Myeloma Myth Busters: Investigating the Now, Soon, and Future Clinical Implications of CELMoDs

 

So let me just start and level set, and I think this is good for level set, in terms of this session, but also just as we look towards this meeting and all the data that is going to come out in this meeting of the new agents, the trials, and the sort of state of where we are in myeloma.

 

So smoldering, I am not going to talk about because that, I think, as you have heard me say, myeloma doctors would rather talk about politics than talk about smoldering myeloma because I would say that is probably the most controversial thing we deal with right now.

 

Less controversial, I would say, and these 2 gentlemen can certainly feel free to disagree with me when we get to Q&A, is in terms of induction therapy. I think, really for most of us now, quad induction therapy is really the standard for most patients except for the frail, elderly patient.

 

The third point of this is in terms of the role of stem cell transplant. Certainly, I am a transplanter biased towards that, but I would say it still is a thing that right now offers us the longest progression-free survival and still remains a backbone of many of our treatments. Last thing is, of course, we are going to hear a lot of great data at this meeting in terms of T-cell engages, trispecifics, CAR Ts, new CAR Ts, and clearly these drugs are all active therapies, but even then, if you look at the amazing data we saw from, for example, CARTITUDE-1 with the long-term follow-up in terms of long-term progression-free survival, still the majority of patients are relapsing, so there is clearly a need for other therapies. Certainly, it is especially therapies that are not necessarily so T-cell dependent.

 

[00:12:14]

 

What Are the Unmet Medical Needs in 2025?

 

The other thing is we recognize there are categories of other unmet needs. Extramedullary disease remains a huge challenge for us, even with T-cell-directed therapies.

 

As I mentioned earlier, frail patients, again, another challenge of how do we optimize efficacy, but minimize toxicity for those patients. Then I would say really the issue also for us, now we are seeing this more and more, is patients who are resistant to the major targets. We have data at this meeting.

 

We are used to hearing about triple-cross refractory, then penta-refractory. There is a couple abstracts at this meeting now about hepta-refractory. What do we do for those patients?

 

[00:12:58]

 

What Are the New Options?

 

What are the new options? CELMoD agents are certainly 1 of those options, and we are going to delve into the preclinical rationale for that, and then Dr Berdeja is going to talk about some of the clinical trials supporting that. Of course, at this meeting, we are going to hear about new CAR T therapies.

 

There are multiple new ADCs as well with various targets in early phases of trial. Of course, we are very excited about the trispecifics as well. Really, I do not think any of these are going to be standalone necessarily in the future, and it is really, how do we optimize combination strategies to prolong remissions or to even recapture responses in patients who have had relapse.

 

I think this is a very exciting time for us in myeloma.

 

[00:13:42]

 

IMiDs Are Highly Effective in Combinations at All Lines of Therapy

 

Of course, looking back, this is no mystery now, that IMiDs really have been a very effective therapy for us, frontline, maintenance, and in the relapse setting.

 

[00:13:57]

 

Mechanisms of IMiD Resistance

 

But of course, patients do become resistant to IMiDs, and certainly in the second-line setting, many of the approvals are predicated upon being resistant to lenalidomide.

 

So why do patients become resistant to lenalidomide? We know some of this is dependent on cereblon, and cereblon, in terms of cereblon mutations, binding to cereblon, many different mechanisms, which Niels is going to sort of delve into a little bit further, so I am only going to touch the surface.

 

Also, extrinsic factors to the myeloma cell in terms of the immune microenvironment may also play a role in resistance.

 

[00:14:36]

 

CELMoD Agents Co-opt Cereblon via Unique Binding Features, Inducing Distinct Conformational Changes

 

CELMoD agents can overcome some of these resistance mechanisms, in part by the fact that they bind to cereblon more actively and putting it into the more closed conformation, which is the active conformation. As you can see, quite a significant difference in the degree of closed conformation between pomalidomide and Iber, for example. And again, we will delve into that a bit deeper in the next talk.

 

[00:15:07]

 

Iberdomide and Mezigdomide Affect Immune Cell Populations in the Bone Marrow Microenvironment

 

Also, I think for us as cellular therapy people, some of the excitement about these CELMoD agents is not just on the effects on the myeloma cell, but also the effects on the other immune cell population in terms of decreasing T-cell exhaustion and increasing T-cell activation. And indeed, and Dr Berdeja is going to sort of touch upon this in some of the trials in terms of use of these drugs in the maintenance setting. For example, we have a trial using mezigdomide in a post-CAR T maintenance setting for these very reasons in terms of its effects on T-cells.

 

[00:15:42]

 

Cemsidomide (CFT7455) Binds Cereblon, Facilitating Ubiquitination and Degradation of Key Proteins

 

And of course, cemsidomide, probably the newest kid on the block, we are going to talk more about that. But here again is preclinical data suggesting why we are, again, very excited about this drug is increased binding affinity to cereblon and activity in IMiD-resistant cell lines.

 

[00:16:01]

 

Topics to Discuss Today

 

So what we are going to talk about further today is what does this class of drugs offer over the existing therapies? I sort of touched a little upon that in terms of not being T-cell dependent. And how do we use them in appropriate combinations and appropriate settings, frontline, relapse, and in maintenance to optimize their activity and use?

 

So now I will turn it over to Dr van de Donk. Thank you.

 

[00:16:36]

 

Round 1 Continued: The Why and How of CELMoD Agents for MM

 

Dr van de Donk: Thank you, Amrita, for your introduction to my part of this first round.

 

[00:16:44]

 

Ubiquitin-Proteasome System (UPS)

 

Protein homeostasis is a very important thing for normal cells and for malignant cells. So the synthesis, the production of new proteins is highly regulated, but also the degradation of proteins is highly regulated.

 

And you know that because when you inhibit the proteasome in multiple myeloma, there is accumulation of proteins in the myeloma cells, and then these myeloma cells die. So protein homeostasis is of utmost importance. And when it comes to protein degradation, the ubiquitin proteasome system plays an important role.

 

On the left, you see in light blue, cereblon E3 ligase. It is a complex of different proteins. And this protein complex can bind to specific substrate molecules, specific proteins can dock to the cereblon molecule and subsequently become ubiquitinated, as you can see in the middle.

 

And once proteins have a ubiquitin tag, they are recognized by the proteasome, and these ubiquitinated proteins are subsequently degraded. This process is very specific. So some proteins can bind to cereblon and get a ubiquitin tag. And other proteins, like the yellow protein in this case, they cannot bind and therefore do not get ubiquitinated. So it cannot bind and does not become ubiquitinated.

 

[00:18:40]

 

Molecular Glues Can Hijack the UPS

 

Interestingly, we have now available in our clinic immunomodulatory drugs like Len and Pom and CELMoDs like Mezi and Iber that bind to cereblon to the thalidomide binding domain. And by doing so, the ability of cereblon to bind substrate molecules changes. For example, in this case, in the presence of an IMiD or in the presence of a CELMoD, the yellow protein is now able to bind to cereblon, becomes ubiquitinated, and now becomes degraded in the proteasome. So we can use IMiDs and CELMoDs as molecular glues, which enable us to remove difficult-to-drug proteins in tumor cells.

 

[00:19:34]

 

IMiDs Are Molecular Glues

 

To be more specific, when we talk about multiple myeloma, we know that in the presence of IMiDs and in the presence of CELMoDs, neosubstrates that are being ubiquitinated are Ikaros and Aiolos, and these are subsequently degraded. And this is relevant because both these molecules are critical transcription factors for B-cell health, but also for plasma cell health. And when they go down, this results in reduced expression of c-Myc, IRF4, and other molecules, and in the end, leading to myeloma cell death.

 

[00:20:14]

 

Protein Degradation in MM

 

So this is also shown in this figure. In the presence of CELMoD agents, you get ubiquitination of Ikaros and Aiolos, and subsequent degradation of these proteins, and that results in immune modulation, apoptosis, and inhibition of cellular proliferation.

 

[00:20:35]

 

Cereblon E3 Ligase Modulators

 

And that is also represented here. CELMoDs and IMiDs have direct anti-myeloma effects. They induce apoptosis, they inhibit proliferation, but importantly, they are also able to activate the immune system.

 

And I think that is very unique to IMiDs and to CELMoDs that are able to kill myeloma cells, but at the same time, they can improve immune function. Most of the other anti-myeloma drugs are not able to do both of these effects at the same time.

 

In terms of immune activation, we see T-cell activation, an increase in T-cell proliferation. We also see an increase in NK cell activation and improved NK cell proliferation. So these immunomodulatory effects make IMiDs and CELMoDs very interesting combination partners for, for example, bispecifics and CAR T-cell therapies, and we will discuss this in more detail later.

 

[00:21:37]

 

Novel CELMoD Agents in Development

 

Here you see on the left Len and Pom. We have been using these agents now for 2 or maybe even 3 decades, if you also include thalidomide. And on the right, you see the CELMoDs, iberdomide and mezigdomide, which were developed based on improved understanding of cereblon and myeloma biology.

 

[00:22:02]

 

Novel CELMoD Agent Iberdomide

 

Amrita already showed a little bit about the fact that cereblon, but also mezigdomide, are binding to cereblon, to the thalidomide binding domain, much more efficiently.

 

So you only need a few molecules of Iber and Mezi to bind efficiently to cereblon. And because they bind so efficiently, they are also able to induce a conformational change from an open to closed configuration. And this closed configuration leads to efficient degradation of the neosubstrates, Ikaros and Aiolos.

 

And in the table on the lower left of this slide, you can see that you need much lower levels of iberdomide to reduce Ikaros or Aiolos by 50% as compared to what you need for pomalidomide or lenalidomide. So you need 67x more lenalidomide to degrade the same amount of Ikaros, and you need even 90x more lenalidomide to degrade the same amount of Aiolos. So the CELMoDs bind more efficiently and are more effectively degrading these neosubstrates.

 

[00:23:22]

 

Degradation and Antiproliferative Activity of CELMoD Agents

 

And that is also shown in the figure on the left. You can see that lenalidomide and pomalidomide are able to reduce Aiolos levels, but at the same time you can see that Iber and mezigdomide are much more efficient at low concentrations, and they also reduce Aiolos to a much deeper level as compared to Len or Pom. And this also translates into a better anti‑proliferative activity of iberdomide and mezigdomide as compared to lenalidomide and pomalidomide.

 

The only cell line on the right of this slide that is not sensitive to Len, Pom, Iber and Mezi is the dark blue cell line, and that is a cell line that is made in the laboratory by knocking out cereblon. And you can imagine when you do not have cereblon, then neither of the CELMoDs or IMiDs is working. So it is a control cell line.

 

[00:24:27]

 

Iberdomide and Mezigdomide: Synergy With Other MM Treatments in Preclinical Studies

 

So CELMoDs and IMiDs have direct anti-myeloma effects. They induce apoptosis, they inhibit proliferation, and they are also very good combination partners for other drugs. Iberdomide, for example, can be well combined with bortezomib or carfilzomib, and this leads to better killing of myeloma cells as when you compare it to PI or CELMoD alone.

 

And Iber and a proteasome inhibitor is also more effective than pomalidomide and a proteasome inhibitor. Maybe a little bit surprising because I showed you before that the proteasome is also needed to degrade Aiolos and Ikaros, but apparently the extent of inhibition of the proteasome is not 100% all the time, and this allows still a synergistic combination of a CELMoD and a proteasome inhibitor. Not only in the lab, but you know that these type of combinations is also highly synergistic in our patients.

 

And on the right, you see that also mezigdomide is very effective in combination with a proteasome inhibitor and dexamethasone. And that is the green line. The green line is Mezi plus bortezomib and dexamethasone. This triple combination is much more effective in inducing cell death in myeloma cells as compared to either agent alone. And this forms a preclinical rationale for several ongoing Phase III trials that we will discuss in the other parts of this symposium.

 

[00:26:10]

 

Iberdomide Inhibits Proliferation in POM-Resistant Cell Lines

 

Importantly, and Amrita already alluded to that in her pretest question, CELMoDs are also effective preclinically and also in the clinic against myeloma cells that are resistant to lenalidomide or resistant to pomalidomide.

 

And this is also shown in a paper published in Leukemia 5 years ago by Björklund, where you can see on the left, upper left, that in KMS12BM cell line, Aiolos is efficiently degraded by pomalidomide. But in the variant that is made Pom-resistant by prolonged exposure, pomalidomide is no longer able to reduce Aiolos expression. In contrast, on the bottom left, you can see that both in the wild-type cell line and in the Pom-resistant variant, Aiolos is still degraded by iberdomide.

 

And this is seen in various pomalidomide-resistant cell lines. And this also explains why iberdomide, on the right, is still able to inhibit proliferation in most of the pomalidomide-resistant cell lines. And in red, you can see that some of these cell lines have very low levels of cereblon as compared to the wild-type that was still sensitive to pomalidomide.

 

Iber and Mezi are also effective in vitro, in preclinical models, against cell lines with low cereblon levels. And some of these also had mutations in the cereblon gene.

 

[00:27:52]

 

IMiDs Have Activity Outside Direct Myeloma Cell Targeting

 

Next to the direct anti-myeloma effects, so apoptosis induction, inhibition of proliferation, the IMiDs and CELMoDs also have immune modulatory effects. And importantly, at least in vitro models, the immune stimulation by Mezi and Iber is more potent than the immune stimulation that we see with lenalidomide or pomalidomide. And this immune stimulation is very broad. It is not only involving T-cell activation and induction of T-cell proliferation. It also involves NK cell activation and NK cell proliferation. But there is also improved presentation of antigen of peptides by dendritic cells to T-cells. So there is improved co-stimulation of T-cells.

 

And finally, IMiDs are also able to modulate stromal cells in that they become less supportive for myeloma cell growth. So multiple effects of IMiDs and CELMoDs on the immune system, which makes them very attractive partners for other immunotherapies, naked antibodies, bispecifics, and CAR T-cells.

 

[00:29:04]

 

Iberdomide Associated With T-Cell Activation and NK Cell Proliferation and Activation

 

And here you see some data from Mount Sinai. Samples were obtained from the CC220-MMO1 trial, in which iberdomide was evaluated in very heavily pretreated multiple myeloma patients. And you can see that in T-cells at cycle 2, Day 15, so after 6 weeks, there was an increase in HLA-DR, reflecting T-cell activation. There was an increase in Ki-67, which is a proliferation marker, also an increase in granzyme B, which is very important to kill target cells. And this was accompanied, interestingly, by a reduction in proteins that are associated with T-cell exhaustion and T-cell senescence. So next to activation, there is also a reduction in TIGIT, KLRG1, and CD57.

 

And in fact, the same can be seen in NK cells obtained from patients treated with iberdomide in this trial. Also here, we see more proliferation, a better killing capacity, as reflected by an increase in granzyme B. And also importantly, these NK cells have higher levels of CD16, which is the gamma receptor, which is very important for the activity of NK cells in the presence of naked antibodies like daratumumab and isatuximab.

 

And at the same time, also NK cells downregulate exhaustion markers like TIGIT and KLRG1 in the presence of iberdomide. And these type of changes, as I mentioned, is much more substantial with the CELMoDs than with the IMiDs, lenalidomide, and pomalidomide.

 

[00:30:50]

 

Conclusions

 

In conclusion, when it comes to mode of action, I think I tried to show you that CELMoD agents are very potent protein degraders. They can overcome lenalidomide and pomalidomide resistance in preclinical models. But Jesus will also show that CELMoDs are also effective against myeloma tumors that have become resistant to Len and Pom, so in heavily pretreated myeloma patients. And I showed you the rationale of why CELMoD agents are interesting partner drugs for new immunotherapies like post-CAR T as a maintenance strategy or in combination with a bispecific antibody. And there is also synergy with proteasome inhibitors, and I did not show you also with CD38 antibodies.

 

[00:31:46]

 

Let's Return to an Earlier Question

 

I already mentioned that some of these questions will come back to see if there is an increase in the good answer. And let us go back to 1 of these questions.

 

[00:31:57]

 

Posttest 1: Which of the following best describes the properties of novel CELMoD agents vs IMiDs in regulating myeloma cell proliferation?

 

Posttest 1, that is the question about which of the following best describes the properties of novel CELMoD agents vs IMiDs in regulating myeloma cell proliferation.

 

1. Higher cereblon affinity, increasing pro-differentiation transcription factor expression;
2. Higher cereblon affinity, enhancing prosurvival transcription factor degradation;
3. Lower cereblon affinity, reducing off-target effects and promoting immune cell activation; or
4. Bypass cereblon and directly reduce prosurvival signaling and enhance immune cell activity.

 

We see here the pretest. Before round 1, 70%, 68% had a correct answer, and now it is 96%. So I think a substantial increase.

 

[00:33:10]

 

Poll 5: Which of the following questions would you like the experts to discuss further?

 

And then you can, well, to make the symposium a little bit more interactive, you can choose what you would like to debate during the last 2 or 3 minutes.

 

1. Is there a rationale for combining CELMoD agents with an anti-CD38 antibody or a proteasome inhibitor;
2. Could CELMoD agents enhance immune activation in combination with CAR T-cell therapy or bispecifics; or
3. Should or could CELMoD agents replace IMiDs.

 

Two stand out, but we have to move forward with the second question. 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 1 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 1 question for my clinic. Last week, 2 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 1 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 1 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.

 

All right. I think we have to switch to the second part. We are a little bit behind schedule, but Jesus can talk very fast.

 

Dr Berdeja: I can.

 

Dr van de Donk: Jesus, it is to you now.

 

[00:40:49]

 

Round 2: Emerging Data, Early Disease: CELMoD Agents in Maintenance and Early-Relapse Settings

 

Dr Berdeja: All right. So we have heard all these great things about these drugs, but do they actually work? We have no idea. We have not seen any data whatsoever.

 

So here we go.

 

[00:40:59]

 

Poll 6: Which of the following statements is a myth about the clinical trial data with iberdomide and mezigdomide?

 

So we will start with a truth and myth. Which of the following statements is a myth about the clinical trial data with iberdomide and mezigdomide?

 

1. Mezigdomide is currently being assessed in a Phase III trial in combination with Dara as maintenance therapy for multiple myeloma;
2. In a multicohort Phase I/II trial in transplant-ineligible patients with newly diagnosed multiple myeloma, iberdomide was associated with an overall response rate of 95% when combined with Dex and Dara; or
3. Neutropenia is the most common grade 3/4 AE associated with iberdomide and mezigdomide.

 

So which is your myth?

 

It is like 30%, 30%, 30%. I am very disappointed. A is the myth. Mezi is currently being assessed in a Phase III trial in combination with Dara as maintenance therapy for myeloma. And I will show you that that is not the case.

 

[00:42:18]

 

CELMoD Agents in Development

 

So there are no FDA-approved CELMoD agents for myeloma at this time. But there are 3 CELMoDs or protein degraders that have clinical data, iberdomide, mezigdomide, and cemsidomide.

 

[00:42:32]

 

Initial Proof of Activity

 

These are the 3 trials, the phase I trials that kind of got the initial proof of concept.

 

[00:42:39]

 

CC-220-MM-001: Iberdomide for R/R MM

 

We will start with iberdomide with a CC-220-MM-001 trial, which looked at many cohorts, but we will concentrate right now on the orange and blue boxes, which are the monotherapy and the monotherapy with dexamethasone.

 

And so, here, iberdomide was given on days 1 through 21, Q28 days, with a dose escalation from 0.3 mg to 1.6 mg, with the RP2D being 1.6 mg with dexamethasone in the combination trial of 40 mg weekly or 20 mg weekly for older patients.

 

As you know, usually these agents tend to do better with dexamethasone. So if we actually look at the cohort D, which is iberdomide and dexamethasone, those patients required to have at least 3 prior lines of therapy, prior Len, Pom, PI, anti-CD38 antibodies.

 

[00:43:36]

 

CC-220-MM-001: Baseline Characteristics and Prior Therapy With Iberdomide + Dex

 

107 patients were treated in this cohort, with 30% showing high-risk cytogenetics. But you see on the right that the median prior lines is 6, so pretty heavily pretreated. But more importantly, 100% of these patients are IMiD refractory, almost 100% were PI refractory, 100% were anti-CD38 refractory, and obviously almost 100% triple-class refractory by definition.

 

[00:44:06]

 

CC-220-MM-001: TEAEs With Iberdomide + Dex

 

When we look at the toxicity profile, I think the most salient thing, and this will become a recurrent theme, is that the most common AE for iberdomide is neutropenia. 60% of patients had neutropenia, with 25% grade 3, 20% grade 4. Other cytopenias as well, but not as prominent as in neutropenia.

 

But I think what I am most intrigued by is the middle box here, which is the non-hematologic toxicity, and you see that there is actually very little. So in terms of fatigue, diarrhea, the usual GI things that we think of, rash, is 20%, and all really grade 1/2, which is a little bit different than what we are used to with the IMiDs. Infections, unfortunately, because of neutropenia and the relapse/refractory setting, we are seeing mostly respiratory tract infections.

 

[00:45:02]

 

CC-220-MM-001: Iberdomide + Dex (Cohort D) Efficacy

 

The overall responses were 26.2%, but before, and the PFS was, they put it in weeks here, which I do not like, but 13 weeks, about 4 months or so, median duration response was 30.3 weeks. And so before you walk out of this room, I remind you that these are the kind of numbers that we saw with pomalidomide when it was approved, with daratumumab single-agent when it was approved, and even belantamab vedotin when it was approved. So these do not look as impressive as the CAR Ts and the bispecifics, but as an agent itself, these are the numbers we would expect. And also, this is a much more refractory population than what we are used to. These are still very active drugs, in my opinion.

 

[00:45:52]

 

EMN26: Iberdomide Maintenance After ASCT in NDMM

 

So much so, that Dr van de Donk and his group basically decided that this was good enough to look at it in the maintenance setting posttransplant. So the EMN-26 trial looked at iberdomide at different doses in patients who had newly diagnosed myeloma and had achieved response, underwent, after induction, with a PI + IMiD and then transplantation, and the goal was to see if you can basically improve on that response. That was the primary endpoint.

 

[00:46:24]

 

EMN26: Baseline Characteristics and Prior Treatments

 

And so you see here, you are looking at the 3 different dose levels of 0.75-1.3 in each column, and the main thing I will say here is that the majority of patients on the right here had a VGPR or better at the time of study entry, and about half the patients were MRD-negative.

 

[00:46:44]

 

EMN26: TEAEs in Cycles 1-12

 

This is the toxicity, and again, the main thing, it is in the very top, grade 3/4 neutropenia was seen in 52% and 45% when you drop the dose a little bit at 1.0 mg. And then the non-heme toxicity, again, 20% or less, mostly grade 1/2.

 

[00:47:08]

 

EMN26: Response Improvement

 

This is the response. You see that on the left you have the response improvement. So basically, on the different cohorts, you see that about 30-60% increase in the depth of response with the addition of iberdomide, and on the right, you see the MRD conversion. Basically, about 30-50% of patients improved from MRD-positive to MRD-negative.

 

[00:47:35]

 

EMN26: Progression-Free Survival

 

And obviously, survival, these are small numbers, but Dr van de Donk actually will present or update this data tomorrow at 10.30, so if nothing else, please show up to heckle him in case you feel like this is too much CELMoD already.

 

So anyway, so this is good, and I will show you that this led to now a Phase III trial.

 

[00:47:52]

 

CC-92480-MM-001: Mezigdomide + Dex for Patients With R/R MM

 

What about mezigdomide? So mezigdomide was looked at in the CC-92480-MM-001 trial, and this was in patients with 3 or more prior lines of therapy, prior Len, Pom, PI, anti-CD38. The RP2D was mezigdomide of 1 mg per day, days 1 through 21, Q28 days.

 

[00:48:20]

 

CC-92480-MM-001: Baseline Characteristics and Prior Treatments (Dose Expansion)

 

And so you see the baseline characteristics, 101 patients.

 

I will point out that 40% of the patients had extramedullary plasma cytomas, 37% high-risk cytogenetics. And then if you look on the right, these patients were heavily pretreated, 6 prior lines of therapy, and lots of 100% there. So 100% IMiD-exposed and IMiD-refractory, 100% PI-refractory, 100% anti-CD38-refractory, and 30% of the patients have had prior anti-BCMA therapy. So very heavily pretreated population.

 

[00:48:54]

 

CC-92480-MM-001: TEAEs (Dose Expansion)

 

And you look at the toxicity profile. Again, on the left, the hematologic toxicity. Again, neutropenia is the most salient thing, 77% neutropenia with 54% grade 4, so it seems a little bit worse than iberdomide.

 

Granted, it is an even more heavily pretreated population, but I think that is what we have seen with these 2 agents, that maybe Mezi has a little more neutropenia. But in terms of the other toxicities on the right, aside from the upper respiratory infections, you see everything is 20% or less, and mostly grade 1/2.

 

[00:49:30]

 

CC-92480-MM-001: Response Rates With Mezigdomide + Dex (Dose Expansion)

 

The response rate for the whole group, on the left here, is overall response rate of 40%. And what is interesting, if you move to the 2 subgroups, so patients with extramedullary disease, which is a difficult group to treat, a response rate of 30%, and then patients with prior BCMA therapy, a response rate of 50%, a PFS of 4.4 months and a median duration of 7.6 months.

 

[00:49:54]

 

CFT7455-1101: Cemsidomide + Dex for Patients With R/R MM

 

What about cemsidomide? So this also was tested in a very similar highly refractory population, and looking at dose escalation from 37.5 ug to 100 ug a day, and the schedule's a little bit more different here. It is daily for 14 days and then 14 days off.

 

[00:50:12]

 

CFT7455-1101: Baseline Characteristics and Prior Therapies With Cemsidomide + Dex

 

And patient characteristics, the main thing, I will go to the right because I think that is the most interesting profile here.

 

So again, 7 prior lines of therapy. But if you go all the way to the bottom, you see that these patients were 100% triple-class exposed, and 75% prior BCMA therapy, and 50% prior GPRC5D therapy, so a very heavily pretreated population as well.

 

[00:50:42]

 

CFT7455-1101: TEAEs With Cemsidomide + Dex

 

So in terms of toxicity, I sound like a broken record, neutropenia. So this, unfortunately, is expected. Cereblon is important for neutrophils as well, so binding it does affect them. 61% neutropenia with 24% grade 3, 33% grade 4. Infections, again, upper respiratory infections, and about 20-30% of the non-hematologic toxicities like diarrhea and fatigue.

 

[00:51:18]

 

CFT7455-1101: Efficacy With Cemsidomide + Dex

 

This is the efficacy. So to the very right, you see a response rate of 34%. But if you look at just sort of the group with the highest dose, which is the recommended Phase II dose of 100 ug per day, it is looking like 50% response rate, so that is not too bad.

 

[00:51:35]

 

Combinations Data: Beyond Single-Agent Activity

 

So what about beyond single agents? In my lab, we do not do anything with single agents except maybe CAR T. Even bispecifics, everything combined. Now, you see that a lot in this meeting this year.

 

[00:51:44]

 

CC-220-MM-001: Iberdomide for R/R MM

 

So what about combination? Because that is where we need to go.

 

So if we look back to iberdomide, back to CC-220-MM-001, you see that cohort E, F, G on the left there in orange are combinations. E is with Dara and Dex. F is with bortezomib and Dex.

 

And G is with carfilzomib and Dex. And then on the right, you actually see some newly diagnosed cohorts as well.

 

[00:52:11]

 

CC-220-MM-001: TEAEs With Iberdomide Combinations

 

So this is the relapse cohort in combination.

 

So the first column is the data I presented before with the Iber-DEX. And then you have Iber-DEX-Dara next to it, followed by with bortezomib and then carfilzomib. And the main thing here is that basically you do not see too much overlapping toxicity.

 

You do see the emergence of some of the toxicity expected from the other agents, like peripheral neuropathy with bortezomib. Surprisingly also with the carfilzomib arm, which I do not understand too well. But nothing too dramatic in terms of sort of extra toxicity with the combinations.

 

[00:52:49]

 

CC-220-MM-001: Responses With Iberdomide + Dex + Daratumumab (Cohort E)

 

These are the response rates with Iber-Dex-Dara in the relapse/refractory population. You see an overall response rate of 46%. And many that are ongoing.

 

[00:53:02]

 

CC-220-MM-001: Iberdomide for NDMM

 

So based on that, they decided to enroll cohort K, which actually is the same triplet but in the newly diagnosed transplant-ineligible population.

 

[00:53:14]

 

CC-220-MM-001: TEAEs With Iberdomide + Dex + Dara (Cohort K)

 

And this is the toxicity profile. Again, neutropenia in 80% of the patients. 40% grade 4. But very little febrile neutropenia. But again, infections, mostly upper respiratory. And then on the right you see the non-hematologic toxicity, 26-30% of rash and fatigue, etc.

 

[00:53:36]

 

CC-220-MM-001: Efficacy With Iberdomide + Dex + Dara for TNE NDMM (Cohort K)

 

But this is what the impressive part is. So the overall response rate in this group cohort is 95% with a CR or better rate of 68%. So this actually looks much better than what we are used to with this kind of agent combination. MRD negativity of about 48% and an MRD-negative CR rate of 42%.

 

[00:54:03]

 

GEM21menos65: Iberdomide + Isa-Vd for Patients With Transplant-Eligible NDMM

 

So based on that and some other data, the Spanish group has started this large randomized trial called the GEM21menos65.

 

The patients are transplant-eligible and they either receive iberdomide, Isa, bortezomib, and Dex vs Isa, lenalidomide, bortezomib, Dex, or Len, bortezomib, Dex.

 

Patients then all go through transplant. You do 2 cycles of consolidation, which is like our standard of care where they are quadruplets, and then maintenance either with Iber, Isa, Dex, Isa-RD or RD.

 

This trial's primary endpoint will be MRD-negative rate, and the secondary endpoints will actually be PFS and ORR. So again, now we are starting to see trials where MRD is becoming the primary endpoint.

 

[00:55:17]

 

EXCALIBER Maintenance: Iberdomide vs Lenalidomide Maintenance After Primary MM Therapy + ASCT

 

This also has led to now 2 randomized trials with iberdomide. So the EXCALIBER trial is EXCALIBER maintenance trial, which is patients who have undergone their induction and transplant and then are randomized to either iberdomide or lenalidomide.

 

This is a very large trial of over 1,000 patients with the primary endpoint being PFS and secondary endpoints of MRD and overall survival, etc.

 

[00:55:44]

 

EXCALIBER RRMM: Iberdomide + Daratumumab + Dex vs DVd for R/R MM

 

There is also EXCALIBER relapse/refractory trial, which is looking at iberdomide, daratumumab, and dexamethasone vs daratumumab, bortezomib, and dexamethasone, 664 patients with, again, the primary endpoint being PFS and MRD-negative rate.

 

This trial actually has completed accrual, so we are just waiting for the data to mature, but we should hopefully see presentations and meetings soon. And I would argue that if this is a positive trial, this actually might get Iber approved for us in this setting.

 

[00:56:30]

 

CC-92480-MM-002: Mezigdomide Combination Therapy R/R MM

 

What about mezigdomide? So mezigdomide also has been combined. So we go back to, actually, this is the MM-002 trial. So cohort A was mezigdomide with bortezomib, dexamethasone, and then cohort C was mezigdomide with carfilzomib and dexamethasone.

 

[00:56:46]

 

CC-92480-MM-002: Baseline Characteristics and Prior Therapies

 

And so, again, we look at those triplet combinations, and you see they are actually a different inclusion, so just kind of keep that in mind.

 

If we look at the right again, you see that the median prior lines for the Mezi-Vd arm is just 1 vs 2 for Kd, and the refractoriness is higher for the Kd cohort as well. If you look at usage of anti-CD38, 40% in the Mezi-Vd arm vs 81% in the Mezi-Kd arm. And then, same with refractoriness, 34% vs 74%.

 

Triple-class refractory, 2% vs 37%. So difficult to compare the 2 arms. One is much more heavily pretreated.

 

[00:57:32]

 

CC-92480-MM-002: Dose Escalation Efficacy

 

But nonetheless, you see here on the left, the Mezi-Vd arm, you have an overall response rate of 86% with a median duration of 19 months with a median PFS of 20.8 months. And then the Mezi-Kd with an overall response rate of 85%, with a duration of response of a year and a median PFS of 11.7 months.

 

[00:58:00]

 

CC-92480-MM-002: Mezi-Vd Dose Expansion Efficacy

 

And so this is just the dose expansion of the Mezi-Vd arm. You see the overall response rate is maintained around 82% in many patients with ongoing responses.

 

[00:58:11]

 

SUCCESSOR-1: Mezigdomide + Bortezomib + Dex vs PVd for R/R MM (1-3 LOT)

 

And so this has led to the SUCCESSOR-1 trial, which is Mezi-bortezomib and dexamethasone vs pomalidomide, bortezomib and dexamethasone in patients with 1-3 prior lines of therapy. So again, patients had to have had 1-3 prior lines, being progression and have included prior pomalidomide, but they cannot be PI refractory.

 

And so patients within randomized Mezi-bortezomib and dexamethasone vs pomalidomide bortezomib and dexamethasone with the primary endpoint of this trial being PFS and secondary endpoints of OS and ORR, MRD negativity, etc.

 

[00:59:02]

 

SUCCESSOR-2: Mezigdomide + Carfilzomib + Dex vs Kd for R/R MM ( ≥ 1 LOT)

 

There is also the SUCCESSOR-2 trial, which takes the other combination of mezigdomide, carfilzomib, Dex vs carfilzomib, Dex. And so this is in patients with at least 1 prior line of therapy with PD, and they must have had prior lenalidomide, prior anti-C38 antibody, and no prior carfilzomib.

 

So again, I am not really telling you about the stage I, but basically, the FDA forced us to do different doses with the combination just to kind of then pick the best dose and then move forward to stage II. So both of these trials are in stage II, which now are looking at the Mezi combination carfilzomib-Dex vs carfilzomib-Dex with the primary endpoint of PFS. And the secondary endpoints, the same overall survival response rate and MRD negativity.

 

[01:00:06]

 

Notable ASH 2025 Abstracts

 

So here at this ASH, we are going to have quite a bit of data, and I think it is actually good. I listed the trials or the presentations that include some of the CELMoD agents, and I think what you see, at least with the first 1, is we are starting to see now bispecifics in combination with the CELMoD.

 

So the first 1 is cereblon in combination with iberdomide in patients with relapsed/refractory myeloma, and that is going to be presented by Dr Suvannasankha tomorrow as well. And then if you actually go all the way to the second to last, 5835, is basically mezigdomide with elranatamab by Dr Byun. And so, obviously, we were talking earlier about which of these makes more sense in combination. I think it would be interesting to see what the toxicity profile and efficacy, just even with these 2, since the only difference is Iber vs Mezi. There will also be some very interesting combinations with some other novel agents.

 

So there is presentation 249, is actually going to be looking at patients with translocation 1114 with the use of venetoclax, iberdomide, and dexamethasone. So I think that is actually very intriguing. That will be Dr Sim on Saturday at 14.30. And then 4010, it is actually looking at selinexor, mezigdomide, and dexamethasone in patients with relapsed/refractory myeloma who are not eligible for T-cell-directed therapy. And that is by Dr Mo on Sunday, December 7^th. That is actually very interesting because both selinexor and mezigdomide have immune-modulating therapies, improve T-cell fitness.

 

It will be interesting to see what this combination is doing. And I would argue that if this is tolerable, this actually may not be a bad combination to also think about with our T-cell-directing therapies. And then there are other trials that are going to be updating some of the triplet combinations.

 

And then there is an actually interesting trial, number 251, which is looking at iberdomide, carfilzomib, daratumumab, dexamethasone, so quadruplet therapy for patients in relapse. And that is called the REKINDLE Study. That is going to be by Dr Diamond Saturday. So lots to go and look, so please peek at these presentations. I think they will be worthwhile.

 

[01:02:58]

 

Poll 7: Which of the following questions would you like the experts to discuss further?

 

So now, see, they are not even paying attention, so I am going to call on them. So please make it the hardest 1 to see what you want our experts to talk about. So which of the following questions would you like the experts to discuss further?

 

1. Are CELMoD agents active against extramedullary disease?
2. Do dose modifications affect CELMoD agent efficacy?
3. How best to manage neutropenia and other AEs frequently associated with CELMoD agents?
4. Which ASH abstracts focused on CELMoD agents are you most interested in?

 

So people want to know which abstracts are you most interested in.

 

Dr Krishnan: Well, I guess I am going to go with the Elra-Mezi combination, really, to your points. One, I want to know about toxicity. I do not, to be honest, know the details of did they stop Elra, continue Mezi, or how were they able to continue both in the infection profile, to Niel's point. If you now have neutropenia and B-cell depletion, is that a challenge?

 

[01:04:46]

 

Additional Questions?

 

Dr Berdeja: Yes, and you?

 

Dr van de Donk: Yes, I am also looking forward to the Elra-Iber combination, Elra-Mezi combination. Hopefully they will also show some translational data on whether T-cell exhaustion is indeed prevented, mitigated, by adding a CELMoD to the bispecific antibody. And I think, if I remember correctly, the CELMoD is already added to elranatamab from the very beginning.

 

While with pomalidomide, we typically did this in combination with other bispecifics from cycle 2 on, because we were scared of cytokine release syndrome. But I think here it is all together from the very beginning. So I am also curious to see the CRS profile.

 

Dr Krishnan: And I guess my other point, actually the first question, would be what is happening with Em-D when you do that? Because we know, obviously, with bispecifics, still the response in PFS with Em-D is lower. These drugs clearly have, especially Mezi, have activity in Em-D. So with that combination, is that going to be the new strategy for Em-D?

 

Dr Berdeja: Yes, and I think that is interesting. Because there you are actually thinking of the CELMoD also as part of the activity. You actually want the activity, as opposed to what we talked about with the CAR T's, where it is mostly about the CEL, the immune modulations.

 

So I think that will be interesting. I agree with you. I think, hopefully, these combinations will help us overcome some of the challenges we have seen with just the bispecifics.

 

I am actually going to pick 1 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 1 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 1 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 1 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 6 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 2 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 velcade was very effective. And I think also Iber with velcade 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 vs 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.

 

Dr Berdeja: So maybe we will save some of the questions for later, and then we will move on. But thanks. That was an excellent discussion. So thank you.

 

[01:14:26]

 

Lightning Round: MRD – Trial Endpoint or Clinical Tool?

 

But we are going to move on now to the lightning round, the MRD trial endpoint or clinical tool. And this is Dr Krishnan once again.

 

Dr Krishnan: Thank you. I guess that means I have to speak very quickly if it is lightning round now.

 

[01:14:43]

 

Poll 8: Which of the following is a myth about MRD?

 

So I think let us start with our 2 truths and a myth.

 

1. FDA ODAC has voted in favor of MRD-negative CR as an early clinical endpoint;
2. MRD-negative rate is a primary endpoint in specific CELMoD agent clinical trials;
3. NGS is preferred over NGF for evaluating MRD negativity.

 

So we will touch a little bit about this, that they are actually both methods, NGS and NGF, have advantages and disadvantages. It is not really 1 is preferred over the other. It is, again, depending on capacity at your center, how you make that decision.

 

And MRD-negative rate, some of the trials that Dr Berdeja talked about, you know, I was happy to see that they listed MRD as a primary endpoint, sometimes as a co-primary endpoint. And that is in part, of course, because of the FDA ODAC ruling allowing that as a valid clinical endpoint.

 

[01:16:08]

 

MRD Wish List

 

I guess we are coming up Christmas, so we put this talk together sort of thinking about what is your wish list. And I cannot even remember if you guys remember, maybe it was 7-8 years ago, I cannot remember when MRD was still not sort of widely clinically used. We said why not, and what are the things we want for MRD? And so, we wanted a test that was sensitive.

 

We wanted, probably even equally important, was something that was standardized. Because you cannot have something among different trials with different levels to be able to interpret what that means.

 

Of course, widely available, cost-efficient. I think that is, you know, again, a little bit more debatable what constitutes cost efficient. And ultimately, really, of course, accepted by the FDA. And so the good news is, as we will get into, we do have that now. We have tests that are standardized, widely available, and accepted by the FDA.

 

So then we moved on to our next wish list, which is the current wish list, we want all the clinical trials to incorporate MRD testing. And as you have seen from Dr Berdeja, they have indeed done that. Generally, I think, accepted. And, you know, I made the statement at the beginning that induction therapy with quads, transplant is a backbone of our myeloma therapy, in part because of this goal of getting sustained MRD negativity.

 

So then we became sort of more greedy and said, fine, we have all that. We have these goals. We have MRD testing. We now want to use MRD testing to guide our clinical decision-making. And so that is where now I think where our future is. And we can have that discussion, really, about how we are doing that in the current state and later, actually, in the future state.

 

[01:17:56]

 

Myeloma Response Criteria

 

One can say myeloma response criteria has improved over time, and become more widely available, quicker, more sensitive, better. So we have to adapt, per se.

 

[01:18:11]

 

IMWG Criteria for MRD in Multiple Myeloma

 

And certainly the IMWG has adapted to that as well in terms of, of course, now looking at MRD-negative as a CR. And you can see they have both. So they have it by sequencing, and they have it by flow.

 

I am not going to read this to you, but you do also have to just understand that there is some nuance to calling something MRD-negative. And that is both in the flow setting and also even with next-gen sequencing. So the biggest thing I would say here is sample quality matters.

 

And so when you look at an MRD report, you really have to do it in the context of was this a truly good sample to be able to call something MRD-negative? So this is, you know, from Dr Fonseca. And I like this because he sort of makes the point, I think we have not stopped doing chest X-rays because we have chest CTs, right? So both have a place. So, for example, yes, we still use blood serologic markers to assess response in myeloma. But we also have more sensitive tests that have the role, specifically, of course, MRD.

 

[01:19:32]

 

Immunoglobulin Loci Can Be Used to Quantify and Track Immune Cells Over Time

 

And so, this is just, of course, for the next-gen sequencing, how MRD works.

 

[01:19:39]

 

Monitoring Technique for Myeloma

 

You have a trackable sequence from the immunoglobulin, a unique sequence that I am going to show you a little bit later that we then identify at baseline and then use that, track that sequence in subsequent bone marrows.

 

Now, you know, getting back to my chest X-ray vs chest CT point, it is kind of the same thing, right? So in a way, blood-based markers are like your chest X-ray, easy to get, quick, you can do it all the time.

 

MRD testing right now is still marrow-based, so it takes a little more effort, right? It is like getting your chest CT. More effort, more time. And so that is in part why we do not do that as sort of our routine monthly monitoring of patients.

 

Of course, there are multiple studies and trials and technologies trying to look now at MRD in the peripheral blood, as well as more sensitive markers of even just detecting monoclonal proteins in the peripheral blood. So how we assess response currently, relying on marrow as our most sensitive test, is probably not going to be the future.

 

[01:20:58]

 

Flow Cytometry

 

Flow cytometry. As I said in the 2 truths and a myth, really one can use either one, and it depends on what your capabilities are at your institution. So the proof of flow cytometry is you do not need to get that baseline trackable sequence. You can do flow at any time point, but, you know, it has to be a fresh sample. You need probably a larger volume to get enough cells to be able to do flow, and you need to have a pathologist who is very experienced to be able to interpret that flow. There are multiple things, so it is a real commitment from your own institution or the lab that you use to that.

 

[01:21:44]

 

Next-Generation Sequencing

 

Next-gen sequencing, in a way, is a little bit easier. As I said, it is looking at a trackable sequence on the immunoglobulin. So you need to identify that sequence from the baseline specimen. The good news is it can be done on stored samples, so you certainly have longer turnaround time for that.

 

Analysis does take time, but I would say generally the turnaround time from the reports that we get has really become much quicker. You need a smaller volume of sample as well. So for our institution, we use next-gen sequencing as our method to detect MRD, and we will hear from my colleagues what they do at their institutions.

 

[01:22:28]

 

Evaluation of MRD as Surrogate Marker for PFS

 

Now, why are we so sort of focused on MRD? Because we now know from meta-analysis it is a surrogate endpoint for progression-free survival, and this was on multiple studies, and I will not go into the details, but you can see that, again, with large numbers of patients, over 8,000 patients, we validated this as a surrogate endpoint.

 

[01:22:51]

 

MRD in Recent Phase III Trials in Transplant-Ineligible NDMM

 

And this is important as we look at more and more therapies.

 

So going back to my initial comment, quad induction, transplant, or quad induction in the non-transplant patients really has become our standard of care. And because of those intensive inductions, at least half of our patients are now becoming MRD-negative. And even more important is the point that the progression-free survival with these intense therapies in the up-front setting has greatly lengthened.

 

[01:23:24]

 

Many Years to Show Significant Effect of New Therapy on PFS

 

And so, really, if you are going to test a new therapy, if you have regimens now with medium progression-free survivals of 5, 6, 7 years, you are going to be waiting a long time, if that is your control arm, to see a benefit of an experimental therapy. And no one wants to wait a decade for an experimental therapy to read out, right? So that is why we need endpoints that can be measured sooner.

 

[01:23:52]

 

EVIDENCE Meta-analysis of MRD as an Intermediate Clinical End Point For Multiple Myeloma

 

And now that we have validation of this, and this was some of the data that was presented to the FDA of a meta-analysis. This is Ola Landgren's work done on 16 data sets. And you can see here, again, 5,000 newly diagnosed patients, about 3000 relapsed/refractory. He looked at it in both settings, at individual patient-level associations as well as trial-level associations.

 

[01:24:22]

 

EVIDENCE Meta-analysis: Individual-Level Association

 

And you can see, again, the meta-analysis showed that MRD continued to hold true as a surrogate for progression-free survival and overall survival, both in transplant-eligible and transplant-ineligible patients. And so this is probably part of the reason that the FDA approved this as a valid surrogate endpoint.

 

[01:24:48]

 

MRD in Patients With R/R MM Treated With CAR T-Cell Therapy

 

We know, of course, in CAR T here, in fact, we see MRD negativity as really the most early endpoint for us. And again, it remains a surrogate for progression-free survival.

 

[01:25:03]

 

FDA Industry Guidance on Regulatory Considerations for MRD

 

And here, again, it was exciting for us. April 2024, ODAC voted in favor of MRD-CR as an early endpoint in myeloma clinical trials to support the accelerated approval of new treatments based on some of the data that I showed you.

 

[01:25:21]

 

MIDAS: MRD-Adapted Therapy After Induction Isa-KRD for Transplant-Eligible NDMM

 

So then the question on our wish list became, great, now we have it as an endpoint, but in the current state, how do we use it to guide our clinical decision-making?

 

So I would say this is where trials are starting to read out and give us some sense of this. And the MIDAS trial that was presented last year is 1 of those trials where patients, again, who became MRD-negative (10^-5) were randomized to a transplant arm or a non-transplant arm. And then MRD was looked at again at the next time point post that.

 

I do not think I put the results of that trial in, but, of course, they were similar between the transplant and non-transplant arm. So raising the question again, I am not going to debate this trial yet, but just to see now this idea that we are using MRD to guide our clinical decision-making.

 

[01:26:16]

 

PERSEUS: VRd ± Daratumumab in Transplant-Eligible NDMM

 

Of course, PERSEUS also, again, you can remember quad induction, transplant consolidation, de-escalation of maintenance. But the other important thing is after patients are de-escalated from Dara-Len maintenance to Len alone, they could be re-escalated and daratumumab restarted upon loss of CR or MRD recurrence. So, again, this idea that using MRD to guide our therapy, either to de-escalate or escalate therapy.

 

[01:26:50]

 

DRAMMATIC: MRD-Guided Maintenance Therapy

 

And the DRAMMATIC trial, which completed accrual in January of this year, we are waiting for a readout. But this trial is using it to de-escalate and not just de-escalate, but actually stop therapy. So patients who are MRD-negative at 2 years are randomized to either continuing their maintenance on whatever arm they were on or stopping maintenance.

 

[01:27:14]

 

Did We Get Our MRD Wish List?

 

I would say we, in the future, are really going to get our wish list, which is that we have all the trials have incorporated MRD testing, and most of them now is a primary, a co-primary endpoint.

 

And now we are starting to use MRD to guide our clinical decision-making. So, thank you. And now we will go into the hot seat questions.

 

[01:27:42]

 

Poll 9: Which of the following questions would you like the experts to discuss further?

 

And the first one, which one would you like us to discuss further?

 

1. Should MRD status guide therapy decisions in practice outside of clinical trials?
2. What are the prognostic differences between MRD-negative CR vs VGPR?
3. Should MRD negativity be used as an endpoint for studies with high-risk myeloma?
4. Can patients with sustained MRD negativity stop taking their CELMoD agent?

 

Seems to be a theme here going on. So I am going to go pick, so I guess I get to pick this. I am going to pick the first one because we already could have started this. But let us see, should MRD guide us now outside of the clinical trial?

 

All right, gentlemen, which one of you wants to?

 

Dr Berdeja: So the answer right now is probably not. The way I use MRD for patients is to sort of say, "Great, you have achieved that. You are in a good position. You are going to be doing great." The question becomes, we do not know from the prior trials if the reason that person may be on this trajectory is because they continued their therapy. So at least for now, I feel uncomfortable unless the patient's having toxicity.

 

And I think that is where I really use MRD, is a patient that is on maintenance, for example, lenalidomide, and they have sustained MRD and they are having a lot of toxicity. I feel more comfortable stopping therapy than if they are still MRD-positive. So even though, you know, I think we have some data to maybe help us decide that, I think that is really where I use it. But I am not sure we are quite at the point where we can use MRD to really guide all decision-making.

 

Dr Krishnan: And then I will let Dr van de Donk have the last word.

 

Dr van de Donk: Well, I have a little bit the same practice. I also weigh risk, cytogenetic risk. I feel more comfortable to stop in patients that are sustained MRD negativity during Len maintenance if they have standard risks, cytogenetic abnormalities. Because we know, for example, from the U.S. What is the name now? The stop study from Dr Costa?

 

Dr Krishnan: MASTER?

 

Dr van de Donk: MASTER study. Patients with 2 high-risk abnormalities are the ones that tend to relapse even though they have 2 MRD-negative assessments in a row.

 

So I feel more comfortable to stop in case of toxicity, standard risk, ISS stage I/II as opposed to high-risk and ISS stage III. Because the Spanish group has shown that those are the patients that still relapse, while the other ones can have very durable remissions when stopping Len maintenance and having sustained MRD negativity.

 

Dr Krishnan: Thank you, Niels. You answered question 1 and question 3, so thank you. I will turn it back to you.

 

[01:31:20]

 

Posttest 4: Now, how likely would you be to consider a treatment for multiple myeloma that was FDA-approved based on MRD-negative CR data?

 

So how likely would you be to consider a treatment for myeloma FDA-approved based on MRD-negative CR?

 

I think we did not really move the needle. Most people were already going to consider it.

 

[01:32:08]

 

Additional Questions?

 

Dr van de Donk: In many clinical studies that use MRD for decision-making it is when you are MRD-negative that you can stop or you continue. When you are MRD-positive, you continue with the same type of maintenance strategy. Do you think that is a good strategy, or would it be better in those patients that remain MRD-positive after 2 years of maintenance to switch to something completely different like a bispecific or a CELMoD or what is your opinion?

 

Dr Krishnan: My opinion is yet unproven, but mine is actually I would consider switching and escalating therapy. I know there is a European trial, it is not exactly that question. It is more of if you MRD relapse, do you start treatment then? So in a way, I guess it is that same question. And also, of course, it is been 1 year, 2 years of maintenance, and you are MRD-positive. You are unlikely to convert at that point.

 

Jesus, you are looking skeptical on that one.

 

Dr Berdeja: I do not know what to do in that setting. So I think it is an open question, right? But I agree. I guess the question becomes, is your goal to get to MRD negativity at any cost, or is sustaining that non-MRD response sufficient?

 

Dr Krishnan: Yes, because I think if someone's been MRD-positive for 2-3 years already, you are not going to change that because they have already biologically sort of. So I think maybe it is more that if you were negative and you became positive, right?

 

Dr van de Donk: Yes, I think that is a different question. Yes, because the ones that are sustained positive can have this MGUS-like profile. I think you are referring to that.

 

Dr Berdeja: Yes.

 

Dr van de Donk: And have a very good outcome despite very low number of residual cells in the marrow.

 

Dr Berdeja: Yes, I agree.

 

Dr van de Donk: Maybe the immune profiling will help to determine that subset of patients.

 

Dr Krishnan: All right. All right. Well, I will turn it back to you.

 

[01:34:24]

 

Round 3: The Now, Soon, and Future: Integrating CELMoD Agent Therapy Into Treatment of MM

 

Dr van de Donk: So I think I will end this symposium with the third round.

 

[01:34:29]

 

Poll 10: Which of the following statements is a myth about the potential future roles for CELMoD agents?

 

So again, a 2-truth and 1-myth question. Which of the following statements is a myth about the potential future roles for CELMoD agents?

 

1. Mezi is being studied in Phase III trials in combination with a proteasome inhibitor and Dex for relapsed/refractory multiple myeloma;
2. Iber appears active in extramedullary disease;
3. Mezi is being evaluated in a posttransplant maintenance therapy setting.

 

So which is the false statement?

 

I think most of you had it right. The myth is mezigdomide is being evaluated in a posttransplant maintenance setting. Because Jesus already showed that it is iberdomide because of its, well, different safety profile, less neutropenia, which makes it more suitable for prolonged treatment.

 

[01:35:42]

 

Topics to Discuss Today

 

So other topics that we can discuss are what are the relative additions to our treatment with CELMoD agents? What does this class offer over existing therapies? And how do we put together the optimal approaches to combination therapy in ways that improve duration and depth of response, but still maintain normal and tumor-related immunity?

 

[01:36:11]

 

Novel CELMoD Agents in Development

 

So we have IMiDs, we have CELMODs, and how can we now best use Iber and Mezi in the treatment algorithm of multiple myeloma?

 

Well, IMiD agents we have been using for a long period of time now. We started with thalidomide, then lenalidomide, and then pomalidomide. And now, based on more rational design of drugs, based on the discovery of the cereblon pathway, we have iberdomide and mezigdomide.

 

[01:36:39]

 

CELMoD Agents Co-opt Cereblon via unique binding Features, Inducing Distinct Conformational Changes

 

So this slide has been shown before. CELMODs are more effective than IMiDs. They can bind with higher affinity to cereblon. They induce a shift towards an active conformation, which is 100% with Mezi, 50% with Iber, and much lower with lenalidomide or pomalidomide. And that is why these agents are much more effective in substrate degradation, like degradation of Ikaros and Aiolos. Another important aspect is that classic IMiDs are given as a mixture of S- and R-isomer, while CELMoD agents are given as a single S-isomer.

 

And we know now that this S-isomer is also more efficiently binding to cereblon than the R‑isomer. On top of this, we also know now that the R-isomer is probably responsible for some of the side effects that we see with lenalidomide and pomalidomide, like the sedation and also the fatigue, which are less common with iberdomide and mezigdomide compared to IMiD agents. So this rational design of the CELMODs not only improves their efficacy but also results in a different side effect profile.

 

[01:38:04]

 

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.

 

[01:38:28]

 

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.

 

[01:39:22]

 

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 vs 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.

 

[01:40:24]

 

GEM21menos65: Iberdomide + Isa-Vd for Patients With Transplant-Eligible NDMM

 

So which studies are now being performed to look at the future role of iberdomide and mezigdomide?

 

And this slide has already been shown by Jesus. This is the Spanish GEM21menos65 study where iberdomide is now already introduced as part of induction prior to transplant. So Iber-Isa-Vd is compared to lenalidomide-Isa-Vd to see whether we get a higher rate of MRD negativity and hopefully also a better safety profile. And after transplant, patients continue with iberdomide during consolidation and during maintenance.

 

[01:41:06]

 

EXCALIBER Maintenance: Iberdomide vs Lenalidomide Maintenance After Primary MM Therapy + ASCT

 

And this is the EXCALIBER maintenance study. This study started with a stage I dose optimization phase, which led to the definition of the recommended Phase II dose together with data from the EMN26 study.

 

So we have now picked Iber 0.75 mg as the dose that is probably the best for iberdomide as maintenance treatment. And in stage II, 1,100 more patients are now randomized against iberdomide at a dose of 0.75 mg vs standard-of-care lenalidomide. And this study is enrolling very rapidly, and we expect that it will be enrolled in July of next year.

 

And the primary endpoint is PFS, and secondary endpoint is MRD-negative rate. And because it is a maintenance trial, we will have to wait a couple of years before we have the readout.

 

[01:42:09]

 

EXCALIBER RRMM: Iberdomide + Daratumumab + Dex vs DVd for R/R MM

 

And this is EXCALIBER relapse/refractory.

 

Same design, a dose optimization, and then stage II, where Iber-Dara-Dex was tested against Dara-Vd. This study has been completed, is fully enrolled, and BMS has put a message online that MRD negativity was substantially better with Iber-Dara-Dex as compared to Dara-Vd. And we hope to see the data in the course of 2026.

 

And this will probably be 1 of the first studies that goes to the FDA with MRD negativity data and, hopefully leading to a more rapid approval than otherwise would have been the case when you have to wait for PFS data. So it will be a test case for the myeloma community to see whether we can get this study approved based on the MRD negativity rate.

 

[01:43:08]

 

SUCCESSOR-1: Mezigdomide + Bortezomib + Dex vs PVd for R/R MM (1-3 LOT)

 

And already mentioned by Jesus, also with mezigdomide, we have 2 interesting studies, now with a PI as backbone.

 

So in SUCCESSOR-1, Mezi-Vd is tested against Pom-Vel-Dex. And this study is close to enrollment. Almost all patients have been enrolled, maybe a couple of months more before enrollment is completed.

 

And SUCCESSOR-2 is now completed. All patients have been enrolled. And this study compares carfilzomib-Dex standard of care vs Mezi-Kd.

 

[01:43:42]

 

CELMoD Agents More Efficiently Stimulate T-Cells and Overcome T-Cell Exhaustion vs IMiDs

 

So we already discussed in the beginning that Iber and Mezi have very interesting abilities to activate the immune system. So they have direct anti-tumor effects, but they can also reduce T-cell exhaustion. On the right, you can see that both Iber and Dex and MeZ and Dex are able to activate T-cells, but also to mitigate T-cell exhaustion.

 

And this is, of course, very relevant when it comes to combination strategies with bispecific antibodies or with CAR T-cells. Because in patients with very heavily pretreated multiple myeloma, the T-cells are typically not so fit anymore. But on the left, you can see that when you have very exhausted T-cells, that iberdomide and mezigdomide can mitigate this T-cell exhaustion and really boost or improve the efficacy of a BCMA bispecific antibody.

 

And I think this is the preclinical rationale for studies like Elra plus Iber and Mezi. No, not Elra. Yes, Elra with Iber and Elra with mezigdomide. And also other bispecific antibodies are now being combined with CELMoDs, and hopefully we will see those data in the next few years.

 

[01:45:08]

 

Iberdomide Associated With T-Cell Activation an NK Cell Proliferation and Activation

 

This slide is, again, showing that CELMoDs are interesting partner drugs for immunotherapies because of their stimulatory effects on T-cells, but also on NK cells. And, of course, when you think about NK cells and better function of NK cells, CELMoDs are good partner drugs for antibodies that induce ADCC, like daratumumab and isatuximab.

 

[01:45:32]

 

Responses With Mezigdomide in Patients With Extramedullary Plasmacytoma

 

We already discussed that mezigdomide has high efficacy in patients with extramedullary disease. So probably mezigdomide can be an interesting backbone for patients with extramedullary myeloma, either in combination with carfilzomib but maybe also in combination with bispecific antibodies.

 

[01:45:51]

 

Emerging Strategies

 

So emerging strategies that we will learn more about are the CELMoDs in combination with T‑cell engagers. At this ASH meeting, we will learn about iberdomide and elranatamab and elranatamab and Mezi to enhance depth and duration of the response by mitigating T-cell exhaustion. We will also learn in the near future about the use of iberdomide and mezigdomide with CAR T-cell therapy, either as maintenance, but maybe they can also be very useful prior to T-cell apheresis. Because if these drugs improve T-cell function prior to the T-cell harvesting procedure, maybe you get better CAR T-cells than when you exposed the T-cells prior to the harvest to alkylators or proteasome inhibitors, which have a negative effect on T-cell function.

 

[01:46:46]

 

Discussion Questions

 

We have some discussion questions that we can raise and try to answer.

 

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 1 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.

 

And the second question is, how do you see this class partnering with new and emerging agents? So, well, you already mentioned the combination with bispecifics with CAR T. What do you think about the proteasome inhibitors? What will be the place of Mezi-Kd? With all the new interesting studies showing very promising data in early lines of therapy with BCMA-CAR T, BCMA-bispecific, is there still a role for Mezi-Kd in that setting?

 

Dr Krishnan: Maybe I am going to be very controversial and say maybe that is going to be actually, you are going to try T-cell-directed therapy combinations plus Mezi earlier and then think about a Mezi-Kd as actually a later option.

 

Dr Berdeja: I mean, I think the Mezi-carfilzomib combination, I think, is a good one, but especially in those difficult-to-treat patients where you need active, aggressive agents. So Em‑D high-risk patients, I think that is where, and I would argue that you would have to kind of do more. Like there is the poster, I think it is a poster, that uses a quadruplet as a salvage for patients. So that might lend itself well for that, and there I think Mezi would be a better agent than Iber.

 

Dr van de Donk: Patient with extramedullary disease, high-risk genetics, and Iber-Dara-Dex, that would probably be the first approval for Iber. Which patient segment would you think of that triplet? Where could that triplet be useful?

 

Dr Berdeja: Iber-Dara? Well, I think it would be useful in the patient that somehow is Dara-naive. I think, obviously, we will have to see what the actual data looks like. If it is really way superior to what we are seeing with the current IMiD combinations, which I think most of us were not that impressed by compared to the Dara or Isa-carfilzomib combinations, the IMiD combinations seem to be a little bit less active. But if we are seeing that with Iber or with Mezi, with Dara, you are seeing a much improved PFS, I think those would be easier combinations than the proteasome inhibitors. So I do see them as, especially in those patients who at least are not refractory to the anti-CD38s.

 

Dr van de Donk: And also, I was impressed by the high MRD negativity rate, actually, that you showed of Iber-Dara-Dex in the newly diagnosed transplant-ineligible patients. Because with MAIA, across the whole treatment, I think MRD negativity rate is approximately 30% or so. And here you showed 50% MRD negativity after a much shorter period of time that the patients were on treatment.

 

So hopefully, that will translate also in a longer and better PFS with a better tolerability profile, as we already discussed, lower rate of diarrhea, neuropathy, and fatigue.

 

Then, the last discussion question that I have is, what is the impact of highly effective immune therapy on the treatment model paradigm? We have now in this ASH meeting novel data on CAR T in first relapse, Tec-Dara in first relapse.

 

So how can you still use CELMoDs in this context? I think Tec-Dara is, of course, a very effective combination, but many patients, in Europe at least, but I think also in the US, when they relapse from MAIA or from CEPHEUS, a Dara refractory. And I think there the combination of a bispecific or maybe another immunotherapy in the future with a CELMoD, with Iber or Mezi, could be a very attractive alternative.

 

Is that also your opinion?

 

Dr Krishnan: I think also just what we talked about earlier, I agree with you in that relapse, because obviously bispecifics are moving earlier upfront. But also to your point, for example, even with MajesTEC-7, the upfront setting, again, those are not frail patients. So there is also that consideration. You still have a fairly effective immune therapy that could be given to somewhat of a more frail population. Again, untested, but I think that is where it is going to have a space as well.

 

I guess you could say how do you partner with the other T-cell therapies to really have this idea of a cure, right? And in terms of is that front-loading it, or is it using it as somewhat of a maintenance strategy and stopping? I do not know.

 

Dr Berdeja: I agree. I think as we are moving these really highly active therapies to the frontline in our attempt to cure, we do not want to hurt people either. So where I see the CELMoDs in that sense, so if we somehow decide all of a sudden that everyone is getting bispecific combinations, frontline and/or CAR T, is can you use drugs like this to be able to really limit that duration?

 

We had that discussion before about continuous therapy should no longer be the standard. We have to figure out how to do limited duration, but how long is limited? Is it 1 year, 2 years, 3 years? So 3 years of bispecifics is still a lot of therapy and potentially very toxic.

 

So if adding Iber allows you to do 6 months of a bispecific and still maintain that, that may actually be a very attractive use of these drugs, at least in my opinion, as we incorporate these other more potent therapies.