Next-Generation Approaches for Relapsed Refractory Multiple Myeloma: A Focus on Novel Therapeutic Targets and Pathways

So I am going to start off with the need for novel therapeutic approaches in the context of relapsed and refractory myeloma.

[0:15:26]

Current state of the art

So I think it is important I am going to sort of set the stage, if you will, in terms of what is the current state of the art and where can these new drugs potentially come in and offer significant benefits. So we now have randomized phase III trials that demonstrate the benefit of early intervention amongst the highest risk group of smoldering multiple myeloma. And this is really important because we think in the US we are on the cusp of the first FDA approval in the context of smoldering myeloma based on the AQUILA trial. So an area where I think we have all wanted options for those patients, we may soon have them, at least in the US, and I believe that it is being filed in Europe as well.

Induction therapy with 4 drugs, including an IMiD, PI and Anti-CD38 for all except the frail patient. And, I would argue, the frail patient, I am not sure I want to give them a quad. I might stick with things that we have been using for a while, based on the MAIA study, that are highly effective in a much more frail patient population.

I do believe, and I think my colleagues will agree with me, that transplant does continue to offer significant benefit for patients who are fit, and in the US, we consider transplant up to age 78 or age 79. We may reduce the dose of melphalan, but certainly we do use high dose therapy in a broader group of patients.

And finally, immune therapies like T-cell engagers, CAR T-cells or antibody drug conjugates are clearly active, but they do not ultimately cure a large fraction of patients.

So we still have a number of patients that need new opportunities and new challenges in the context of relapsed and refractory disease.

[0:17:02]

What are the unmet medical needs in 2025?

So what are those unmet medical needs outside the lines of what I just discussed a moment ago? Well, patients who have or develop high-risk disease, particularly patients with extramedullary myeloma, those continue to remain a challenge. And while cytotoxic chemotherapy-based approaches may ofer some benefit, they are often limited, and even with the newer immune therapies, the benefit in extramedullary disease is less clear. Frail patients, patients whose comorbidities limit aggressive treatment options, we need new treatment approaches to make sure that we can continue to take them from first line when they relapse, to second line and third line. A large percentage of patients who are frail do not get past first line therapy. So recognizing how to approach more gentle approaches in that context is really important.

Patients with 3 or more prior lines of therapy. In the modern era, this likely means you've exhausted PIs, the IMiDs, as well as CD38 antibodies, and certainly in some contexts, maybe even BCMA directed therapy. So these are patients that have seen a lot because of the combinations we use and we probably need to do something different.

And finally, patients who are resistant or intolerant to these major targets. These include IMiDs, PiS, and as I mentioned before, these are increasingly becoming a large fraction, particularly of my clinic, where I tend to take on the more sort of heavily pretreated patients, the refractory patients. Those are the ones that tend to show up and hope I've got a trial to be able to help them. These are where we really need new treatments and new approaches.

[0:18:48]

What are the new options?

So what are those new options? Well, CELMoDs certainly represent an important next set of treatment options, both iberdomide and mezigdomide, which while we think about them as cereblon binding agents, agents that target cereblon, you are going to hear more from my colleagues about how they really are different and may offer significant, subtle responses and depth of response, as well as mechanisms than what we see with the older IMiD class.

We have new classes of CAR Ts that are targeting more than BCMA. They are now beginning to target GPRC5D. We have new antibody drug conjugates that are targeting GPRC5D.

We have trispecifics. They were presented at ASCO just a few weeks ago and are going to be presented at this meeting as well.

And finally, I am a firm believer that each of these novel immune therapies may be effective, but the ultimate utility is going to come as part of combination packages. And as we begin to think about what are the mechanisms of resistance for many of these immune therapies, it is T-cell exhaustion. We are dependent on a limited pool of T-cells. And so having new drugs and new targets that expand that pool of T-cells or wake them up, as I've often said, I know that I will often use the analogy that the CELMoDs are like cappuccino for T-cells. It is early, hopefully everybody's had their cappuccino this morning, but oftentimes in myeloma patients, their T-cells need that wake up and that is where new drugs can really offer significant benefit.

[0:20:23]

CELMoDs co-opt cereblon via unique binding features, inducing distinct conformational changes

So I mentioned earlier that the CELMoDs do represent a real difference from the IMiD class, and they are really engineered to do more than the IMiD class was really focused on doing. And some of that has to do with conformational changes. You can see here that the binding affinity for cereblon is significantly higher for both iberdomide and mezigdomide. And in fact, if you look at mezigdomide, mezigdomide almost puts 100% of cereblon targets within the closed conformation. And what we know about that closed conformation is that it has a much quicker on rate and that it has a much more significant impact in terms of cell death.

When we think about the IMiD class, I think about them as being cytostatic. They prevent proliferation. They do not always kill the cell. The CELMoD class actually is cytotoxic. By inducing this closed conformation, you get a lot more cells that ultimately die directly because of binding of iberdomide or mezigdomide, and more so with mezigdomide even than with iberdomide.

[0:21:31]

Iberdomide and mezigdomide affect immune cell populations in the bone marrow microenvironment

Now what about the effect? You've heard us call them CELMoDs. I think of CELMoDs because they really do focus on activating cellular immunity. That is not what they are named for, but that is how I think about it. And you can see that in patients. These are patient samples from the phase I and phase II trials. You increase activation of T-cells and NK cells and you decrease the exhaustion phenotype. And this really is important. And this happens both with iberdomide and mezigdomide. And this to me is why they are potentially perfect partners with T-cell engagers, CAR T-cells. Thinking about it in the pre and post CAR T-cell context, pre to perhaps increase the frequency of better T-cells to make a better CAR product, and post as a way to maintain the persistence of the CAR over a longer period of time.

[0:22:24]

Cemsidomide (CFT7455) binds cereblon, facilitating ubiquitination and degradation of key proteins

Now there is another cereblon binding agent that is in very early drug development, and this is cemsidomide or CFT7455. This also has novel properties, you can see that listed here, in terms of binding affinity. We have reported on some early clinical data in this trial. It is much earlier in its development in terms of being able to function, so how it compares with agents that are much further along in the pipeline, like iberdomide and mezigdomide, is unclear. But as I told you before, we would like to have more potential ways, more potential drugs to be able to target many of these pathways.

[0:23:04]

Topics to discuss today

So we are going to talk about a number of topics today. The first is what are the relative additions to our treatment with CELMoDs. And you've heard me sort of tease some of those. You are going to hear that from my colleagues up here in the next few moments.

The second is what does this new class really offer over existing therapies?

And finally, how do we together come up with optimal approaches to improve duration and depth of response and maintain normal immunity? We know, for instance, that if you target BCMA, you will suppress almost all plasma cells. The IgG levels drop very, very low. And so you become very dependent on T-cell mediated immunity to prevent infections. We need agents that augment that T-cell mediated immunity to reduce the risk of infections and reduce the toxicity, perhaps, of many of those highly effective but highly immunosuppressive treatments as we go forward.

So I think that is my last slide. And who is up next? I think Charlotte is up next. Okay. Thank you.

[0:24:20]

How Targeting Protein Degradation Pathways Changed the Approach in Myeloma

Dr Charlotte Pawlyn (Royal Marsden Hospital): Thank you very much for that wonderful introduction, and welcome to everybody who has joined us this morning. Sorry, I feel a bit uncomfortable turning around, but I am going to try and involve all of the audience. My name is Charlotte Pawlyn. I am a hematologist at the Royal Marsden Hospital in London, but in the other part of my life, I spend a lot of time thinking about protein degradation in the lab in the Institute of Cancer Research. So I am going to talk us through a little bit about what we understand at the moment about protein degradation pathways and how this has really changed how we treat myeloma, and why I think these are some of the most exciting new drugs, because they harness this different way of targeting proteins and the signaling pathways within myeloma cells.

[0:25:03]

Serendipitous discovery

So I think you probably have all seen this before and are familiar with the development of the IMiDs that we currently use in clinical practice, but for me, this is 1 of the most interesting drug discovery stories in any drug that we use across oncology. So we use a drug that we did not understand how it worked. But some really smart clinicians noticed that or thought that thalidomide, which had previously been withdrawn from the market in the 1950s and 60s when it was used as a sedative and morning sickness treatment, might have some activity in myeloma. And I think that is really amazing because this from first principles, this is potentially affecting angiogenesis. Maybe this will have some impact in myeloma cells and maybe this would be a useful treatment.

But it wasn't until a long time later, so if you look along this time course, it wasn't until 2010 and then 2014 that we understood why these drugs are working. And we had demonstrated before that that they were, and that is great, we were using them in clinical practice. But that understanding of the mechanism really means that we can take the next step further and enhance these drugs, but also use this approach to target other proteins and potentially other forms of cancer as well.

So just to kind of orientate some of you to the timeline, I think it was in about 1999 that the first phase II publication about thalidomide was published. 2002 lenalidomide, pomalidomide a little bit later. And those have all obviously then subsequently gone on to be approved and we use in our clinic every day to treat patients with myeloma.

But they really changed how we treat myeloma before we understood how they work, and I think that is really important. We spend a lot of time thinking about drug discovery in 2025, and we have to have a target, validated target, demonstrate why that is important. But actually we have been using these drugs without knowing that in the past.

[0:26:59]

This is that original paper from 1999 which is summarized here. And I think it is really testament to the authors that they took this kind of initial thought and took that forward into a trial and demonstrated this in an era when outcomes for myeloma patients were really terrible in comparison to outcomes for our patients today. And so you can see they saw about a 30% response rate and an event free survival that was only a few months, but really a signal that this was going to be something that could change how we treat myeloma patients by moving this drug earlier in our treatment lines.

[0:27:34]

Ubiquitin-Proteasome System (UPS)

And so I just wanted to review just because perhaps you do not all spend as much time thinking about this as me, why these drugs work and how they work and how we did go on to understand the mechanism of action. So really IMiDs and then the drugs that have been developed from them target the ubiquitin-proteasome system of our cell. So in a cell we need some kind of recycling system, some kind of normal cellular processing of proteins. And what happens is that a protein, in this case a purple protein, goes and binds to an E3 ligase molecule, in our case cereblon. And that leads to tagging of the protein by a ubiquitin tag that targets that protein for degradation. So this is how we recycle proteins when they are no longer needed, and break them down into the constituent peptides to remake proteins that the cell then needs to function. Other proteins can't then access that pocket. So you've got this protein that is being degraded.

[0:28:31]

Molecular glues can hijack the UPS

But when we talk about molecular glues, which IMiDs and CELMoDs are, then they act like a Pritt Stick. So I am hoping Pritt Stick translates outside of the UK, it is a ubiquitous glue stick that children use in nursery schools. But really, our molecular glues are acting like a Pritt Stick, and they act in a way that alters what combined into this protein complex. And so now our yellow protein that previously couldn't bind, can bind in here, and that then gets tagged just because it was brought close into this protein complex. And then it can be degraded and broken down. And so this enables us to remove difficult to drug proteins potentially because we do not need to find a binding pocket in that yellow protein to be able to target it for degradation.

[0:29:15]

IMiDs are molecular glues

And IMiDs are molecular glue. So in the context of IMiDs, we have cereblon as part of the E3 ligase complex and the proteins that the yellow blob in this diagram represents are Ikaros and Aiolos, and these are key transcription factors for the survival of a myeloma cell. And when they are degraded, that leads to downregulation of Myc and IRF4, which ultimately leads to myeloma cell death. And we found all of this by accident, and that I think is really incredible to me. If we had gone after these, transcription factors, we would have struggled to drug them. Transcription factors are very difficult to find inhibitors for, but because we can use this method of degrading them, that means that we can target them in this way instead.

[0:29:57]

IMiDs have activity outside direct myeloma cell targeting

But we also know that IMiDs have activity outside of direct myeloma cell targeting. So in this diagram you can see the direct effect on the myeloma cell right down the middle of the diagram, and then on the right hand side you can see all of these effects that IMiDs have outside of that direct myeloma cell approach.

[0:30:13]

Mechanism of action in immune cells

And interestingly it is the same mechanism, so it is still using cereblon to degrade Ikaros and Aiolos, but in a T-cell for example, which I've shown here, degradation of Ikaros and Aiolos prevents the repression of the expression of IL2, and therefore upregulation of IL2 follows, which leads to T-cell activation. And this is probably 1 of the mechanisms that we were talking about in which this cappuccino effect could potentially take place.

[0:30:46]

IMiDs are highly effective in combinations at all lines of therapy

But you will know from your clinical practice that we use IMiDs in highly effective combinations at all lines of therapy. So we have IMiDs and first line in the UK, perhaps in large parts of Europe still, thalidomide in the context of daratumumab VTd, hopefully soon daratumumab VRd instead, so lenalidomide substituted for thalidomide. But all of these other combinations you can see across every line of therapy, after every previous therapy, we are reaching for a different IMiD because we know that they are tolerable treatments, they are oral treatments, and they are very effective in terms of combining with partners to deliver effective care for our patients.

[0:31:25]

Thalidomide vs lenalidomide

We talk a lot about trying to replace drugs, but there is not a lot of data looking at the classical IMiDs kind of head to head. And so there is some data and this is 1 study that did try to look at this question. So this is the Myeloma 11 trial that we performed in the UK and you can see this is the outcome primarily focused on looking at the quadruplet carfilzomib, cyclophosphamide, lenalidomide and dexamethasone, which you can see outperforms the IMiDs triplets. But we did have a comparison between the lenalidomide-containing triplet, cyclophosphamide lenalidomide dexamethasone, and the thalidomide-containing triplet. And you can see that even though the improvement is modest, there is a significant benefit from using that second generation lenalidomide as opposed to thalidomide in its original form.

And even if you are not totally convinced that 3 months of improvement in median progression free survival, in the kind of really long progression that we are seeing at the moment, then I would really focus on the side effect profile. We know that it is a lot more tolerable to deliver lenalidomide than thalidomide, and that is because largely the huge difference in peripheral neuropathy that you see at the top of the right graph on this slide. So a huge reduction in terms of peripheral sensory and motor neuropathy when we switch to lenalidomide compared to thalidomide.

[0:32:49]

Pomalidomide active even in setting of lenalidomide resistance

So that is just 1 way in which we evolved the original IMiDs. And after that pomalidomide. You can see in this data from the OPTIMISMM study, which was a randomized phase III trial looking at pomalidomide, bortezomib and dexamethasone compared to bortezomib and dexamethasone alone for relapsed patients. This is a subanalysis looking only at those patients on the left, who are lenalidomide exposed, and on the right lenalidomide refractory. And you can see that even in those refractory patients you are getting an additional benefit from pomalidomide. And this really just speaks to how we can evolve this approach to improve protein degradation and really target patients who are resistant to the prior version of this protein degradation approach.

[0:33:25]

Summary

So in summary, for the first part of my talk, I think we have thought a little bit about thalidomide repurposing. This is a really great example of repurposing drugs after its prior approval for leprosy, which really changed the course of how we treat myeloma patients today. And for me, it is really interesting because unlike other discovery efforts, IMiDs altered our treatment paradigm before we understood their mechanism of action. But we do now understand that mechanism of action and that that is that IMiDs hijack the UPS system to degrade these critical B-cell transcription factors, which ultimately leads to direct anti-myeloma activity, and also this indirect activity via the immune microenvironment.

[0:34:08]

So that is the end of the first part of my talk, but I think I am moving straight on. So we will go into the second part and we will have lots of time for questions at the end. So if you do have questions, then please put them through the app so that we can approach them.

[0:34:42]

IMiD resistance as a clinical entity

So I've just talked us through I guess the kind of prior generation of protein degraders, these kind of initial approaches that we used and that are currently approved for use in the clinic. But I want to move on and talk about why that is still challenging. So we use those drugs, they are effective but we all see every day that patients unfortunately will still relapse. And even if we move through IMiD therapies, patients will ultimately relapse. And I just pulled this graph because I think it really emphasizes even for patients with really deep responses, MRD-negative responses after transplant patients who were put onto maintenance, lenalidomide, even those patients, they have improved outcomes compared to those patients who do not have maintenance, for example. But ultimately they relapse. And so although we are achieving these really deep responses, we need to think about novel ways of targeting that situation.

[0:35:21]

Mechanisms of IMiD resistance

And we understand a little bit about the science of IMiDs resistance. So there are lots of papers from lots of colleagues from around the world summarized in this diagram, thinking about the changes that we can see to understand why patients might become resistant. And we have talked hopefully through those diagrams I showed you of how proteins are degraded. You can start to think of what might change to lead to those resistance mechanisms. So we know that we can see alterations in cereblon itself through mutations, through copy number change, through exon 10 splicing, through methylation changes. We can also see downregulation of protein expression that is not necessarily associated with genetic change, that often can happen at the point of acquiring resistance. We see changes in that E3 ligase component processing, so alteration of the COP9 signalosome, for example, which is how those E3 ligase complexes are put together.

And then we also see some mechanisms that are sort of independent of cereblon, so kind of bypass the role of Ikaros and Aiolos degradation in the control of IRF4 to maintain IRF or even without those being present. And so we understand a little bit about why this is important. I think we do still understand a little bit less about the myeloma cell extrinsic mechanisms of resistance. So why do patients, if we have these dual targeting approaches both in myeloma cell and in the immune system, why does that immune role not carry on? What happens that means that that is no longer effective for patients?

But overall we can see all of these mechanisms emerge. And so we need novel approaches to overcome IMiD resistance.

[0:37:01]

Novel CELMoDs in development

And that is I think for me where the CELMoD development really comes in to make us think about how could we make more potent versions of protein degraders to try and overcome this? And I think this really was influenced by this understanding of how the original IMiDs were functioning. So we discovered the cereblon pathway in 2010 and then 2014 really understood how they were working, and that enabled the kind of logical evolution of the original compounds into compounds that are more effective in terms of what they can do as degraders.

And you've seen this slide already, but I just want to go through a few of the points in terms of how this is important in overcoming the previous resistance to IMiDs and why these drugs are therefore more effective even in the setting of patients who've had IMiDs exposure before. So there are a few things that make the CELMoDs different to the original IMiDs. One is that classical IMiDs present as a mixture of the S and R isomers, so different forms of the same compound, but the CELMoDs are a single S isomer, which is more effective. We also have this difference in cereblon binding affinity. So this is really important because if you have lower levels of cereblon in the cell, because of resistance acquired from previous exposure to IMiDs, you need a much more potent drug to be able to utilize the less cereblon that is left behind in the cell and potentially overcome some of those other mechanisms of resistance as well.

And then more recently, in the beautiful work shown on the right of the slide, this conformational change that we see when the IMiDs bind to cereblon. So if you remember, you need the IMiD or CELMoD to bind to cereblon and change the binding pocket to enable different proteins to bind. And we know that it is the closed conformation that is where those proteins can bind and be degraded, and that closed conformation is formed much more potently by iberdomide and mezigdomide compared to lenalidomide and pomalidomide, and that is why it can be much more effective as on top of the increased binding affinity.

[0:39:08]

Degradation and antiproliferative activity of CELMoD agents

And so this is just some data looking at those key factors that we thought about when we understood the mechanism of action of IMiDs. But you can see on the left the degradation of Aiolos, 1 of those key B-cell transcription factors, that really is more potently degraded by iberdomide in the green line and mezigdomide in the purple line, just really pulling together that increase in potency.

And on the right you can see the activity in cell lines in terms of drug concentrations that are that are needed to get an antiproliferative activity. And you can see that you need much, much lower concentrations with iberdomide and mezigdomide, really speaking to this increased potency. But also, in the orange bars of that graph, you can see that iberdomide and mezigdomide are overcoming resistance. So in cell lines that have been generated to be resistant to the IMiDs, this can be overcome with the CELMoD activity.

[0:40:05]

Iberdomide activity retained in IMiD resistant context: CC-220-MM-001 study

And this is some data from patient samples included in an iberdomide trial, really just to bring home that we do see some of those mechanisms of IMiD resistance. You can see reduced cereblon expression. You can see that these patients had molecular dysregulation of cereblon through mutation or copy number change or a cereblon defect. And even though lots of these patients had those changes, there was, as we are going to go on and hear, higher efficacy in terms of response rates despite those previous IMiD resistant changes.

[0:40:35]

CELMoD ability to overcome CRBN molecular dysregulation

This is some work that we did in my lab, trying to look at how CELMoDs may be different to IMiDs, and might be able to contribute to this overcoming of prior resistance. And what we did was take a cell line where we knocked out normal cereblon and put back in a variety of different mutations at different points along the cereblon protein. And what we are really showing here, if you look on the bottom, is that for some mutations, not all, but for some mutations you can see that there is resistance to lenalidomide shown in the graph in the middle of the bottom, but that that can be overcome with mezigdomide. So in the black line in the middle, you can see that that activity of the CELMoD is able to overcome the resistance generated by this single point mutation.

And you can see in the Western blot on the left that there is degradation of Ikaros with iberdomide and mezigdomide in that resistant mutation that is not seen with lenalidomide and pomalidomide. And so we really do see differences in these newer generation compounds.

[0:41:39]

CELMoDs generate synergy with other antimyeloma agents

We also have some preclinical studies that suggest that there is good synergy of the CELMoDs. Like with the IMiDs before, I said we look to use these agents in combinations. And kind of looking through ideal combination partners for CELMoDs, we have seen excellent data looking at combinations with proteasome inhibitors, carfilzomib, bortezomib, also with anti-CD38 antibodies, daratumumab for example. And this has been associated with deep induction of apoptosis and enhanced antibody dependent cellular cytotoxicity, really speaking to this kind of cell kill activity that Sagar was referencing before.

[0:42:16]

Cemsidomide (CFT7455): novel molecular glue degrader

I have a slide about cemsidomide. As Sagar was saying, this is slightly behind in terms of clinical development, but equally we see this enhanced degradation of the neosubstrate. So this is Aiolos degradation again, on the left showing a beautiful dose response going down to low concentrations of cemsidomide. And then the antiproliferative activity and cell lines on the right with a 1000-fold lower concentration needed to get anti-proliferation activity with this novel molecular glue as well.

[0:42:52]

CELMoDs have activity outside direct myeloma cell targeting

But again, I showed you before that IMiDs have activity outside of direct myeloma cell targeting. That is also true of CELMoDs, and they seem to do it even better. So when we look at the right hand side of this diagram, we are focused on the NK cells, the T-cells in the immune microenvironment, and where the CELMoDs can have activity there as well. So what we have seen is that samples from patients treated with iberdomide and mezigdomide had increase in activated and proliferating T-cells. They are being woken up in the morning. We have increase in proliferating NK cells. And this can be further increased if we think about adding some of these logical combination partners in to see that synergistic effect. We can see that iberdomide appeared to retain immune stimulatory effects even after patients had BCMA targeted therapy. So even when patients have had some of our most potent drugs at the moment, we can see that the CELMoDs are able to activate their NK and T-cell proliferation and increase the number of activated cells to really enhance the activity of the CELMoDs in that setting.

[0:43:53]

CRBN is not the only potential ligase that could be hijacked

I've just got 2 slides to end on, because this is something I think is really fascinating, and this is to really highlight the potential of this science going forward. So we are really focusing on here on molecular glues for cereblon, but when we are thinking about protein degradation, there are really many, many other things that we could potentially use this new understanding for to improve oncology drugs, not just for myeloma but across the spectrum of oncology.

So this is just really to highlight this ubiquitination, this degradation pathway, is not only driven by proteins like cereblon and VHL, which is part of the same class of E3 ligases as cereblon. But there are many other ubiquitin targeting protein complexes that we could hijack in a similar way. And now we understand how these drugs work and have been able to already improve the IMiDs into the CELMoDs, we can think about how to do this in other ways as well, utilizing perhaps different targets so we could overcome resistance in that way as well.

[0:44:57]

Different approaches to hijacking E3 ligases

There are also different approaches to hijacking these ligases. So what we have been talking about or are talking about today are molecular glue degraders, so they bind to the E3, alter the conformation and enable a protein of interest to bind. But we are seeing now coming through these PROTAC molecules. So this is where you have 2 binding proteins with a linker. And this enables you to bind almost any protein if you can just develop that original protein, protein of interest binder, attach it by a linker to your E3 binder, and then bring that protein close to the E3 to enable the degradation of proteins that we would never be able to inhibit with normal drug targeting approaches. And I think this is exemplified by the BTK degraders that we know there is data being presented here at EHA about as well. So I really encourage you to think about those as novel mechanisms.

[0:45:46]

Why aim for protein degradation rather than inhibition?

I am sorry this slide does not project very well, but I think it is really worth thinking about why we are interested in protein degradation as opposed to inhibition. So if you think about original small molecule inhibitors, where we are trying to bind into an enzyme pocket, for example tyrosine kinase, you need 1 molecule of your drug to inhibit every molecule of tyrosine kinase. The great thing about degraders is that you do not; your E3 ligase can work again and again and again to degrade multiple copies of the protein that you are interested in getting rid of. And that, for me, is 1 of the really important things; you need reduced occupancy of binding. You do not need to bind every protein that is there.

There are improvements in target selectivity. There is help in terms of on target toxicity. This is a good example. VHL, for example 1 of the other E3 ligases, is not expressed in platelets. So if you are worried about thrombocytopenia as a side effect, you can use that E3 ligase to try and target degradation approaches that way.

And then if you look on the right the duration of the drug effect can also be longer. So if you are inhibiting a protein, when the drug goes away, that protein immediately comes back in terms of its activity. Whereas if you are degrading a protein, then you have to wait for new protein to be synthesized. And so the duration of drug effect can be longer.

And then lastly, in terms of overcoming resistance, there are ways in which by degrading proteins, that can help us to overcome resistance by removing the mutant protein that perhaps is acting in a different way to the original protein.

So this for me is a really exciting field. But really, just to come back to what we are talking about today, this really just exemplifies why the CELMoDs have helped us to move on from the original IMiDs, to use all of these mechanisms to help us to target myeloma more effectively.

[0:47:38]

Summary

So in summary, we have talked about protein degradation strategies being used effectively to treat myeloma for many years, even before we understood how they work. But we now have novel approaches, and novel approaches looking at CELMoDs like iberdomide, mezigdomide. And they have really enhanced anti-tumor activity, but not only focusing on the tumor but also on the immune microenvironment. And hopefully I've managed to convince at least some of you that protein degradation as a field in general is also super exciting in terms of how we could target difficult to target proteins. Thank you very much.

[0:48:16]

Let’s return to an earlier question

Just before I hand over, we have to prove that we have educated you in some way and taught you something. So can we return to 1 of our previous questions?

[0:48:27]

Posttest 1

So could we ask you which of the following best describes the differences between novel CELMoDs and approved IMiDs in regulating myeloma cell proliferation?

So A was higher cereblon binding affinity increases the expression of transcription factors.

B was higher cereblon binding affinity by CELMoDs enhances degradation of those key transcription factors that promote myeloma cell proliferation.

C is lower cerebral on binding affinity by CELMoDs, reduces off target effects, and promotes immune cell activation.

D, CELMoDs bypass cereblon and directly induce reduced cell proliferation signaling and enhanced immune cell activity.

So take a couple of seconds. They are all quite long, but please vote now.

Fantastic. Am I allowed to give away that that is the correct answer? So the correct answer is that higher cereblon binding affinity by CELMoDs enhances the degradation of those key B-cell transcription factors that promote myeloma cell proliferation. So well done. I think we did improve from the pretest score. So thank you very much. And I will hand over to Professor Cavo.

[0:49:54]

Key Data with Novel Protein Degraders in Advanced Relapsed/Refractory Multiple Myeloma

Prof. Michele Cavo (University of Bologna): Thank you. I will start from a concept already introduced by Professor Lonial.

[0:50:04]

CC-220-MM-001: Iberdomide ± SoC treatments for R/R MM

CELMoDs are a new class of agent with a new mechanism of action, and I will start by providing a brief summary of the key data from the earlier clinical trials exploring iberdomide and mezigdomide, mainly in patients with very advanced disease phase. Iberdomide, formerly CC-220, was investigated in different combinations at different doses in this phase I, phase II trial. And as you can see in cohort B, iberdomide was explored in combination with dexamethasone at dose escalating from 0.3 up to 1.6mg. And the objective of phase I dose escalation was to identify the recommended phase II dose, which was established for iberdomide at 1.6mg daily, and this dose in combination with dexamethasone was further explored in 2 different cohorts, cohort D and cohort I in the phase II dose expansion portion of the study.

Patients enrolled in cohort D were triple class refractory after at least 3 prior therapies, while patients in cohort I should have received a prior anti-BCMA targeting therapy. In both cohorts, iberdomide at the dose of 1.6mg was given in combination with dexamethasone 40mg once weekly, reduced to 20mg for all patients age more than 75 years.

And the primary end point was the efficacy in terms of overall response rate, although additional efficacy outcomes, including the duration of response, the progression free survival, as well as the safety profile were secondary study endpoints.

[0:52:53]

CC-220-MM-001 (Cohorts D and I): Baseline characteristics and prior therapies

In cohort D were enrolled 107 patients. As previously highlighted, almost all of them were triple class refractory after a median of 6 prior lines of therapy. And please consider that these patients in the very advanced phase of the disease had also additional poor prognostic features, including the presence of extramedullary disease in 25% of them, and of a high risk cytogenetic profile in 30% of them.

In cohort I, with a smaller number of patients, 26 were enrolled patients who had previously received a BCMA targeting therapy. And as you can see, most of these patients had received an ADC based therapy, an antibody drug conjugate. The remaining, either CAR T-cells or T-cell engagers.

[0:54:03]

CC-220-MM-001 (Cohorts D and I): Response

In cohort D, in this heavily pretreated triple class refractory patient population, the overall response rate seen with iberdomide combined with dexamethasone was at 26%, including slightly less than 10% at least VGPR. And if you move to the cohort A, you can see that the overall response rate in patients exposed to a prior targeting BCMA therapy was almost the same, both in terms of overall response rate as well as in terms of deeper response rates.

[0:54:52]

CC-220-MM-001 (Cohorts D): Efficacy

The progression free survival only in cohort D was approximately 3 months, and the median duration of response 7 months. Please consider again that these patients were heavily pretreated, and the median overall survival for the overall patient population was 11 months at the time of the data cutoff, with the median follow up of approximately 8 months. The median was not yet reached in patients who were responders in comparison with known responders.

[0:55:39]

CC-220-MM-001 (Cohorts D and I): TEAEs

The most frequent treatment-emergent hematologic adverse event was neutropenia, which was a seen in the range between 40% and 45% in both cohorts D and I. But in spite of this, the rate of grade 3/4 febrile neutropenia was less than 5%. This means that in the great majority of the patients, neutropenia was manageable. And in terms of infection, more specifically of the grade 3/4 pneumonia, you can see, as expected, that there was an approximately 2-fold higher probability of pneumonia episodes in patients exposed to BCMA targeting therapy, cohort I, in comparison with the cohort D.

[0:56:46]

CC-220-MM-001 (Cohorts D and I): Patient disposition and treatment exposure

Adverse events leading to treatment discontinuation in cohort D were less than 5%, so very few patients discontinued due to adverse events. And as you can see on the right side, an iberdomide dose reduction was required in both cohorts in less than 20% of patients.

[0:57:12]

EMN26: Iberdomide maintenance after ASCT in NDMM

Based on these favorable results, a phase II trial aimed at investigating iberdomide as maintenance therapy after autotransplant was designed. This is the design of the EMn26 trial, which was a trial of maintenance for patients achieving at least a partial response after autotransplant. Initially, 2 cohorts with different doses of iberdomide were planned, but thereafter a third cohort with a lower starting dose of iberdomide was added, and as you can see, the primary endpoint of this trial was the improvement in the quality of response, while the conversion from MRD positivity to negativity, as well as progression free survival, were where secondary study endpoints.

[0:58:18]

EMN26: Baseline characteristics and prior treatments

These are the baseline characteristics. It was planned that 40 patients should be enrolled in each of the 3 different cohorts. Iberdomide was given at typical dosing schedules 3 weeks on, 1 week off, and as expected, in the first 2 cohorts with the higher iberdomide dose, the great majority of patients did receive a tripled induction therapy, while the majority of patients in the third cohort did receive a quadrupled induction regimen, and in the majority of the patients in the range between 75% and 90%, the probability of receiving a single autotransplant.

[0:59:16]

EMN26: Response improvement

Cohort 1.3 and 1.0mg of iberdomide had the longest follow up. This means that in these 2 cohorts, it was possible to evaluate the improvement in the response rate not only within the first 6 cycles, but after 1 year of therapy. And as you can see, this was appreciated with 12 cycles in a range between 46% and 52%, and the probability of switching from MRD positivity before starting iberdomide maintenance after transplant to MRD negativity with iberdomide maintenance was 53% for 1.3mg cohort and lower, 32% in the 1.0mg cohort.

[1:00:19]

EMN26: Progression-free survival

The follow up was not yet mature at the time these data were reported to draw any conclusion about the outcomes in terms of progression free survival.

[1:00:34]

EMN26: TEAEs in cycles 1-12

What about regarding treatment-emerging adverse events? As expected, the rate of grade 3/4 neutropenia was consistent with the prior trial. And grade 3/4 pneumonia episodes were seen in 50% of patients in each of the 3 different cohorts.

[1:01:01]

EMN26: Patient disposition and treatment exposure

The discontinuation due to adverse events was in the range between 3% up to 13%.

[1:01:14]

CC-220-MM-001: Iberdomide ± SoC treatments for R/R MM

Iberdomide has a synergistic effect with daratumumab. It was already highlighted by Charlotte. This is a peculiar activity of CELMoDs, which may be combined with other anti-CD38s as well as proteasome inhibitors. And in cohort E of this trial, iberdomide at different doses was given in combination with daratumumab.

[1:01:51]

CC-220-MM-001 (Cohort E): Responses

We have only data related to the dose escalation portion of the study. 43 patients were enrolled. The majority of them did receive iberdomide at the dose of 1.3 or 1.6 mg. These patients were by definition refractory to prior IMiDs, almost all of them, including 65% who were refractory to pomalidomide and a probability of prior refractoriness to an anti-CD38 monoclonal antibody of 37%. In this heavily pretreated patient population, the overall response rate, in combination with another agent with an anti-CD38 monoclonal antibody was 46%, including 24% of patients achieving at least a very good partial response.

[1:03:03]

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

And now moving to mezigdomide. Mezigdomide, formerly CC-9248, was explored in a dose escalation and dose expansion phase I and phase II trial. This is the design of the phase I portion of the study. 13 different doses across 4 different dose schedules, in order to evaluate the recommended phase II dose.

[1:03:36]

CC-92480-MM-001: Mezigdomide + dexamethasone for R/R MM dose expansion cohort: study design

This was evaluated in a phase II dose expansion at the recommended dose of 1 mg in combination with dexamethasone at the same weekly doses. The dosing schedule 3 weeks on, 1 week off. Again, triple class refractory patients after at least 3 prior therapies. However, in this study it was allowed to enroll also patients with prior exposure to anti-BCMA therapy. And the primary study endpoint was the overall response rate.

[1:04:19]

CC-92480-MM-001 dose expansion: Baseline characteristics and prior therapies

These are the characteristics of these patients. The triple-class refractoriness was acquired after a median of 6 prior lines of therapy and the presence of both extramedullary and paraskeletal disease was seen in approximately 40% of patients, and 37% of these had a high-risk cytogenetic profile.

[1:04:51]

CC-92480-MM-001 dose expansion: Efficacy outcomes

The overall response rate in the cohort of 101 patients was 40%. But what is, in my opinion, interesting, is that the same overall response rate with an even higher rate of high-quality responses, including VGPR or higher in approximately a 30% range, was seen in the population of patients with prior exposure to BCMA targeting therapy.

What about in terms of progression free survival and duration of response? The median values were respectively 4 and 8 months, which increased obviously for the duration of response in patients achieving a high quality response.

[1:05:53]

CC-92480-MM-001 dose expansion: TEAEs

In terms of treatment-emergent hematologic events, the most frequent was myelosuppression, in particular neutropenia, as the great majority of them has already [inaudible 1:06:12]. This is a typical class effect due to the key role of Aiolos in the process of driving the proliferation and maturation of granulocytes. And in this study, you can appreciate how the rate of grade 3/4 neutropenia was higher, roughly below 80%, with a rate of grade 3/4 pneumonia which was at approximately 15%.

[1:06:50]

CC-92480-MM-001 dose expansion: Treatment discontinuation

As you may expect, these patients did require a higher frequency of dose reduction and approximately 65% received G-CSF due to grade 3/4 neutropenia. But at the end of the day, adverse events leading to treatment discontinuation were seen only in 6% of the patients.

[1:07:21]

CC-92480-MM-002: Mezigdomide combination therapy for R/R MM

Preclinical findings do suggest that exposure or combination to proteasome inhibitors do not impair the immunomodulatory properties of mezigdomide, which on the other hand, increases the expression of CD38, and both of these findings provided the basis of this subsequent trial, in which in different cohorts of patients with different dosing schedules, mezigdomide was explored in combination with either bortezomib or carfilzomib. And in cohort A, they recommended the phase to further evaluation in a phase II dose expansion cohort was at 0.6mg or 1mg, in combination with bortezomib and dexamethasone. Other cohorts included also the combination of mezigdomide with daratumumab or of mezigdomide with elotuzumab. Co-primary study endpoint was the recommended dose, the safety and the overall response rate.

[1:08:45]

CC-92480-MM-002: Baseline characteristics and prior therapies

These are the baseline characteristics of patients enrolled in cohort D and cohort C. Patients receiving mezigdomide plus carfilzomib-dexamethasone were more heavily pretreated. They had a higher percentage of triple-class refractoriness in comparison with the cohort D. What was common to both cohorts was the very high rate of a high-risk cytogenetic profile at approximately 50 to 60% of the patients.

[1:09:28]

CC-92480-MM-002: Dose escalation efficacy

And if you look at the progression free survival curves of the combination of mezigdomide plus bortezomib and dexamethasone, cohort D, you can see that the overall median progression free survival was very encouraging, was 17 months.

[1:09:49]

Mezigdomide + dexamethasone ± SoC regimens: response rates

This cartoon recapitulates the overall response rate seen with both the CELMoDs given with dexamethasone, or combined with the 2 different proteasome inhibitors, or with the 2 monoclonal antibodies targeting CD38 and SLAMF7. And as you can see in the combination portion, the overall response rate did increase up to 90%. So very promising results.

[1:10:37]

Mezigdomide + dexamethasone ± Vd or Kd Cohorts: Neutropenia and infections

 In terms of neutropenia and infections, what I already highlighted in terms of a class effect, particularly neutropenia, which importantly was not increased when either iberdomide or mezigdomide, in this case mezigdomide, were combined with proteasome inhibitors.

[1:10:59]

Let’s return to an earlier question

Posttest 4

So we can go back to the previous question related to what you might expect more frequently in a patient receiving CELMoDs, meaning either iberdomide or dexamethasone, hypertension, neutropenia, peripheral neuropathy and ocular toxicity. Please vote, but the first vote was very good. We expect it to go up to 100%.

Charlotte Pawlyn: Close.

Sagar Lonial: Close.

Michele Cavo: 3% of not yet convinced. Okay. We hope.

Okay. And I already highlighted this concept.

[1:12:30]

Phase III Studies of Novel Protein Degraders in Earlier R/R and Newly Diagnosed MM

Dr Michele Cavo: I would like to go to my subsequent presentation.

[1:12:45]

EXCALIBER Maintenance: Iberdomide vs lenalidomide maintenance after primary MM therapy + ASCT

The trial already discussed provided the basis for phase III clinical trials, which are currently running in different subsets of the disease. This is the design of the EXCALIBER maintenance trial, a 2-stage phase III trial evaluating in stage 1 3 different doses of iberdomide, again for transplant-eligible patients achieving at least a partial response after a previous transplant, either single or double. And in stage 2 they identified the optimal dose in head to head comparison with lenalidomide, and the primary study endpoint was the progression free survival, although as in the previous phase II trial, MRD negativity rate, overall survival, safety and the quality of life were secondary study endpoint. This is the EXCALIBER maintenance.

[1:14:15]

EXCALIBER RRMM: Iberdomide + daratumumab + dex vs DVd for R/R MM

Another EXCALIBER trial is currently running. It is aimed at evaluating iberdomide plus daratumumab-dexamethasone vs daratumumab-Vd, and in this trial are enrolled patients with 1 to 2 prior lines of therapy. So we are moving in the treatment of earlier phases of the disease, earlier lines of therapy. And these patients could be enrolled, provided that they were not refractory to bortezomib and were mainly not exposed to an anti-CD38 monoclonal antibody. Again, 3 different doses of iberdomide: 1.0, 1.3, 1.6mg. And in the stage 2, a head to head comparison of iberdomide daratumumab dexamethasone with daratumumab Vd.

[1:15:27]

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

Two additional trials with the use of mezigdomide in relapsed/refractory patients. This is the SUCCESSOR-1 trial combining mezigdomide plus bortezomib and dexamethasone vs PVd in patients with 1 to 3 prior lines of therapy and prior exposure to lenalidomide. So the main target of this trial is to address patients who are refractory to lenalidomide after mainly the first line of therapy. Three different doses of mezigdomide, starting from 0.3 up to 1.0 mg combined with bortezomib dexamethasone, and in stage 2, once the optimal dose will be established, a head to head comparison with PVd. As you know and as you are aware, based on the results from the OPTIMISMM trial, PVd is recommended in current guidelines for patients with prior exposure and prior refractoriness to lenalidomide.

[1:16:50]

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

While in another trial, the SUCCESSOR-2, the second generation proteasome inhibitor carfilzomib in combination with mezigdomide was evaluated at different doses. And in this trial, patients enrolled should have received at least 1 prior line of therapy and should be exposed to either lenalidomide or anti-CD38 monoclonal antibodies. So the hypothetical target population is that of the growing population of patients who are expected to have acquired a double refractoriness after an upfront therapy.

Professor Lonial previously highlighted that the current landscape of melanoma therapy for newly diagnosed patients is based on a quadruplet therapy plus-minus transplant according to their eligibility to receive a 4-drug regimen. This means that based on this treatment pattern, this evolving treatment pattern, you may expect that almost all patients will be triple class exposed, at least in their first line of therapy, and may be double class refractory at the time of their second relapse.

Once the optimal dose will be evaluated, mezigdomide plus carfilzomib dexamethasone will be compared with carfilzomib dexamethasone, which at this time is 1 of the treatment options available in a patient, in a hypothetical patient who in the second line therapy, for example, a patient treated with daratumumab RD, who in the second line of therapy is refractory to both lenalidomide and an anti-CD38 monoclonal antibody.

[1:18:55]

Phase III studies of iberdomide in NDMM

There are also additional trials evaluating iberdomide in patients with newly diagnosed disease. You can see the MRD-positive arm of the MIDAS trial, in which after the consolidation, iberdomide is given in combination with the isatuximab. This is the experimental part of this MRD driven trial. While in another trial, which will be conducted by and planned by our Spanish colleagues, iberdomide plus isatuximab is planned in 1 of the 3 cohorts after transplant and after subsequent consolidation, as well as in a combination with a triplet regimen as induction before and consolidation after transplant.

[1:20:08]

Notable EHA 2025 abstracts

My first slide is only aimed at highlighting several iberdomide and mezigdomide clinical trials whose results were reported at this EHA meeting. As you can see in different patient population and different stages of the disease, for example, iberdomide bortezomib and dexamethasone. Iberdomide BD will be reported in transplant ineligible patients with newly diagnosed disease. But there is also a trial evaluating iberdomide and dexamethasone in transplant ineligible patients with newly diagnosed disease, as well as there will be a further updated of the results reported at the previous ASH meeting of mezigdomide combined with 1 of the 2 proteasome inhibitors of first or second generation.

[1:21:30]

Conclusions and future directions

And I think that I can move to the conclusion. Iberdomide and mezigdomide in different combinations, combined with anti-CD38 monoclonal antibody and first and second generation proteasome inhibitors resulted in promising efficacy in heavily pretreated patients, mostly with triple-class refractory disease. Clinically meaningful and durable responses were observed in difficult to treat patients, patients for whom there is at this time no standard of care therapy, including, in addition to triple-class refractory patients with extramedullary disease and also patients already exposed to a BCMA targeting therapy. Especially in combination with daratumumab or with proteasome inhibitors, the median progression free survival exceeds 1 year.

The most frequent hematologic treatment-emergent adverse event was neutropenia, a typical class effect of CELMoDs, which, however, was manageable with GCF administration or with dose reduction. Interruptions more frequently with mezigdomide compared with iberdomide, but at the end of the day resulting in a very low discontinuation rate.

And last but not least, as you may appreciate in several of my slides, many of the typical adverse events related to the use of lenalidomide or pomalidomide, such as for example, gastrointestinal disorders or fatigue, were not seen in this patient population receiving the CELMoDs. And finally, we are waiting for the results from the ongoing phase III clinical trials with either iberdomide or mezigdomide. And I thank you for your attention.

[1:24:01]

Future Implications for Selecting and Individualizing Treatment for R/R MM

Sagar Lonial: All right. Thank you very much. And Professor Cavo, so we are going to spend the next few moments going through some future implications in terms of selecting optimal therapies for patients. And I want to make this next section a little bit more interactive. So I am going to show a couple of slides really focused on some data, but I am also going to ask my panelists for their input and thoughts in terms of some of the questions I am going to put up there, and there aren't necessarily right answers to any of these questions. So relax. But certainly I think we will make this a little bit more interactive.

And then we do have a few questions from the audience. Please feel free to send in more now. And if we can get to them we will go ahead and do that.

[1:24:50]

Topics to discuss today

So let us see. Okay, so I think these are the questions that we want to address. These are what we have talked about already in terms of the topics to discuss today.

[1:25:06]

MRD

IMWG criteria for MRD in multiple myeloma

So I think the first really rotated around the ability and comfort using MRD as an endpoint. And I think that is increasingly becoming more and more important, especially in 2025 when we do not want to wait for median PFS that may often be years and years and years, and using early MRD as a validated endpoint has been put by a couple of different groups, both in the US and in Europe. And what they've demonstrated is that it is a good surrogate for PFS if you pick the right time point.

And this was really important from the FDA's perspective. They didn't want MRD anytime, they wanted MRD between 9 and 12 months. And they wanted MRD to be associated with a complete remission. So immunofixation negative and MRD negative. Now, what the FDA did not stipulate was whether it had to be done by flow or whether it could be done by sequencing. And you can see there are different technologies. Here you can see as well.

And in the new IMWG IMS Response Criteria paper that we hope will come out in the next 6 months, we have created these relative categories, which is sustained MRD negativity meaning with a with a time period. And I personally believe that 12 months is an important metric for sustained MRD negativity. There is imaging MRD negativity, where a patient has had PET scans or an MRI in addition to bone marrow negativity. There is flow MRD negativity, and sequencing MRD.

So these are all things that you are going to see more and more frequently and we are going to have to hold ourselves accountable to using the same definitions so that we can compare across different trials.

[1:26:57]

Evaluation of MRD as surrogate marker for PFS

Now is MRD a surrogate for progression free survival? And the answer is absolutely. You can see this meta-analysis published by Nikhil Munshi. This formed the basis of what the FDA used to ultimately approve MRD as an approvable endpoint. And you can see that across the board, MRD clearly has pretty significant impact as a surrogate marker of PFS and overall survival. And the ODAC, which is the Oncology Drug Approval Committee, which is called upon by the FDA to review a potential approval, it was unanimous that they accepted MRD as a potential surrogate endpoint to allow us to not have to wait decades for endpoints, which is where I think we are getting with many of the new drugs we have.

[1:27:49]

MRD in recent phase III trials in transplant-ineligible NDMM

And if you begin to look at MRD negativity in recent phase III trials in transplant-ineligible patients, you will see that even the kinder, gentler inductions that we use in transplant-ineligible patients are achieving a significant fraction of MRD negativity. And in fact, 1 of the studies that Professor Cavo highlighted that is being presented at this meeting from Dr White is actually using iberdomide in combination with bortezomib dexamethasone in a transplant-ineligible patient population. And at least in that very small series, it looks like the MRD negativity rate is actually higher than what was seen for DRD in the MAIA trial. So certainly very encouraging data with these new drugs, and I think highlights a differentiator of the CELMoDs compared to what we have been seeing before.

[1:28:41]

Many years to show significant effect of new therapy on PFS

And this, again, is that rationale in terms of the time that it may take to see it, and that MRD may actually help us to get to that endpoint relatively quickly.

[1:28:51]

EVIDENCE Meta-analysis of MRD as an intermediate clinical endpoint for multiple myeloma

Now, there are a number of trials that have that have been done to really look at this in more detail. These are some of the EVIDENCE meta-analyses that Doctor Landgren published in Blood that in many ways parallels or validates some of the data that Nikhil Munshi had published before as well.

[1:29:10]

EVIDENCE Meta-analysis: individual-level association

You can see the meta-analysis in terms of the benefit of MRD testing as a surrogate for progression free survival and overall survival. This is in the context of newly diagnosed myeloma, both transplant eligible and transplant ineligible.

[1:29:28]

MRD in patients with R/R MM treated with CAR T-Cell therapy

And then again, these are MRD in patients treated with relapsed and refractory, particularly using CAR T-cells as the therapeutic mechanism of therapy. And you can see that MRD negativity clearly predicts for better outcomes compared to patients who do not achieve MRD negativity in this context.

[1:29:47]

FDA industry guidance on regulatory considerations for MRD

And so here are some summary points. Again, many of these slides are available on the website if you want to look at them, so I am not going to spend a lot of time so we can make sure we get to some questions and we get to some discussion with our panelists. But I think it is important to recognize that it is the 9 to 12 month mark that the FDA has requested that that data be limited to. It is not MRD whenever you get it, it is what is the fraction of MRD negativity between that time point. Because then you can compare across different trials and it becomes a little bit easier to look at.

[1:30:22]

MIDAS: MRD-adapted therapy after induction IsaKRD for transplant-eligible NDMM

Now, Professor Cavo referenced the MIDAS trial. This will be presented here as well as was recently presented at ASCO and was published in the New England Journal. And this is using MRD after 6 cycles of induction to make a decision on escalation or de-escalation of therapy. This is a really important trial, because this question about actually using a number to make a decision about what you are going to do next is something that many of us have talked about, but we do not actually have data. And the MIDAS trial is the first hint at data looking at this. And you can see the data that is going to be presented by Dr Perrault at this meeting. It looks very interesting and I think will sort of set the stage for many of the future trials we are looking at in terms of MRD.

[1:31:13]

PERSEUS: VRD ± daratumumab in transplant-eligible NDMM

When you look at PERSEUS, they also used MRD directed therapy to determine what to do in the maintenance setting. So for patients who are MRD positive at the end of 2 years, they continued on daratumumab lenalidomide in the maintenance setting. For patients who were MRD negative, the daratumumab was stopped and they continued on single agent lenalidomide alone.

So these kinds of trials using MRD to make decisions are coming more and more. It was really refreshing to see in the audience you guys embraced this. Again, if we do this, when I asked that same question 2 weeks ago at ASCO, very few of the respondents actually felt comfortable with MRD as an endpoint. And I think that is a testament to the fact that many of you helped generate the data that we are using to justify MRD as an endpoint.

[1:32:02]

DRAMMATIC: MRD-guided maintenance therapy

The dramatic is another trial that is being done. This is a US based trial looking at daratumumab lenalidomide vs lenalidomide in a post-transplant maintenance setting. And again, you can see on the right side of the slide that MRD is used to make treatment decisions about whether you continue with the doublet or whether you proceed with a single approach in the maintenance setting.

[1:32:24]

Let’s return to an earlier question

Posttest 2

So let us come back to an earlier question. This question is how likely would you be to consider a treatment for multiple myeloma that was approved based on MRD-negative CR data?

1. Very unlikely.
2. Would wait for PFS.
3. Unlikely.
4. Neutral.
5. Likely.
6. Very likely.

Go ahead and take a moment to answer. I can't figure out if this is me being Steve Jobs or if this is the Roman Colosseum, and I am waiting for the lions to come out.

Okay, good. We moved people towards the likely or very likely, which is great. All right.

[1:33:10]

Where might novel protein degraders fit into treatment paradigms for MM?

So where might novel protein degraders fit into the treatment paradigms for myeloma?

[1:33:18]

Novel CELMoDs in development

So novel CELMoDs are in development, again differentiating them from the classic IMiD agents. I think my colleagues have done a great job at setting that stage already, so I am not going to relive this because I know time is short.

[1:33:35]

CELMoDs co-opt cereblon via unique binding features, inducing distinct conformational changes

We have talked about this figure as well, the difference in binding and downstream effects and the closed conformation as well as the S isomer. As Dr Pawlyn highlighted earlier, all these are really, really important.

[1:33:48]

Where do iberdomide and mezigdomide fit in?

So this is where I want to sort of ask my colleagues to answer some of these questions, or at least talk about their experience with these drugs as well. Both agents have activity in IMiD exposed and IMiD resistant patients. Tell me a little bit about your experience or what you know from the trials about safety profiles of both of these drugs.

Dr Charlotte Pawlyn: So I think as we talked about earlier, I mean, we do see some neutropenia. So but we kind of manage that very easily. So we are quite used to giving patients G-CSF. It is very kind of manageable from that point of view in my opinion. And other than that they are pretty well tolerated. So they are oral tablets. They suit patients, they take them at home. And for me, we do not have huge other signals of side effects.

Dr Sagar Lonial: Yeah.

Dr Michele Cavo: The main toxicity expected is myelosuppression, in particular neutropenia, higher with mezigdomide compared with iberdomide. However, these events are manageable. You need to reduce the dose and in a quite large fraction of patients, especially those treated with mezigdomide, we should use prophylactic G-CSF. However, the great majority of them are manageable and do not lead to a high rate of infection complications.

Dr Sagar Lonial: Yeah. You know, I think that you've highlighted some really important points. The safety profile. I've got a smoldering trial using iberdomide, and I've got a couple of patients who said to me, ‘You told me there was no placebo on this trial. I do not feel like I am taking anything.’ I do not know that that is absolutely everybody. But certainly that experience is not 1 that we have had with lenalidomide or pomalidomide. And so the patient experience is certainly better. And you are getting many of the synergistic or laboratory events that you mentioned before.

[1:35:40]

Comparing CELMoDs: Similarities vs differences

So these are sort of some similarities between the CELMoDs, between iberdomide and mezigdomide specifically, sort of comparing them head to head. Again, iberdomide is really being studied in earlier lines of therapy. Iberdomide does seem to be a little bit better tolerated with less neutropenia reductions than we see with mezigdomide. But what's interesting about mezigdomide is that it may do something that this entire class of drugs, and if you combine the IMiDs and the CELMoDs together, the IMiDs we know do not have great activity in extramedullary disease. They simply do not penetrate into plasmacytomas very well. And I think the group in Barcelona has shown that both with thal, with lenalidomide and with pomalidomide. It may be a little bit better with pomalidomide, but certainly that has been a major issue.

[1:36:37]

Responses with mezigdomide in patients with extramedullary plasmacytoma

When we begin to think about how these drugs can really be differentiated, 1 of the unique aspects of mezigdomide, even more so than iberdomide, is its ability to be effective in extramedullary disease. And if you measure mezigdomide or the metabolites of mezigdomide in plasmacytomas, the drug actually gets into the plasmacytoma, which is a major problem for the IMiD class of drugs. So this certainly raises the bar on. In addition to the immune effects, mezigdomide may actually have preferentially higher activity and utility in the context of high-risk myeloma, where you need that ability to get into tissue to be able to do things.

[1:37:15]

Emerging strategies

So emerging strategies, these are trials that are ongoing looking at both iberdomide and mezigdomide. There was a question that was sent in about a patient who was on mezigdomide and had really multiple infection complications. To me, when I look at that question, my first thought is what T-cell engager or CAR T-[inaudible 1:37:35] did this patient have before? Because you do not really see those kinds of things in patients who are getting iberdomide or mezigdomide, like PML or CMV activation, those really are unique to things like bispecifics or CAR T-cells, where the profound immunosuppression is much deeper, the T-cell depletion is much deeper. Mezigdomide may help that, but if you've already had that, it may be a little bit more challenging to manage overall.

[1:38:00]

Discussion questions

So I am going to ask you guys as we are wrapping up, because I think we are a minute over, in a perfect world, where would you like to see iberdomide or mezigdomide fit?

Dr Michele Cavo: Just moving to 1 of the points you highlighted, the issue of T-cell exhaustion, especially in patients treated with T-cell redirecting therapies, we have data suggesting that a pretreatment with CELMoDs may increase the fitness of these patients. So I see that a pretreatment which is aimed potentially at enhancing the immune system, but also providing a bridging therapy before, for example, CAR T, may be an option to be explored.

Dr Sagar Lonial: Okay.

Dr Charlotte Pawlyn: For me, I think the increased efficacy means we should be thinking about moving them forward and replacing the old IMiDs. So the results of EXCALIBER-Maintenance, looking at iberdomide and maintenance, and looking at mezigdomide in the kind of early relapse setting.