Aiolos, Ikaros by the proteasome. So you would argue that the combination with the proteasome inhibitor is a very bad one.

But in the clinic, luckily enough, before we knew about the existence of cereblon, we tested this combination. And Len with bortezomib was very effective. And I think also Iber with bortezomib/dexamethasone in transplant-ineligible patients is very effective.

But also from the immune perspective, the combination with CD38 antibody looks very promising. I have some patients from the CC-220-MM-001 study that are still on Iber and CD38 antibody since many, many years with a very good quality of life. So I think it is also a very good combination, which we will learn more from when the data from EXCALIBER relapse/refractory study will read out.

Should we test T-cell exhaustion prior to starting a bispecific antibody in older patients, and can that help us in the future to make a better choice when it comes to combination strategy?

Dr. Berdeja: Should we do it? I think it would be nice to do it. But it would be nice to have a specific definition of what is likely to work and what is not likely.

I think we all kind of know, but it does not always pan out on everybody. And it is also, I think, difficult to do in real-time to do that. At least in the community, it would be very difficult to kind of get that information.

But ideally, yes. I mean, I think if we could identify the patient that is likely to respond versus not respond to a therapy, we definitely should do that, especially with these T-cell-directing therapies.

Dr. van de Donk: Yes, I think it would be nice to see which patients are doing very well with monotherapy because some patients with teclistamab or elranatamab or linvoseltamab as monotherapy achieve CR that is very durable, and they do not need a partner drug, which can also induce extra toxicity, and which patients are really doing better with daratumumab, with a CELMoD. So in the future, hopefully, this type of translational study will give us more information.

Where Do Iberdomide and Mezigdomide Fit in?

So where do Iber and Mezi fit in? Well, both agents have activity in IMiD-exposed and IMiD-resistant patients, as shown by Jesus. But the profiles of adverse events and relative opportunities are different.

So let us see how Mezi and Iber differ from each other and what are their similarities.

Comparing CELMoDs: Similarities vs Differences

So both Mezi and Iber are orally administered agents. They are effective in heavily pretreated patients, including those refractory to lenalidomide and pomalidomide. And they are all studied in early lines of treatment and in combination with other anti-myeloma drugs. The type of clinical trials where these agents are being evaluated is different. They have a different design, different partner drugs.

Another difference is that mezigdomide has greater cereblon binding potency and greater subsequent downstream anti-myeloma effects. However, this is at the cost of a higher rate of neutropenia, because iberdomide is probably more tolerable, especially when you give it as a long-term exposure because of the lower rate of severe neutropenia.

Potential Role of CELMoD Agents in the Future Treatment Landscape of MM in Earlier Lines of Therapy

So these agents probably have a different role in the future treatment landscape of myeloma. Iberdomide is probably a good option as a posttransplant maintenance therapy. When you think about maintenance, you want to give it for a prolonged period of time. And this is probably very well possible with iberdomide because of fewer non-hematologic adverse events versus IMiDs and a lower rate of neutropenia compared to mezigdomide.

On the other hand, mezigdomide has probably an important role in patients with poor prognosis, such as patients with high-risk cytogenetics, and in patients with extra-medullary disease. And of course, in combination with other drugs, mezigdomide has also a potential role as a relapse therapy in earlier lines of treatment.

In a perfect world, Amrita, where would you see the roles of the new CELMoD agent category?

Dr. Krishnan: I think in the maintenance setting, certainly replacing lenalidomide for the reasons you mentioned in terms of toxicity. And in the post-CAR relapse or post-BCMA therapy relapse setting, I would say there is a big space there for them as well.

Dr. Berdeja: So I have to say I think some people want me to say that at all stages of myeloma, we should be using them, but I actually have been intrigued by the patients who have progressed on BCMA and GPRC 5D-directed therapies immediately after those agents and then putting them on one of these agents and actually seeing some very impressive results. And so I think that is an unmet need, and I think that is actually a place where I would love to see them now if I had my hands on.

Dr. van de Donk: Absolutely. I also have that experience because when patients are BCMA, GPRC 5D-exposed, that is the true unmet need today. And I also saw very good results with iberdomide, and you showed some interesting results of mezigdomide in that setting.

Maybe they improve, again, T-cell function and thereby inducing these sometimes very durable responses post-bispecific or post-CAR T.

Thank you, Dr Berdeja, Dr. Krishnan, and Dr. van de Donk, and many thanks to you, our listeners, for joining us. As a reminder, to view the full program “Myeloma Myth Busters: Investigating the Now, Soon, and Future Clinical Implications of CELMoD Agents,” please click the link in the show notes. And be sure toa check back regularly for more episodes on important Decera Clinical Education Oncology Podcast topics!