I'm going to spend the next few moments really talking about is some of the unmet needs in the treatment of patients with relapsed and refractory myeloma.

 

[00:07:53]

 

What Are the Unmet Medical Needs in 2026?

 

So let's start off with, in 2026, where we've got so many new emerging targets and therapies, what really do represent the true unmet medical needs? And you'll see there are a number of factors that I think represent this. Patients that have high-risk or extramedullary disease, those continue to remain a challenge despite all the new agents that we have.

 

Frail patients, particularly older patients, where we know that the median age that myeloma will present is about age 70. And so older, frailer patients certainly represent almost a third of patients with newly diagnosed myeloma.

 

Patients with more than three prior lines of therapy, particularly those that have been exposed to the major classes of drugs, represent an unmet medical need. And then patients resistant to or intolerant to the major targets, particularly IMiDs, PIs, anti-CD38, BCMA-directed therapy and GPRC5D-directed therapy. When you're resistant to those, the treatment options become a little bit more limited.

 

[00:08:54]

 

What Do Patients Prioritize/Desire in Novel Therapies for MM?

 

So what are patients looking for in the context of novel therapies to manage patients with – with their – with their own disease, and obviously extend survival while minimizing treatment-related toxicities?

 

And as we're getting better and better at treating patients in every phase of their disease, recognizing that the median overall survival is now greater than 10 years, it's really important that we start paying more attention to many of these quality-of-life-related issues, treatment-related adverse events, particularly adverse events that may either continue through the course of treatment or may be persistent beyond the course of treatment as well. And then allow them the opportunity for potentially meaningful off therapy time so that they can enjoy the benefit of the remission they've received and not have the burden of continuous ongoing therapy.

 

[00:09:49]

 

What Are the New Options for MM?

 

So what are the new options for myeloma? Well, the CELMoDs are what we're going to focus a good deal about today. Obviously, new CAR T-cell therapies, new antibody drug conjugates, trispecific antibodies, combination strategies for immune therapy, and then recapturing responses or enhancing responses to existing immune therapies.

 

And this is something many of us have noted with the older IMiD class of drugs, particularly in the context of, say, bispecifics, patients who may be losing a response. If you add an IMiD, you may be able to recapture some of that response. And what is the potential for the even more potent CELMoD class to either enhance responses or bring back responses when they've been lost early on?

 

[00:10:32]

 

Novel CELMoDs in Development

 

So when we think about CELMoDs in development, again, look at the old school classic IMiD agents. Again, they did have an important role in transforming outcomes as part of backbones of many treatment approaches.

 

But back in 2010, when we understood how the IMiDs actually worked, that they bound cereblon, that led to a big – a scientific exploration of ways to enhance the efficacy of that old IMiD classification, and that ultimately led to the new class of drugs called CELMoDs. And they had very important and specific activities that are, in fact, very different from what we see in the context of older IMiD categories.

 

[00:11:15]

 

Topics to Discuss Today

 

So the topics we're going to discuss today is what do novel protein degraders offer over existing therapy? You're going to hear a great discussion around that today. And how do we put together the optimal approaches to combination therapy in ways that improve duration of response, but maintain normal and tumor-related immunity?

 

And as I said before, as we're thinking about a 10 to 20-year horizon for newly diagnosed myeloma patients, it's really important that we use treatments that allow restoration of normal immune function and reduce the risk of infections over time, not necessarily increase the risk of infections over time as well.

 

And with that, I'll turn things over to my colleague, Dr. van de Donk.

 

[00:12:07]

 

Novel Approaches in MM

 

Dr. Niels van de Donk (Cancer Center Amsterdam): Thank you so much, Sagar, for your kind introduction. And I also want to thank the organization for getting this together.

 

[00:12:19]

 

Protein Degradation in MM

 

So I will provide you a overview of how IMiDs work and why CELMoDs are, indeed, as Sagar alluded to, more effective in killing myeloma cells and improving the immune system.

 

Well, for cells, it's crucially important that protein production and protein degradation are very well regulated. If there is a disturbance between both processes, cells can die. The ubiquitin proteasome system forms a primary means for cellulary – cellular protein degradation. And the ubiquitin ligase enzyme complex is a component of this system, and it tags proteins for proteasomal degradation with a ubiquitin tag.

 

IMiDs, and especially the novel CELMoD agents alter the target protein binding properties of cereblon to promote interaction with protein substrates that would otherwise not be candidates for degradation.

 

[00:13:25]

 

Ubiquitin-Proteasome System (UPS)

 

And in this cartoon, which I borrowed from Charlotte Pawlyn from London, I show you more specifically how IMiDs and CELMoDs work. So in a normal situation, the blue protein in this case is being recognized by cereblon. The blue protein binds and becomes ubiquitinated by the ubiquitin ligase enzyme. And you know that when a protein has this ubiquitin tag, it will subsequently be degraded in the proteasome into peptide fragments. The yellow protein is not being recognized and will not be eliminated.

 

[00:14:13]

 

Molecular Glues Can Hijack the UPS

 

However, when we treat a patient with an IMiD drug or a CELMoD agent, then the substrate specificity of cereblon changes. And in this case, the yellow protein is able to bind to cereblon and gets ubiquitinated and subsequently degraded in the proteasome.

 

So IMiDs or CELMoDs are also called molecular glues because they enable the removal of difficult-to-drug proteins.

 

[00:14:46]

 

IMiDs Are Molecular Glues

 

So which are these yellow proteins that are recruited to cereblon in the presence of an IMiD or a CELMoD agent?

 

Well, these yellow proteins include proteins such as Ikaros and Aiolos, and these are critical B-cell transcription factors in multiple myeloma. If you reduce the expression of these proteins, c-Myc levels go down. IRF levels go down. And in the end, that induces myeloma cell death.

 

[00:15:18]

 

Novel Protein Degradation Modulators in Development

 

So here you see the molecular structures of IMiD agents on the left: lenalidomide and pomalidomide. And here you see the CELMoD agents: iberdomide and mezigdomide, which were developed based on improved understanding of cereblon and myeloma biology.

 

And here you see another CELMoD, cemsidomide, which is also under investigation in patients with heavily pre-treated multiple myeloma, as we will also discuss in the subsequent presentations.

 

[00:15:49]

 

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

 

So CELMoDs are quite different from IMiDs. First of all, CELMoD agents are able to bind to cereblon with much higher affinity because of their chemical structure.

 

So here you see the IC50 values for iberdomide, which are much lower than what you see for lenalidomide and pomalidomide. And mezigdomide has even lower IC50 value than iberdomide.

 

And because of this very potent binding to cereblon, the CELMoDs are more capable of changing the open configuration of cereblon to a closed configuration. And this closed configuration is the configuration that results in degradation in the recruitment of the neosubstrates, Ikaros and Aiolos.

 

So here you can see how effective iber and mezi are in terms of this conformational change as compared to lenalidomide or pomalidomide.

 

Another important difference between CELMoD agents and IMiD agents is the fact that IMiD agents: thalidomide, lenalidomide, pomalidomide are administered to patients as a mixture of S and R isomers, whereby the R isomers bind less efficiently to cereblon and we have evidence from several preclinical and clinical studies that R isomers are also responsible for the neurotoxicity that comes with IMiD agents. So the neuropathy, the sedation may be related to the fact that we administer R isomers and not only S isomers.

 

In contrast, CELMoD agents, so iber and mezi are administered to patients as a single S isomer that not only binds cereblon with greater potency, but also may explain why CELMoD agents have a different safety profile with less fatigue, less sedation, and less neuropathy as compared to what we see with the IMiD agents.

 

So CELMoDs have higher binding affinity, are administered as S isomer, which may explain a different safety profile.

 

[00:18:10]

 

Degradation and Antiproliferative Activity of CELMoD Agents

 

And in the next slide, I will show you that these different binding capabilities translate into much more efficient degradation of Aiolos, in this case, with mezi and iber as compared to what was – what is happening with len or pom.

 

So more rapid degradation and also more profound degradation. And this degradation of Aiolos and Ikaros translates into strong, potent anti-myeloma activity. So len and pom are not so much effective in inhibiting proliferation. But iber and mezi, as you can see, are much more potent in inhibiting myeloma cell proliferation, not only of parental cell lines, but also these purple cell lines, which were made IMiD-resistant.

 

The only cell line that is not sensitive to mezi and also not sensitive to iber, pom or lenalidomide is the cell line with cereblon knockout. You can imagine that when you knock out cereblon, cell lines are no longer sensitive to IMiDs and CELMoDs.

 

[00:19:19]

 

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

 

Here you see some data from cemsidomide, a CELMoD agent developed by C4 Therapeutics. Also, this agent is able to bind with high affinity to cereblon, leading to potent degradation of Ikaros and Aiolos, and explaining why also cemsidomide is more effective in terms of reducing viability of myeloma cells compared to pomalidomide.

 

[00:19:47]

 

IMiDs Have Activity Outside Direct Myeloma Cell Targeting

 

Importantly, IMiDs not only have direct on-tumor activities, but IMiDs and CELMoDs also have activities on other cells that are present in the bone marrow microenvironment.

 

So here you can see that IMiDs and CELMoDs reduce expression of various important adhesion molecules on stromal cells, for example. And when these adhesion molecules are downregulated, this results in a impaired adhesion of myeloma cells to stromal cells. And well, we all know that this interaction, this adhesion protects myeloma cells against various drugs that we give to our patients, like proteasome inhibitors and – and also bispecifics and CAR T cells, as we showed in our lab.

 

Here you see the direct effects of the IMiDs and CELMoDs. And on the right, you see that these agents also have profound immune stimulatory activities. So NK cells are activated and are induced to proliferate. And this is interesting when you think about combination partners like daratumumab.

 

And on the right, you can see that also T cells are activated. And this is also interesting when you think about combination partners like bispecifics and CAR T cells. And on the bottom, you can see that also dendritic cells are activated. So they present tumor peptides and also viral peptides to T cells leading to better immune responses.

 

[00:21:30]

 

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

 

So to be more – in more depth, you can here, see what IMiDs and CELMoDs do with T cells, and on the right with NK cells. And this is data that I showed you for iberdomide. But similar observations have been made with mezigdomide.

 

So this is data from iberdomide and dexamethasone in the CC-220-001 study, which will be discussed in more detail by Fredrik. But what we saw with iberdomide in this trial, in very heavily pre-treated multiple myeloma, so patients with impaired immune function, is that T cells become activated. They have more expression of the activation marker HLA-DR. They are stimulated to proliferate because they have – as evidenced by higher expression of Ki-67. They have better ability to kill cells, granzyme B expression is increased. But at the same time there is a reduction in exhaustion markers like TIGIT and also senescence markers like KLRG1 and CD57.

 

So you get a better T-cell phenotype with iberdomide and mezigdomide. And this is more profound than what we saw before with lenalidomide and mezigdomide – sorry, lenalidomide and pomalidomide.

 

And on the right, you see a summary of what can be happening with NK cells. NK cells also exhibit a better proliferative profile. They have more granzyme B expression, so better killing capabilities. They have higher expression of CD16. And we have shown, for example, that CD16-positive NK cells are having substantial prognostic value when you treat patients with daratumumab, because CD16 is the Fc gamma receptor, which is needed to bind daratumumab in order to induce antibody-dependent cellular cytotoxicity.

 

And on the right, you can also see that on NK cells, expression of exhaustion markers and senescence markers is going down in the presence of iberdomide.

 

[00:23:41]

 

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

 

So here you see that these effects are in fact happening in almost all the patients. So this is again data from iberdomide and dexamethasone. You see T-cell differentiation. You see an increase in HLA-DR expression virtually on all patients. You see a substantial increase in DR expression. And at the same time, the decrease in the exhaustion marker, TIGIT, from screening to treatment.

 

And on the right, you can see that these changes also occur with the mezigdomide CELMoD, increased activation and decreased exhaustion again in heavily pre-treated multiple myeloma patients.

 

[00:24:23]

 

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

 

So I showed you up till now that IMiDs and CELMoDs have direct anti-tumor activity that they improve immune function. And this makes these agents very interesting combination partners.

 

Various pre-clinical studies have looked at the combination of IMiDs and CELMoDs and other anti-myeloma drugs. And on the left, for example, you can see that IMiDs and CELMoDs, like iberdomide, combine very well with proteasome inhibitors with synergistic induction of apoptosis with CELMoD and PI combinations, forming the rationale of, for example, the SUCCESSOR-1 study with MeziVd.

 

And also on the right, you see that CC-92480, that's mezigdomide, combined with bortezomib and dexamethasone is the most effective combination, more effective than either agent alone or pomalidomide combined with bortezomib and dexamethasone. And this forms also the rationale for the SUCCESSOR-1 study.

 

[00:25:36]

 

Iberdomide + Daratumumab Treatment Elicits More Potent Antiproliferative and Cytotoxic Effects in MM Cells

 

Because of the immune stimulatory effects, iber and mezi have also been evaluated in combination with naked antibodies, for example, the naked antibody daratumumab, which works via complement activation and via antibody-dependent cellular cytotoxicity, which is dependent on functional NK cells.

 

On the left, you can see that iberdomide improves the ability of daratumumab to kill myeloma cells in the presence of complement. So there is a synergistic induction of complement-dependent cytotoxicity.

 

And on the right, you can see that iberdomide is able to activate NK cells, explaining why iber and dara are also synergistically inducing myeloma cell death in an ADCC assay.

 

[00:26:28]

 

CELMoD Agents Improve the Efficacy of T-cell Immunotherapy

 

Because of the T-cell stimulatory activities, I think that iber and mezi are also very interesting combination partners for T-cell redirecting antibodies, bispecifics like tec, elran, talquetamab and CAR T cells.

 

And on the left, you see an interesting experiment, where the purple line that's alnuctamab, a bispecific antibody directed at by BCMA in combination with mezigdomide, is very effectively inducing cell death, much more effective than alnuctamab alone or mezigdomide alone, probably because the mezigdomide is reinvigorating exhausted T cells so that they are better effector cells in the presence of a bispecific.

 

And on the right, you can see that mezigdomide maintenance after administration of CAR T cells is also an interesting strategy, probably by improving persistence. And you can see that the blue line, which is the BCMA CAR T plus mezi combination, is substantially more effective in this mouse model than BCMA CAR T alone in red or the green line mezigdomide alone. So clear synergy with CELMoDs and T-cell immunotherapies.

 

[00:27:50]

 

Conclusions

 

So in conclusion, I showed you in various pre-clinical models that CELMoD agents are potent protein degrading molecules, that they overcome lenalidomide and pomalidomide resistance in preclinical models but also in the clinic in patients. They have the potential to improve T-cell fitness – fitness, making them interesting combination partners for bispecifics and CAR T cells. And in preclinical studies, they work synergistically in combination with naked antibodies like dara or isa and proteasome inhibitors.

 

[00:28:26]

 

Let’s Return to a Question From Earlier

 

So let's return now to a question from earlier to see if in this early Friday morning, you have improved your knowledge on CELMoD molecules.

 

[00:28:40]

 

Posttest 1

 

So this is the posttest one. And the question is, the repeat question, in fact, which was already posed by Sagar. Which is – which of the following best describes the properties of CELMoD – novel CELMoD agents versus IMiDs in regulating myeloma cell proliferation? Is that:

 

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

 

So you scan this QR code to provide your answer.

 

Excellent. Very good. So the correct answer was indeed B, and there is a substantial increase in people providing the right answer.

 

And that brings me, I think, to the end of my session. And I would like to hand over to – to Sagar.

 

[00:30:23]

 

Now, What Would You Like the Experts to Discuss?

 

Dr. Lonial: Yeah. All right. Thanks, Niels. And I think – so you did your job. You taught them something which was good. So let's see what you'd like our experts to discuss now. So this is a chance for you all to choose the topic of our discussion in the next few moments. So let's get to the question, if we could. If you can forward it to the question. Here we go.

 

[00:30:52]

 

Experts in the Hot Seat: Poll 3

 

Which of the following would you rather the experts to discuss further?

 

1. Rationale for combining CELMoDs with an anti-CD38 or a proteasome inhibitor;
2. Could CELMoD agents enhance immune activation in combinations with CARs and bispecifics;
3. Mechanisms by which CELMoDs overcome resistance to len and pom;
4. Should or could CELMoDs replace IMiDs; or
5. What do we know about potential mechanisms of resistance to CELMoDs.

 

So please take a moment to vote.

 

Okay, so it looks like there are two that are pretty close. One is, could CELMoD agents enhance immune activation in combination with CARs and bispecifics, or should CELMoD agents – should/could CELMoD agents replace IMiDs?

 

So Niels, why don't you get us started? You can pick either one.

 

Dr. van de Donk: Well, I think – well, I can start with B because it's also based on what I presented, I think. Well, CELMoDs are very interesting combination partners. I showed you some preclinical studies showing that the activation of – of T cells, the – by CELMoDs, increase in proliferation, increase in killing capacity, improves the ability of bispecifics to kill myeloma cells.

 

In fact, there are now several phase I studies ongoing evaluating the combination of a bispecific and a CELMoD, either iberdomide or mezigdomide. At last ASH meeting, there were very interesting data of elran and – and iber, but also etentamig and – and iber, and there was a very promising high response rate reported. Follow-up was still short of these studies. So I think we have to have longer follow-up to – to see the eventual prolongation of – of the responses with this type of combinations.

 

But I think we have now very effective dara-based combinations. But these combinations were tested in patients that were dara-naive or dara-sensitive. So I think there is still a place for bispecific combinations with CELMoDs, especially in the setting of dara refractoriness. So I – I would stimulate further development of such studies.

 

And also CELMoDs after CAR T, maybe especially in high-risk patients, could be an impress – interesting approach to improve responses in these patients.

 

Dr. Lonial: Yeah. Fredrik, do you want to take that one or do you want to take the replace?

 

Dr. Fredrik Schjesvold (Oslo University Hospital): I just want to comment a bit further on what Niels said, because I think we have talked about CELMoDs and IMiDs stimulated T cells for a long time. We – we know they do that. We have seen from the preclinical data that it increases the response or activation.

 

But I think for the clinical situation, I think it's still a very open question. We have many studies with these combinations ongoing. We have studies where you alternate between them or you combine them, but I think it's still a bit unclear and we have to wait for the results of these studies. It's still a bit unclear why – whether the T-cell exhaustion or dysfunction, how important that is in progression.

 

So if that's really important for the progression, then this would be probably important drugs to add. If it's mostly sort of mutated downregulated BCMA clones, then this may be not would help so much, but it might help maybe still on the infection side of it because we see a lot of T-cell dysfunction infections in this. So maybe in the end, it's more about – the combination will be more about preventing that.

 

But I think these are very unanswered questions. And we're going to see the monumenTAL-3 today, tomorrow in the plenary, where the additional pom didn't make a huge difference when you already had added dara. So I think these are really open questions so far.

 

But I think also another point of developing here, I think, could be to use bispecifics for a shorter time with no long-term treatment with that is – is problematic and continue to – to maintain the T-cell activity by a CELMoD. After that, it’s a way also we can test in the future.

 

Dr. Lonial: No, I - I think you're bringing up sort of a bimodal reason for failure of bispecifics. One is immune function and the other is target loss. I mean, I – I – I’ve got many patients who were progressing on a BCMA bispecific or talq, you added in pom, and they recaptured their response. That was quite durable. It wasn't, you know, a transient response.

 

So I think depending upon the mechanism of resistance, you're right, it may offer – it may offer benefit.

 

I know we're running a little short on this session, but I do want to take the should/could CELMoDs replace IMiDs question.

 

From my perspective, what we've learned in myeloma is that you take your most effective drugs and move them earlier into the treatment course and make them part of combination approaches. I think combinations clearly represent what has moved our field forward for so long, given not just safety and adverse events are less with the CELMoDs than with the IMiDs, as well as potential potency and immune activation.

 

I would say, yes, and I'm excited about that. There have been a number of presentations about that already, but I'm curious where you all fall on that.

 

Dr. Schjesvold: So I can start. I think they should. And the remaining question is, if they could? So I'm going to show some clinical data in – in frontline. It's mostly iber. Iber is a more – more efficacious drug and it's a more tolerable drug than len, so it should. But the studies have to sort of confirm that, and there's a post-study process also.

 

And also for the same, the mezigdomide is a more potent drug than pomalidomide in – in – in relapse, and it should. And you also had succeeded somewhat in putting that in – in second-line with the SUCCESSOR-2 data I'm coming back to.

 

Dr. van de Donk: Yeah, maybe – maybe to add because you both discussed efficacy, which I totally agree. We have to bring the most effective drugs upfront, but also for the patients, it’s extremely important that they get drugs that are well tolerated. And we showed in – in a maintenance study, EMN26, that long-term treatment with iberdomide in this case was very well tolerated.

 

And except neutropenia, we did not see a lot of grade 3 or higher non-hematologic adverse events. So no diarrhea, no fatigue, which you commonly see with lenalidomide. And this is very important for the quality of life of our patients. So both efficacy and efficacy make these potentially new agents in the frontline.

 

Dr. Lonial: Yeah. Yeah. All right. So let's keep moving. I do see questions coming. We've got time at the end for Q&A as well. So, Fredrik, why don't you take us through emerging evidence and key ongoing phase III trials?

 

[00:38:17]

 

Emerging Evidence and Key Ongoing Phase III Trials

 

Dr. Schjesvold: Yeah. Thanks, Sagar. So now we're moving from the pre-clinical side to the clinical side.

 

[00:38:24]

 

Initial Proof of Activity

 

I'm going to show the – the data we have on the three – the two drugs or the – the three drugs we have discussed: iberdomide, the mezigdomide and cemsidomide, which is an even more novel CELMoD.

 

[00:38:37]

 

Novel Protein Degraders in R/R MM

 

So most of these data are from relapsed myeloma. In the end, I'm going to go through some in newly diagnosed.

 

[00:38:44]

 

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

 

So the – let's start with iberdomide. So iberdomide was first tested with dexamethasone in – in a very late line disease patients, at least three prior therapies with including len and pom and anti-CD38. While with the dara cohort, since this is a dara combination, they were not – mostly not exposed to – to dara, but it was allowed but not mandated.

 

You can also mention that iberdomide as mezigdomide and as len and pom is giving – is given days one to 21, the way we are used to doing with – with IMiDs. And – and the other drugs, dara and dex are given as – as common.

 

[00:39:27]

 

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

 

So in the late-line iber/dex cohort, this is a very heavily pre-treated population with a median prior lines of six and even up to 23. They are all immune refractory, all exposed to pom, almost all PI refractory and all refractory to anti-CD38. So this is a more a safety sort of proof-of-concept that iber actually has some activity in this more or less fully refractory population.

 

And with the response rate of 26% and some deep responses, I think the – the proof-of-concept that this works in these refractory patients is – is confirmed.

 

[00:40:06]

 

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

 

But – but even more, I think the safety signal of iberdomide is extremely good. We know from – from treating with len and pom that there are lots of non-hematological problems in these patients. Iberdomide, I would say I'm part of both iberdomide and mezigdomide studies, and iberdomide is an extremely tolerable drug compared both to many other drugs, but also to – to the previous IMiDs.

 

You see the grade 3 non-hematological adverse events is almost not – not present. Neutropenia is – is normal with the IMiDs and the CELMoDs. So that's a sort of on-target effect on the myeloid cells. But that's very manageable with the G-CSF.

 

[00:40:52]

 

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

 

If you're looking at the iber/dex/dara cohort, this was a dose escalation study. The patients were less heavily pre-treated than with the iber/dex. Median lines – median prior lines of therapy was four, but still 95% are IMiD refractory, 65% are pom refractory, and 37% are CD38 monoclonal antibody refractory, so leading to overall response rate, 46%. Quite impressive actually.

 

And as you see on the bottom there, not many PDs at this stage in – in the – in the higher doses.

 

[00:41:35]

 

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

 

Looking again in this combination, we have – now we have two very tolerable drugs. Nobody would say that dex is tolerable, but we know that well. But also here you see that the grade 3 non-hematological AEs is almost not present at all.

 

[00:41:49]

 

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

 

This has led to the EXCALIBER trial in relapsed myeloma, where iber/dara/dex is challenging DaraVd. Adults had to be pre-treated with one to two prior lines of therapy, not refractory to bortezomib or to anti-CD38 therapy. There was a dose optimization in the beginning. They were randomized to – to four different cohorts and then arm A1 with iberdomide one milligram was – was chosen as the selected dose, and the rest of the phase III study was – was enrolled.

 

We don't – we haven't seen results here, but we know that from a press release that the – the primary end point of MRD-negative rate is positive. So we will see the full data set on IMS in – in Glasgow in September. So please be there.

 

[00:42:47]

 

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

 

Now going for mezigdomide. Mezigdomide was also first, of course, developed in – in very heavily pre-treated population, which had to – to have used at least three prior therapies and had to have used len and pom and anti-CD38. It was dose escalation and dose expansion. These patients were very heavily pre-treated, as you see on the right. Median prior lines of six. And they were all triple class refractory. So very difficult population to – to treat.

 

[00:43:17]

 

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

 

And with an impressive response rate of 40% in the whole population, including the dose escalation. In the patients with plasmacytomas, 30% response rate. And even in prior anti-BCMA therapy, which was actually 30 patients, the response – the response rate is 50%. PFS of four to – four to five months in this population with a doublet.

 

[00:43:43]

 

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

 

On the right – sorry, on the left, you see that neutropenia is very sort of typical with this drug, as with all limits, very manageable with G-CSF, preferable to use G-CSF rather than – than - than dose reduction. And you also see that this is most prevalent in the beginning when the tumor load is higher. But you can also see on the right that the – also with the mezigdomide, the – the – the higher grade non-hematological AEs are not very prevalent.

 

There is a bit higher degree of fatigue, diarrhea in this than in iberdomide. And I think that's correct. And there are infections as we always see in this – this patient population.

 

[00:44:25]

 

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

 

So the next step for mezigdomide was to – to – to – to have combination cohorts. They were looking mostly at cohort C and D here, the – the red and the blue. In cohort C, where you combine carfilzomib – carfilzomib, you had to have two to four prior lines of therapy while in the cohort D for combination with bortezomib, you had to have had one to three prior lines of therapy.

 

And the aim here was to find the recommended dose and – and show the safety of these combinations. There are many cohorts in this – in these trials, but I'm not going through the other ones, so it's not so relevant now.

 

[00:45:05]

 

CC-92480-MM-002: Efficacy

 

The PFS of the mezigdomide-Vd in one to three prior lines of therapy. This is sort of pom/vel/dex type of patients which ended up challenging in the SUCCESSOR-1. It's quite impressing, PFS of 17.5 months. Looking to – looking sort of – please don't speak in the microphone, Niels and Sagar.

 

Dr. van de Donk: Oh, sorry.

 

Dr. Schjesvold: You have to be a professional.

 

Dr. van de Donk: We were discussing your presentation.

 

Dr. Schjesvold: Yeah. So with MeziVd, a PFS of 17 months. You know pom/vel/dex, which is a similar regimen, similar population, but with pom instead of mezi, had about 11, 12 months. And with Kd, 13 months in a population that was very heavily pre-treated with almost 90% immune refractory, 74% anti-CD38 refractory and triple-class refractory in 37%.

 

[00:46:12]

 

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

 

So these two phase II studies led to the two randomized trials with SUCCESSOR-1 and SUCCESSOR-2. The first one is mezigdomide/bortezomib/dex challenging pom/vel/dex. So it's a sort of head-to-head between mezigdomide and – and – and pomalidomide for patients with one to three prior lines of therapy. Patients had to have been treated with – with len, but no – no – no mandates otherwise. But you – you could not have received prior pom and not be PI refractory, of course.

 

Also here a stage I with a dose optimization, and we went all the way with mezigdomide 1.0 milligram in the – in the larger phase III part of the trial. This trial is completely enrolled. It's been followed up and the results will be available in 2027. We don't know anything about the results as of today.

 

[00:47:00]

 

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

 

SUCCESOR-2, on the other hand, we know the results are going to show them. Many of you have maybe seen it at ASCO. This was a patient population that was very different from most other relapsed randomized trials. It was presented as a late breaking abstract at ASCO. These patients had to have received anti-CD38 antibodies in addition to – to prior lenalidomide.

 

It was a 1+ line study. So they can – had to have received one line previously, had to have received dara, but could have as many lines as – as there was no upper limit to the number of lines.

 

Also here dose optimization. The 1.0 mezigdomide was also chosen to – to move – move on here. And the results for this study are ready. The PFS is a primary endpoint.

 

[00:47:52]

 

SUCCESSOR-2: Prior Therapy

 

Just going – showing you a little bit about the study population first. As you see on the left, one prior line of therapy was not so much, the 15%. The biggest part was the patient population with two prior lines, but – but 25% and above was – had at least four prior lines of treatment.

 

On the right, you can see that they all, of course, had anti-CD38 and len or over 90% with triple-class exposed also to a PI. Third of them had pomalidomide and 5% to 10% had BCMA-targeted therapy or T-cell redirecting therapy.

 

Triple-class refractory about 40% and pomalidomide refractory 30%.

 

[00:48:36]

 

SUCCESSOR-2: PFS

 

So this is the main result, PFS benefit, a hazard ratio of 0.48 with 18 months versus a Kd of eight months. This was – I don't know if I even mentioned. This is a sort of add-on trial. So Kd is the control arm and MeziKd is intervention. And as you know from the Kd trials, we know that that usually ends up previously when it was not exposed to dara before at – at around 18, 19 months of PFS.

 

So you see clearly that this is a worse population to treat when they are dara exposed and more heavily pre-treated in – in general.

 

You can also mention that cilta-cel in second-line, the CARTITUDE-4 trial. If you look at the dara-exposed patients, the PFS there is 19 months more or less the same as – as this study.

 

[00:49:20]

 

SUCCESSOR-2: PFS Subgroup Analysis

 

Very importantly, the – the mezi addition worked well in all subgroups. And quite impressively, if you see on the left here, usually in randomized trial, the high-risk patients do not benefit as much. So here you see that the benefit in high-risk cytogenetics was – was as good. In soft tissue plasmacytoma and in pure extramedullary plasmacytoma, you can all almost see the benefit being bigger in this very difficult patient population to treat.

 

[00:49:53]

 

SUCCESSOR-2: Response, PFS2, and OS

 

Of course, response rates were also higher in the MeziKd, but more importantly, PFS2 is extremely much longer in MeziKd than in Kd. So – so confirming that also after the next line, you still see the benefit of being on mezigdomide in this line of treatment.

 

[00:50:11]

 

SUCCESSOR-2: TEAEs

 

Looking at the – the treatment-emergent AEs, neutropenia is common. This has to be managed, but it's not very difficult to manage. Anemia a little bit higher as we see with all the IMiDs and CELMoDs. Here, you also see the signal of diarrhea but it's not high grade but it's there in – in more patients than – than with Kd.

 

But I really like this fatigue part, which I think is a problem with len and pom that you don't actually get anymore fatigue when you add the mezigdomide to – to carfilzomib. A little bit more infections, which you also recognize.

 

[00:50:51]

 

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

 

But there's one more, as Niels mentioned, cemsidomide, novel CELMoD from C4 Therapeutics, not as – as – as long in the – in the development. This is a late-line trial first with a dose escalation and then a dose expansion in very heavily pre-treated patients.

 

[00:51:12]

 

CFT7455-1101: Efficacy With Cemsidomide + Dex

 

And this is a dose escalation. I would point to the – the – the – the higher dose here with the ORR, overall response rate of about 50% in this very heavily pre-treated patients, quite similar to – to mezigdomide confirming the – the efficacy of the CELMoDs in this patient population.

 

[00:51:32]

 

CFT7455-1101: TEAEs With Cemsidomide + Dex

 

AEs are very similar to the other ones and I’m not going through that in detail, but it seems most of these are known side effects to the IMiDs and CELMoDs.

 

[00:51:43]

 

Let’s Return to a Question From Earlier

 

So then we're going to return to a question from earlier.

 

[00:51:46]

 

Posttest 2

 

Which of the following is a CELMoD agent that demonstrated significantly improved PFS in a phase III trial when combined with Kd versus Kd alone for patients with relapsed/refractory myeloma with at least one prior line of treatment?

 

And the answers here are not so long. It's just a name. So you just have to remember which name is correct. So let's start.

 

And nobody is allowed to answer B. Good 0% on B. Happy with that and very good. I think I had better results than you, Niels.

 

Dr. van de Donk: Easier question.

 

Dr. Lonial: All right. I think that's it for the -

 

Dr. Schjesvold: No, no, no, no.

 

Dr. Lonial: There's another posttest?

 

Dr. Schjesvold: There's more.

 

[00:52:55]

 

Novel Protein Degraders in NDMM

 

So just a few slides about newly diagnosed myeloma.

 

[00:53:00]

 

CC-220-MM-001: Iberdomide + Dex + Dara for Transplant-Ineligible NDMM (Cohort K)

 

The development here is not as – as – as – as mature. This is a cohort where you treated transplant-ineligible newly diagnosed myeloma with the combination of iberdomide/dex/dara sort of letting iber replace len in the dara-VRd regimen with a response rate of 95% and the MRD-negative CR rate of 56%. This is in line with the quads we see from the randomized trials, IMROZ and – and CEPHEUS.

 

So – so really – really promising data. But that's all we know about that as of now.

 

[00:53:40]

 

EMN26: Iberdomide Maintenance After ASCT in NDMM

 

It's a bit more mature in the maintenance space. So this is Niel’s study, EMN26, iberdomide maintenance after transplant. This is not a randomized trial. This is a dose-finding trial testing out different doses of iberdomide. In this situation, patients had to be newly diagnosed and receive transplant plus/minus consolidation and induction with the PI on IMiD.

 

So as you see, as the cohorts run, we get to lower doses.

 

[00:54:12]

 

EMN26: Safety in Cycles 1-12

 

The – the safety is really good with iberdomide. Not going through that in details, but there was a bit higher cytopenias in the higher doses.

 

[00:54:23]

 

EMN26: Response Improvement

 

What we saw was that the response improvement was actually not very different between the different doses of iberdomide. I have to – I can also mention that the – the lowest dose here came a bit later. So induction therapy might have been a little bit better.

 

[00:54:38]

 

EMN26: Progression-Free Survival

 

And the PFS, you see the same that actually the lower dose is a bit better. If this is caused only by better induction or also that you're able to – dose intensity was a little bit higher because it's a lower dose.

 

[00:54:57]

 

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

 

And – but anyway, because of this – this study, the chosen dose for the randomized phase III part against len was chosen as a 0.75. So this study isn't going. These are patients with induction and transplant plus/minus consolidation randomized between iberdomide and len.

 

This study is – is completely enrolled. The primary endpoint is PFS. So I'm not completely sure when we will see the results from this. But we just have to wait and see.

 

[00:55:24]

 

Let’s Return to a Question From Earlier

 

Now, Sagar.

 

[00:55:28]

 

Posttest 3

 

Yeah. First, we're going to return to this question, sorry. So which of the following patients with myeloma might be eligible for an ongoing phase III EXCALIBER trial evaluating iberdomide monotherapy?

 

1. So transplant-eligible newly diagnosed;
2. Transplant-ineligible newly diagnosed;
3. Post primary therapy for newly diagnosed myeloma with at least a PR; or
4. Relapsed myeloma with three prior lines of treatment.

 

Well, the correct answer is A, transplant-eligible newly diagnosed myeloma. So now you know that. That's a take-home message.

 

Dr. van de Donk: We’ll see actually, right? Post primary.

 

Dr. Lonial: Yeah.

 

Dr. Schjesvold: Okay.

 

Dr. Lonial: Maybe we should have kept talking.

 

[00:56:40]

 

Posttest 3: Rationale

 

See, it’s C.

 

Dr. van de Donk: We'll – we'll explain you.

 

Dr. Lonial: Yeah. You had to have at least a PR.

 

Dr. Schjesvold: So - so I acknowledged that the question was difficult.

 

Dr. Lonial: All right. Thank you. Thank you, Fredrik.

 

[00:57:10]    

 

Notable EHA 2026 Abstracts

 

So these are a number of abstracts again that are going to be at EHA that really focus on CELMoDs as well as one that is on cemsidomide. But let's go to the next slide because I think – I think they get a chance to ask us, right?

 

[00:57:30]

 

Now, What Would You Like the Experts to Discuss?

 

Here we go. So if you can bring up the question.

 

[00:57:35]

 

Experts in the Hot Seat: Poll 4

 

What would you like us to discuss further?

 

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

 

So please take a moment to vote. And there's no right answer for this one.

 

[00:58:25]

 

Additional Questions?

 

Okay, so it looks like people want to know the EMD question. And then if we've got a moment, we can focus on abstracts or neutropenia. Maybe neutropenia management is worth discussing as well. So why don't we take the one on EMD. Either of you guys want to tackle that?

 

Dr. Schjesvold: Yes, I can start. I think – I think in the mezi/dex phase II trial, we saw that the response rate was 30% in the patients with plasmacytoma, which is impressing. It's a signal, but I – I often hear about signals in early line trials. We see responses in extramedullary myeloma, and it ends up being that it's – it's – any drug can probably work and they just work worse.

 

So – so I was a bit skeptical based on the phase II results. But then because I'm used to getting disappointed when the phase III trials come, I was actually impressed by the SUCCESSOR-2, where you see that even though it's not significantly different, the – both the pure extramedullary myeloma – plasmacytomas and the soft tissue in general actually have a better hazard ratio with adding mezigdomide. And that's unusual. You used to see these things more crossing the line than being the other way.

 

So I think that's one of the clearest signals I've seen, especially with mezi. We don't know so much about iber yet. But so – so I would say the answer is yes. Now the signal is clear even – even to me.

 

Dr. van de Donk: Yeah. I was also positively surprised by SUCCESSOR-2 data for patients with extramedullary disease. Often these patients respond but respond very briefly. And here you see a – a clear benefit also when it comes to PFS and the hazard ratio. So I think that's very important and very relevant to build upon.

 

Dr. Lonial: Yeah. And – and I think unlike the IMiD class, if you biopsy an extramedullary lesion and try and measure levels of the drug, you don't see len or pom there. You do actually see mezi there. So I think there's something about its structure that allows it to get into the plasmacytomas more effectively than what we saw before.

 

Let's talk about the neutropenia question, and then I'll – I’ll get up and do the last section there. We know that targeting cereblon an on-target effect is neutropenia and hem toxicity in general, at least from what my experience with mezi has been, is at least early on in the first few cycles where you're trying to get a deep response, use G-CSF liberally.

 

We will often use it two or three times a week, as opposed to daily for a period of time. Once you get that response, you can potentially back off the dose as needed. But I'm curious what you all have done as well.

 

Dr. van de Donk: Exactly the same.

 

Dr. Lonial: Yeah.

 

Dr. Schjesvold: Not exactly the same. No. I think that – I also want to touch upon the other question about dose reductions, because I do believe that dose reductions impact efficacy. And I think it’s – that's why neutropenia becomes so important. It's important to use G-CSF instead of dose reduction. Dose reduction is for – is for other things like fatigue, diarrhea, but not for neutropenia.

 

But I don't like the – I like the PEGylated version. That was the difference. So – so we – I only use PEGylated. And usually patients – this problem is biggest in the beginning, but for some it – it lingers also later. So – so what we end up doing there is just to – they have their – their – their shots at home. They take one some days before cycle one day one.

 

They come. The neutrophils are good. We start treatment and we – for some, we – we don't need to continue this, but for some they just do that. Most patients don't have any side effects from PEGylated G-CSF. Some do. And then we have to be sort of find a different way. But – but I think that is both more tolerable and – and less – less sort of needle shots and a much easier way to do it.

 

Dr. Lonial: Yeah. No, but I think the take-home message is use growth factor support rather than – I think particularly early when the marrow may have heavy tumor burden, where your mylo – myeloid reserve may be lower, and then later on you may not need it.

 

Dr. Schjesvold: Yeah. But I think it's – it’s an important thing that many of those who need it in the beginning don't need it later. But – but it's also – some also need it later. And I think, of course, the situation of the patient impacts. If this is an aggressive patient, you want to keep the dose, you just continue G-CSF. If it's a more indolent situation, you kind of want at one point go to dose reduction instead, if they don't want to take the shot anymore. But for most patients, it doesn't matter taking this monthly shot, I have to say.

 

Dr. Lonial: Okay. All right. Good. All right. Let me get up and do the last one.

 

[01:03:09]

 

Future Implications and Directions for Individualizing Treatment of R/R MM

 

All right. So let's talk about future implications and directions for individualizing treatment of relapsed and refractory myeloma. And for those of you who have been sending questions in, we can see them. We will do them in the Q&A as soon as we're done here in just a few moments.

 

[01:03:25]

 

MRD: Trial Endpoint or Clinical Tool?

 

So MRD is a trial endpoint or clinical tool?

 

[01:03:29]

 

Poll 5

 

So how likely would you be to consider a novel treatment for myeloma that was approved by the FDA or EMA based on MRD-negative CR data?

 

1. Very unlikely;
2. Unlikely;
3. Neutral;
4. Likely; or
5. Very likely.

 

Go ahead and vote please.

 

All right. So it looks like almost 80% were in the likely or very likely category, which is – which is good. Okay.

 

[01:04:16]

 

New Considerations: MRD as an Endpoint in MM

 

So I think as we begin to think about MRD as an endpoint in myeloma, I think there are a couple of caveats to this. And the first is if you look at the IMWG and the IMS consensus guidelines, MRD testing really should be done in the setting of serologic complete remission.

 

And so I think that's an important objective number to look at when you compare clinical trials that give you an MRD rate, but don't necessarily tell you the MRD CR rate. And that, in fact, has been accepted and validated by the FDA. And I think EMA is – is considering that as well.

 

We do know that the methodology doesn't necessarily matter. Is it NGF, meaning flow cytometry, or is it NGS, meaning looking at something similar to the adaptive test or the adaptive test? Either one of those is okay.

 

We also know that testing within the bone marrow is, on average, a log more sensitive than testing within the peripheral blood. So bone marrow-based MRD testing is sort of where the standard is today. Likely that will evolve in the next few years to the use of peripheral blood testing for other potential markers that may be equally as accurate or more accurate down the road.

 

[01:05:31]

 

Evaluation of MRD as Surrogate Marker for PFS

 

So if you look at evaluation of MRD as a circa – surrogate for PFS, this is data published by the i2TEAMM group that looked at MRD testing MRD-positive versus negative in over 10,000 patients from large randomized phase III trials. And they looked both at transplant-eligible and transplant-ineligible, as well as in the relapsed and refractory myeloma trials. And across the board, patients who were MRD-positive had better progression-free and overall survival compared to patients who were MRD-positive.

 

And based on that analysis and the publication of that, over 10,000 patient experience, the Oncology Drug Advisory Committee, or ODAC in the US, unanimously voted to allow MRD testing as an end point in early multiple myeloma for accelerated approval.

 

[01:06:24]

 

MRD in Recent Phase III Trials in Transplant-Ineligible NDMM

 

Now, I think some of this comes on the heel of the fact that MRD negativity, as you can see, particularly in the transplant-ineligible group, but in all patients in general is increasing dramatically, as you see on the x-axis on the right. And so with subsequent more modern trials, if we end up having to wait for PFS, it could have significant delays in terms of offering benefits to patient based on these important triplets, quads, immune therapies, CAR T cells, all of these things could be limited if we have to wait for progression-free survival.

 

[01:07:00]

 

MRD and CR Used as Endpoints in MM to Support Accelerated Approval

 

So I think the FDA does in fact allow MRD-negative CR as endpoints to support accelerated approval in certain new drug indications. And this, again, as I mentioned, is because overall response rate, PFS and OS are becoming increasingly more difficult to use.

 

So this – this assessment by ODAC and then accepted by the FDA is part of the EXCALIBER relapsed/refractory myeloma accelerated approval that we hope to hear about. The FDA has – has reported that they're going to tell us something in August regarding that approval. And that is the basis for that initial approval as well.

 

[01:07:43]

 

Practical Considerations With Novel Protein Degraders for MM

 

So what about practical considerations with novel protein degraders in multiple myeloma?

 

[01:07:49]

 

Where Do Iberdomide and Mezigdomide Fit in?

 

Where do iber and mezi really fit? Again, both agents have activity in IMiD exposed and IMiD-resistant patients. And profiles of adverse events and relative opportunities are actually quite different.

 

[01:08:02]

 

Comparing CELMoD Agents: Similarities vs Differences

 

So if you think about the similarities versus the differences, they're both oral. They both have activity in heavily pre-treated patients, and they're being studied in earlier lines and in combination with other anti-myeloma trials.

 

The differences are really the trial populations that are being studied. Mezi we know, does have greater cereblon binding potency and in fact is able to overcome some cereblon receptor mutations. And so that is a unique attribute of mezi that it is able to – to achieve that even in patients that have mutations in cereblon. And then you get more rapid and greater downstream anti-myeloma effects.

 

My – iberdomide is – does have a very, very clean safety profile. The best example I always give is we actually have a trial looking at iberdomide in smoldering myeloma. And I have one patient who said to me, “You told me there was no placebo in this trial. Am I really getting the drug?” There was no placebo. It was a single arm trial. So they were, in fact, getting the drug.

 

And the neutropenia is probably a little bit less with iber than it is with mezi as well.

 

[01:09:12]

 

Potential Role of Protein Degradation Modulators in the Future Treatment Landscape of MM in Earlier Lines of Therapy

 

So what about the potential role of protein degradation in – in the future of treatment landscape? Well, again, iber, as I said, potential post-transplant maintenance early as a partner, replacing lenalidomide in triplet or quadruplet-based regimens. Mezi activity in high-risk disease, heavily pre-treated advanced disease, extramedullary disease, and again, as a partner with many other bispecifics or immune-based therapies.

 

And cemsidomide is being evaluated in very similar circumstances as well in partnership with bispecifics as well as with proteasome inhibitors as well.

 

[01:09:52]

 

Practical Considerations: How Do the Safety Profiles for Novel Protein Degradation Modulators vs Each Other and With IMiDs?

 

So what about practical considerations? Well, again, I think differences in neutropenia relate to potency for binding cereblon and neutrophil maturation. You heard the very nice robust discussion around the use of growth factors. This is different from chemotherapy. When you give chemotherapy, adding growth factors too soon may enhance the anti-marrow effect of chemotherapy.

 

This is really a matter of neutrophil maturation. And with – with G-CSF or – or versions of that, you may be able to overcome that maturation effect more quickly, almost like bortezomib with platelets 20 years ago, where it didn't wipe out megs, it really just impaired platelet maturation through its process.

 

Again, the major AEs are hematologic, which is hematologists were pretty used to managing. And again, whether it's infection risk mitigation or the use of growth factor support for mitigating neutropenia, those are in fact really important.

 

[01:10:50]

 

Emerging Strategies

 

I think emerging strategies are, to me, really incredibly exciting. Iber plus elra and other T-cell engagers to enhance depth and duration of response. Iber or mezi with CAR T-cell either as a priming before apheresis or as post CAR maintenance as a way to enhance CAR T-cell efficacy and persistence and reduce T-cell exhaustion. These are all strategies that are being tested as we speak now.

 

[01:11:19]

 

Panel Discussion: Potential Fits for Novel Protein Degraders Into Current Treatment Paradigms for MM

 

So what are the potential fits for these novel protein degraders into current treatment paradigms? Where would you see CELMoDs? These are things that we're going to discuss here in just a moment as a group here.

 

So I'm going to go back over there or maybe I'll ask my colleagues to comment on this. I think, are there any other roles for CELMoDs that you can see that we haven't discussed either Niels or Fredrik? Go ahead. That we haven't discussed already.

 

Dr. Schjesvold: What was the question again?

 

Dr. Lonial: In a perfect world, where would you see CELMoDs fit?

 

Dr. Schjesvold: In a perfect world, I think iberdomide replacing len in frontline. I do believe in mezigdomide being more active, but I think iberdomide is extremely tolerable. Mezigdomide is tolerable, but not as extreme as iberdomide and frontline is a very long treatment, so I would definitely see iberdomide there and mezi at – at relapse. That's in the – in the perfect world. Yeah.

 

Dr. Lonial: Okay. Niels, you want to add anything?

 

Dr. van de Donk: No, I think iberdomide is safe, effective, is a good maintenance drug. And – and mezi can be used in the – in the – in the relapse setting. Also as a bridging therapy, I think MeziKd could be a very good bridging therapy before CAR T to deepen – to debulk the tumor, which results in better efficacy of the CAR T cells. So not only before apheresis, but also as a bridging and mezi probably also as a maintenance after CAR T.

 

And I think because we also have increasing access to different T-cell immunotherapies, when we move from one T-cell immunotherapy to another, I think there is some, although sometimes limited data available, that shows that it's better to have something else in between two different immunotherapies to give the T cells some rest. And I think also there, mezigdomide or iberdomide-based therapy could be a perfect option.

 

Dr. Lonial: Yeah, yeah. Thank you. And I think we've addressed a lot of these questions already. So I don't know that we need to spend a lot more time in terms of mechanisms of resistance. So why don't we get to the Q&A? Because there are a number of questions on the panel for us to – to discuss.

 

[01:13:40]

 

Q&A

 

Okay. All right. So there are a few here. So as the breadth of treatments and combinations for myeloma increases, are technologies such as ex vivo drug screening for patient samples going to play a role in guiding treatment decisions?

 

You know, I – I think the biggest challenge with ex vivo screening is we've been doing this for almost 30 or 40 years in oncology, and very often it doesn't pan out. There's something about the innate immune system, the microenvironment that just can't necessarily be mimicked in a test tube. And I think it makes it really challenging to – to use those kinds of screening regularly to predict efficacy. But you guys are maybe know more about this than I do.

 

Dr. van de Donk: Yeah, I think these – this – this type of ex vivo screenings is very good in getting an idea of whether two drugs are good combination partners and whether a drug has activity in – in primary samples from patients. But I think we are not there at this moment to predict whether based on in vivo screenings, a certain therapy should be given or not.

 

Maybe in the future we will use next-generation sequencing to identify specific mutations. For example, maybe in the future RAS mutations and use the novel RAS inhibitors which are now showing very promising efficacy in – in pancreas carcinoma.

 

Dr. Schjesvold: So – so – so – so I – I totally agree, we have actually tried to do it and it's – it's – it's extremely difficult. I think PIs, they work in the lab in PI refractory. IMiDs sometimes don't work even if they are PI sensitive, I think. And the problem is if you're going to use that to say – it's one thing to use it to say that you can get the drug, but to use that to say that you cannot get the drug, it's very dangerous.

 

Dr. Lonial: Yeah.

 

Dr. Schjesvold: So I think the models we're going to have for this, I don't see them coming actually.

 

Dr. Lonial: Yeah. Yeah. All right. So there's a question here about infection prevention. Is it necessary to use acyclovir/biseptol, which I'm guessing is Bactrim? Is that – or voriconazole for the entire treatment period for multiple myeloma?

 

So I'll – I'll take the first stab. So acyclovir we use indefinitely in anybody with a plasma cell disorder. It's pretty benign. It's very, very cheap. The – the – the Bactrim or PJP prophylaxis we only use when patients are on dex in general. And then voriconazole, we don't really use that much at all, except in patients with prolonged neutropenia. But tell me how you all at your centers do it?

 

Dr. van de Donk: We use a lot of co-trimoxazole, in fact, not only to prevent PJP, but there are also data from the UK group, the TEAMM study that cotrim also prevents against gram-positive coccal infections and gram-positive coccal pneumonias, etc., are quite common in – in – in – in myeloma. So we use cotrim a lot.

 

Voriconazole or posaconazole to prevent fungal infections. We rarely use it, maybe sometimes in the setting of prolonged neutropenia after CAR T, but that's a very few patients or patients after CAR T that have a lot of immune suppression to manage HLH or other complications. Getting cyclo steroids, toci, and other immunosuppressants. Those patients we consider posaconazole irrespective in fact of neutropenia.

 

Dr. Lonial: Okay.

 

Dr. Schjesvold: So – so the – the – the usage of antibiotics especially is very sort of country specific, and we are very sort of conservative in Norway. So Bactrim we use mainly in – in the immunotherapy space. But I think this is an important message also in – in the SUCCESSOR-2 trial and SUCCESSOR-1 trial, the mezigdomide trial, Bactrim was – was mandated because there is a – there is a signal for mezigdomide in PJP.

 

So for iberdomide, you don't need to do that. But for mezigdomide, it's part of the package, like for the immunotherapies.

 

Dr. Lonial: You don't think that's dex?

 

Dr. Schjesvold: We don't see it so much in – in other dex combinations, I would say. We see it a little bit more mezigdomide. So it's at least a stronger signal there. For the others, you can consider.

 

And then when it comes to acyclovir/valacyclovir, we use it in the immunotherapies and in CD38 and MPIs. So it becomes almost everywhere. But we don't do it without those drugs. And I have this question which many patients have. Do we really need it after vaccination? And we don't have the answer to that after zoster vaccination.

 

So I would like that answer to be, no, you don't need it. But we don't know that. So we still do both. But maybe in the future, we will know more about that.

 

Dr. van de Donk: Yeah. I think from the study post-transplant, it was shown that there was still breakthrough infection. So I think after transplant, we – we vaccinate but we still continue valacyclovir for one year. And also when I combine, have a proteasome inhibitor-based combination, I think your baseline risk of zoster is so high that I continue valacyclovir irrespective of vaccination. I only stop it in – after vaccination, for example, if the patient only gets CD38 antibody and IMiD, then I think the baseline risk is so low that I can stop valacyclovir.

 

But you are correct. This is not based on firm evidence.

 

Dr. Lonial: Yeah. So there's a question here about clinical data on the combination and tolerability of mezi plus a bispecific. So the trial that probably has data so far is the MM-MELT study looking at mezi plus elra and the preliminary activity. It's a very small representation that's been shown. Looks very encouraging, consistent with what we've seen in MagnetisMM-30, which is elra plus iber as well.

 

So I think some of this proof-of-concept I think will be there. Well, how it pans out in larger trials, I think we don't know.

 

Dr. van de Donk: Yeah. And durability.

 

Dr. Lonial: Durability. Yeah.

 

Dr. Schjesvold: I think this – this thing about – as we discussed previously, the thing about the CELMoDs and the bispecifics, there are – there are so many questions. We really don't know how to – how to do that, but many signals that there are some things to gain from that. But how to do it is very unclear as of now, I'd say.

 

Dr. Lonial: Okay. So Niels, there's a song here or there's a question here. Is iberdomide much more tolerable to even consider to use if mezi is more potent? Why should we have both?

 

Dr. van de Donk: Well, I think we already discussed this a little bit. I think iber is an effective CELMoD probably better tolerated. So it's a good upfront drug for maintenance for first relapse treatment and mezigdomide more potent, but more neutropenia I think is a – is a good drug that can be used even when the patient has been exposed to iberdomide. So iber followed by mezi.

 

Dr. Schjesvold: But I think part of what you're saying there is that the – the outcomes and the survival and prognosis of especially standard risk patients is becoming so good that safety in frontline becomes more important than and efficacy. And in relapse, the situation changes. So it's – it's not always now about putting the most efficacious first. It has to be efficacious and tolerable.

 

Dr. Lonial: So Fredrik, there's a question here about the PFS at the lowest iberdomide dose seems to be better at least in the maintenance setting. The lower maintenance dose seem to have in the EMN study. So I guess it's probably for both of you.

 

Dr. Schjesvold: Yeah. I – I said something about it, but since this is Neils study, I'll let him answer the question.

 

Dr. van de Donk: Yeah. First of all, this is 40 patients enrolled in each of the three different cohorts, cohort 0.75. Iber started a bit later. So there was more patients, so a higher proportion of patients that was treated with four-drug induction, so dara-VRd or Isa-VRd.

 

So they had already a higher rate of MRD-negativity at baseline at screening. So it's difficult to compare head-to-head all these three cohorts. But overall, I think the rate of MRD conversion from positive to negative, the upgrade in response was similar across all three cohorts.

 

However, the 0.75 cohort was associated with a lower rates of neutropenia, lower rate of infections. And we also know that the immune stimulatory effects of the CELMoDs plateau at doses above 0.75. So we felt taking all these data together, that iber 0.75 is – is a very good dose to further evaluate in the randomized phase III EXCALIBER maintenance study, which was fully enrolled last week. So we hope to see the results of iber versus len in the near future.

 

Dr. Schjesvold: Yeah. And – and you have to have a PR to –

 

Dr. van de Donk: You learn something.

 

Dr. Lonial: Reverse – reverse education. All right. So there's a couple of questions here about thrombosis risk. And I think for all the iber and mezi trials, you were required to be on something in terms of anticoagulation. Aspirin typically, as we would do for low risk patients, was used across the board. If you had a history of prior thrombosis or had other risk factors, similar to what we have done with the other CELMoDs. I think that's – that's not unique.

 

It's not – it’s – it’s ubiquitous to anything that binds cereblon. And so we – we – we do recommend at the minimum to use an aspirin as prophylaxis.

 

Dr. van de Donk: Yeah. And in an high-risk, DOAC.

 

Dr. Lonial: Yeah. Yeah. So there is a question here about cereblon mutations which can occur anywhere between 10% to 30% of cases post IMiDs. How does that – how does that impact sensitivity to iber or mezi?

 

Dr. van de Donk: Well, I think ongoing studies are looking at all these relapse samples and identifying mechanisms of resistance to IMiDs and CELMoDs. And I think from preclinical studies, it has already been shown that mezi and also iber are able to bind also to mutated to specific certain mutated cereblon molecules and thereby still can – can still be active. But I think this is still an ongoing research field.

 

Dr. Lonial: Okay. Anything to add? So there's a question here about activity in other B-cell neoplasms, given the importance of or dependence of IKZF1. Any – any experience or thought about that?

 

Dr. van de Donk: Well, BMS is also developing a third CELMoD, not iber, not mezi, but gamocidomide[?], if I pronounce it correctly.

 

Dr. Lonial: Golcadomide.

 

Dr. van de Donk: Golcadomide. Sorry. Golcadomide in the lymphoma space. And in the Netherlands, we have a HOVON study, for example, with this agent in diffuse large B-cell lymphoma, but also in primary central nervous system lymphoma, because this compound, golcadomide, is penetrating the blood-brain barrier. So might be also very interesting in that subset of lymphoma.

 

Dr. Schjesvold: We also know that lenalidomide is used in follicular lymphoma with good effect. So I think they are all B cells. Sometimes they – they – they respond to the same drugs, sometimes not. And usually you have to test it before you know. It's not so easy to predict. So many of these drugs are tested in – in different.

 

And why gum – golcadomide is used for lymphoma and the others? For myeloma, it's beyond me. I don't know if you know anything about that?

 

Dr. van de Donk: I think they showed that it penetrates very well in lymphoid tissues. And lymphoma, of course, is a lump. Mezigdomide also penetrates well in plasmacytoma. So – but I think based on specific properties in that space penetrating blood-brain barrier, probably they prioritized golcadomide in lymphoma.

 

[01:26:00]

 

Poll 6

 

Dr. Lonial: So do we have another question? Oh, we do have another poll question. All right. We've got time for one more of these questions. But then while we're doing it, do the poll question.

 

Do you plan to make changes in your clinical practice based on what you learned in today's program?

 

1. Yes;
2. No; or
3. Uncertain.

 

And Fredrik, you can answer this one.

 

Dr. Schjesvold: I'm uncertain.

 

Dr. van de Donk: Still uncertain. We learned here so much.

 

Dr. Lonial: All right, so about a third are yes. We'll take the uncertainties as maybe. All right.

 

Dr. Schjesvold: But I think, you know, this – this question is always a bit premature when we mostly talk about things that are not on the market. So it's – but some of the messages here are for – for the things we have on the market also.

 

[01:27:09]

 

Poll 7

 

Dr. Lonial: Yeah. Yeah. No, I think you're absolutely right. So please take a moment to text in one key change that you plan to make in your clinical practice based on what you've heard today. And you can use the app in the QR code to do that. And where are we time wise? We are 9:27. We'll do one more question and then we'll wrap up.

 

[01:27:29]

 

Questions?

 

So there's a question here about why is dexamethasone always chosen as the first combination partner rather than other things?

 

And I think what we know about the cereblon binding agents is that there is huge synergy with corticosteroids. That's – that's not unique to iber or mezi. And in fact, you see that in – in both the 001 trials for mezi and iber. Those patients were resistant to dex, and yet you saw a significant increase in the activity with the combination there.

 

Dr. Schjesvold: Okay. So – so I have a comment. I think every time it's not that common, but every study that has done a monotherapy plus/minus dex in relapse, it has increased the efficacy with dex. On the other hand, every study that has a dose of dex and randomized to reduce dose is at least as good and sometimes even improving.

 

So I think main message is that dex is part of very many things you do. It's always the first thing to take away.

 

Dr. Lonial: That's right.

 

Dr. van de Donk: Absolutely. So I also reduce the dex dose. I stopped the dex dose in the end if patients are getting into a deep response.

 

Dr. Lonial: Yeah. Yeah. No I think that makes sense.