Dr. Ramasamy: My role is to set the scene around how we think about unmet needs in multiple myeloma today, with the advent of exciting immunotherapies.

What Are the Unmet Medical Needs in 2026?

In this slide, I really tried to capture all of the thoughts that many of the academic and community doctors we have attending today online, as well as in person. Although we are all massively excited about the projected survivals that we have heard from trials such as PERSEUS, CEPHEUS and IMROZ and IsKia, and so on, we still have a significant unmet need in our patient population.

On the top left corner is a disease biology that, interestingly, we are increasingly focusing on in the last three or four years. If you look at presentations 10 years ago, nobody would actually have a slide saying the proportion of patients having extramedullary disease. Today, we have because redirecting T cells into an extramedullary disease is a real challenge.

If that is going to be a potential mode of action in a newly diagnosed patient population or an early relapsed patient population, then that may be failing this group of patients, unless you can tweak it better, particularly with combinations with other drugs. A big unmet medical need is patients with extramedullary disease, and also plasma cell leukemia.

Plasma cell leukemia is really an understudied patient population. There is a very nice trial recently that has come out from the European Myeloma Network, and there was a historical trial of use of carfilzomib, but if you look beyond that, there is very little that is being done in including patients with plasma cell leukemia. We really hope that trials in the future will include, in the high risk population, patients with plasma cell leukemia, both cooperative group trials as well as the pharma trials.

On the top right corner is the frail patient population. These are a significant growing patient population for two reasons. The population is ageing across the Western world, particularly as we see in the UK, 45% of newly diagnosed patients are over the age of 75. We are predicting most of our patients are going to be relapsing, meaning getting to first relapse will be around the 75 mark because of the projections that we have seen with IMROZ, CEPHEUS dataset.

Therefore, frailty and additional comorbidities which affect their ability to receive therapies becomes critically important. CLL have really jumped into this space around looking at frailty, but IFM are leading the way in our ability to think about frail populations. We really need more and more focus on this frail patient population. The bottom two panels indicate the challenges that we have when patients relapse multiple lines of therapies, that brings in additional comorbidities for patients.

More recently, there is more and more data coming through around resistance to immunomodulatory drugs, proteasome inhibitors, and particularly the surface membrane antigens that we go after and target the loss of those antigens, the mutations in those antigens, are all complicating disease biology at relapse. What could have been a pure lenalidomide refractory disease that had early relapse, could be more complex around multiple refractoriness with loss of one or two antigens at relapse in the future, as we would see it, so how do we actually combat that, are things that we need to think about today.

What Do Patients Prioritize/Desire in Novel Therapies for MM

What do patients really want out of the exciting therapies that we are developing? They only want two important things, really. One is to live a long life, and then on the right-hand side, to live a meaningful life. That is really what they ask of us. Therefore, taking these two important concepts of improving overall survival is still a goal that is critically important, and also offering meaningful time off therapy. Therefore, moving from continuous therapy, from diagnosis to death, which is what the myeloma treatment paradigm right now is, to potentially meaningful breaks from therapy. Improving the quality of life of patients should be our treatment goal, aligned with what our patients' treatment goals are.

Therefore, when we are designing studies, we should be increasingly thinking of how do we actually accommodate these important shared decisions from patients.

What Are the New Options for MM?

To set the scene, there are a number of new options for myeloma. You have heard a number of them yesterday and day before. Today, you are going to hear quite a lot about cell therapies within this session, alongside other therapies. We are excited about the new CAR T therapies for myeloma. Obviously, BCMA targeting is out there, but GPRC5D targeting and dual targeting is being actively investigated as we speak in Phase 3 trials.

We have got the antibody drug conjugate in Belantamab mafodotin, but also there is a GPRC ADC that is being tested in clinical trials. You have got trispecific antibodies are actively being investigated in trials. Also, a combination of all of these are also being developed, particularly for the difficult-to-treat patient population. It is very important that we look at how do we enhance responses to the existing immune therapies, which is a concept that we will touch upon today.

New Considerations: As an Endpoint in MM

As we have more and more therapies in myeloma, we want to try and understand what the activity of these agents are as early as possible, so that we can combine them effectively and also get them into clinic. What has really paved that way for us is minimal residual disease appearing as an endpoint in myeloma. It is a massive boon that we should all capture, utilize, to effectively investigate our therapies, as well as clinical strategies, as we move forward in the newly diagnosed and relapsed myeloma patient population.

What did we get from a regulatory endpoint? We now have MRD negativity assessed by bone marrow, by flow or sequencing, in patients with complete response. You have got the myeloma cell-based assays, as you can see on the left-hand side. These are either looking at down the microscope, a flow cytometry technology, which I am going to cover a little bit. Then, the genetic technology that has been covered yesterday, the adaptive clonoSEQ technology.

The session before was capturing all the M protein-based technologies that we currently have. Obviously, the first two ones, the M-spike and monoclonal band, are routinely available in clinic, but we are really now looking at MALDI-TOF and clonotypic peptide technologies as ways of understanding the levels of disease in patients as we diagnose them and treat them during the course.

Flow Cytometry

Flow cytometry is an important methodology through which we assess patients' bone marrow. This does require a quick turnaround because we want a fresh sample, and we do need a large volume, particularly if we want a very high sensitivity in our patients, which we increasingly want. There is no need for baseline sample, which is critically important for patients who need clonal C-based assessment or even clonotypic peptide assessment at baseline. These plots, as you can see here, clearly show that, with an eight color flow cytometry, you can look at very significant amount of residual disease, even in patients in deep serological response.

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

MRD and CR is now currently used as endpoint in myeloma to support accelerated approval. Obviously, PFS data still needs to be gathered, but it is an intermediate endpoint for us to get over the line. Many trials are looking at utilizing this gateway to bring therapies to clinic.

Minimal Residual Disease and Complete Response in Multiple Myeloma: Use as Endpoints to Support Accelerated Approval

This is in January 2026, the draft guidance that was out from FDA, and more recently, EMA has also aligned to this vision of offering this endpoint as a supported accelerated approval for us to use drugs in clinic.

Poll 3

I am going to finish up with a poll, having shared with you the unmet need of our patients and the burgeoning choice of therapies and combinations available to you all, how likely would you be to consider a novel treatment for multiple myeloma that was approved by FDA and EMA based MRD-negative CR data?

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

If you could poll now. Interested to hear your thoughts as to whether you are convinced by an accelerated approval strategy for us to adopt these newer technologies in clinical practice. Thank you.

Dr. Lonial: To discuss around that response, I think, as we have seen in pretty much every presentation in the last two days, MRD is becoming an important endpoint. I think the therapeutic decision-making around that is really important. It is encouraging to see the FDA accept that as a potential benchmark. I will tell you the NCI steering committee for the cooperative groups in the US is not willing to accept MRD as a preliminary endpoint in large cooperative groups. They are very resistant to that right now. I think demonstration of those in large trials is going to be really important. I am curious how the uptake is where you all are accepting this as a reason to move forward or change clinical practice.

Dr. Ramasamy: I think what we really want, and I think our payers in the UK, if I could take a UK context to it, is the ability for us to give active therapies to patients, to limit disease burden and disease burden-related poor quality of life that our patients live with. If you take that type of a backdrop, our payers have been completely fine with looking at that data.

Even if I were to just take us back about three, four years back, we used CASSIOPEIA data with D-VTd induction, which is still our current standard of care, with the proportion of patients being MRD negative being the main reason why NICE wanted to approve. We still give lenalidomide maintenance to those patients, but, when we took those data to NICE, we essentially projected the proportion of patients who were MRD negative at the end of D-VTd. We took the myeloma 11 data, and if you were MRD negative at the time of start of maintenance, what your projected PFS and overall survival was. That was a significantly better than what we were doing at that time for VTd for that patient population.

Certainly, in my geography, we are actively looking for drugs that can change the landscape and the life chances of patients. We recognize that all of these need to be durably assessed with additional time to event endpoints. We absolutely recognize that. There is also scope for all these payers to actually switch the tap off when it requires to be when new therapies come through as well. The most important thing is giving access to patients when it is clinically effective and cost-effective as well.

Dr. Francesca Gay (University of Torino): I completely agree. To add something to that, I believe that it is needed as new endpoints, as we have very active drugs and very hectic combination, if we want to compare with these very active combinations, we need earlier endpoint. The other point, which is probably not for approval, but it makes sense if we think about our strategy, is that we are starting to use MRD to modulate the treatment intensity, particularly maybe to de-escalate in some patients and to avoid unnecessary toxicity. This is extremely important from the patient perspective and should be important also for the payer's perspective as well.

I think it is super important to use the MRD in both ways as an endpoint, but also as a tool to drive the treatment decisions. It is the most reliable so far, probably.

Dr. Lonial: I think that is a good point. Maybe we will save that second part of the discussion for later: escalation versus de-escalation during the Q&A. From my perspective, I wonder if there is a timing there. Does early necessarily prepare you for de-escalation the same way late does? I think that is a good that is a good segue, I think, to your section.

Appraising the Mechanisms and Rationales for Using CELMoDs as Monotherapy and Combination Therapy.

Francesca, I will ask you to go up and give our talk, appraising the mechanisms and rationales for using CELMoDs as monotherapy and combination therapy.

Dr. Gay: Thank you, and good morning to everyone, and thanks to the organizers for inviting me here.

Pretest 1

We start again with a quick poll to understand what is your knowledge of the CELMoDs mechanism of action? Please choose one of these answers to the question, which statement best explains the rationale for combining the CELMoDs with proteasome inhibitors, dexamethasone or monoclonal antibodies? Response

1. If CELMoDs increase the transcription factor expression to promote the differentiation;
2. CELMoDs enhance the degradation of transcription factors via cereblon binding;
3. CELMoDs reduce cereblon binding to limit off-target effects, and D last one
4. CELMoDs bypass the cereblon to directly inhibit tumor signaling pathways.

Let us see what is your opinion on the CELMoD mechanism of action in between these ones. Okay, we see the questions but not exactly the polls, not yet, at least. It looks like most of you think that CELMoD enhances the degradation of transcription factor via cereblon binding, which is indeed one of the main mechanism of action.

Novel CELMoDs in Development

What are CELMoDs? Basically, CELMoDs are a class of agents. The first ones that were discovered were the classic immunomodulatory agents thalidomide, lenalidomide, and pomalidomide that you know very well were included in different combinations in the up-front and in the relapsed setting, but also a single agent, let us think about lenalidomide alone as maintenance after transplant.

Then cereblon was discovered as the direct target of the immunomodulatory agents in 2010, and the novel CELMoDs were then developed based on improved understanding on the cereblon and on the myeloma biology.

Protein Degradation in MM

The key point is the protein degradation, because the CELMoD agents, they act as a molecular glue. Basically, they alter the target protein binding properties of cereblon to promote the interaction with protein substrates that would not be otherwise degraded. Basically, the CELMoDs, and this is true for the immunomodulatory agents and the novel CELMoDs, they bring the ligase and the target proteins into proximity to start the protein degradation by the proteasome system.

Novel CELMoD Agents in Development

Here you see the different chemical structures of different agents, iberdomide and mezigdomide CELMoDs. We have already several data in the newly diagnosed and also in the relapsed setting, and cemsidomide, who is more novel and is under evaluation in the relapsed refractory setting. You see that there are similarities in the chemical structures between these new drugs, iberdomide, mezigdomide, for instance, and the old agents lenalidomide and pomalidomide. Similarities and differences that explains their mechanism of action and also their activity, and their toxicity.

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

Basically, the classical immunomodulatory agents, thalidomide, lenalidomide, and pomalidomide, they are a mixture of S and R isomers. The R isomers bind less efficiently to cereblon compared with the S isomer. The novel CELMoD agents iberdomide and mezigdomide are. S isomers, so they bind to cereblon with a greater potency, they induce a closed conformation of cereblon that leads to a more potent substrate degradation and, consequently, an anti-myeloma effect.

Degradation and Antiproliferative Activity of CELMoD Agents

As you can see here, for instance, with iberdomide and mezigdomide compared with lenalidomide and with pomalidomide, there is a higher affinity, there is a higher degradation of the substrate, for instance, Aiolos, and on a higher anti-proliferative activity.

Iberdomide and Mezigdomide Are Administered as S Isomers Only

The different chemical structure and the S isomer structure basically also explains the toxicity profile, which is a bit different compared with the one of the classical immunomodulatory agents, as for instance, thalidomide, lenalidomide, and pomalidomide. They were a mix of S and R isomers. The R enantiomer is responsible for the sedative effect and not the S one, which is the one that is the stronger binder to cereblon. Typically, all these agents, both the novel CELMoDs and the immunomodulatory agents have hematologic toxicity, but they do not have the novel ones as strong as the others, like the sedative effects and the fatigue.

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

Now, all these drugs, all these CELMoDs have an immunomodulatory effect, which is extremely important if we think about their effectiveness, but also if we think about the potential combination with novel agents. We think about monoclonal antibodies, but also novel immune therapies. You see here as an example, the effectiveness of iberdomide, which is associated with an increased expression of the activation markers on T cells, and a decreased expression of the markers of T cell exhaustion, that could be a mechanism of resistance to T cell exhaustion. You can see also the effect, for instance, on NK cells, where there is an increase in the expression and activation of proliferation markers.

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

In the end, what we see is indeed an increased activation and a decreased exhaustion when using both, for instance, iberdomide and mezigdomide.

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

These agents have been combined with several combinations, and Sagar will show you the clinical data of the different combinations. Of course, first with dexamethasone, then with another well-known class of agents, that are the proteasome inhibitors, showing activity in association.

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

If we think about the mechanism of action, it is of particular interest the potential synergistic effects if we combine, for instance, with anti-CD38 monoclonal antibodies, or also with novel immune therapies. You see here data on the combination of iberdomide and daratumumab anti-CD38 monoclonal antibody, with a synergistic effect that we can see, as they both synergistically activate the complement-dependent cytotoxicity and the antibody-dependent cytotoxicity.

Leveraging Protein Degradation Machinery in MM: Mechanisms of IMiD Resistance

Knowing CELMoDs, knowing what cereblon is doing, also helps us in thinking about what could be the mechanism of resistance to the immunomodulatory agents, to CELMoD agents, and how to try to overcome them. If cereblon is a key mechanism, it is a key mechanism that we can target when we think about what is intrinsic in the myeloma cells.

So how could be the mechanism of resistance? They may involve a lower expression of cereblon for instance. In this regard, if we think about drugs like CELMoDs that binds with a higher affinity, they may be effective even with lower levels of CELMoDs, because they basically activate the protein degradation anyway.

There can be mutations or copy number alteration of cereblon. That could be mechanism of resistance. We may have alteration not directly to cereblon but to the cereblon pathway proteins, or there are some ways of cereblon active also in the cells, not only with the modulation of the ligase activity, but modulating other activity that can be involved in protein resistance. Then, of course, these are not the unique mechanism of growing of the myeloma cells. Pathways that do not involve cereblon may be involved in tumor cell resistance.

Then the myeloma cells grow into a microenvironment. It is extremely important also to think about the mechanism of resistance that are intrinsic to the myeloma cells. They involve the immune microenvironment, for instance, like immune cell exhaustion.

Basically, novel new approaches are needed to try to overcome the immunomodulatory resistance. Cereblon drugs with their higher affinity can be effective, and has shown efficacy. I think this will be included in the next presentation on the clinical data, also, in patients that have resistance to the classical immunomodulatory agents like thalidomide, lenalidomide, and pomalidomide.

Posttest 1

We go back to the poll, and we see again asking to you again how to vote. What is the main mechanism of action that explains the rationale for combining the CELMoDs with the novel agents? 70%, I cannot read well, enhance the degradation of the transcription factors.

Dr. Lonial: Thanks, Francesca. I think that was a great summary of mechanisms of action. One point that I always like to make is, people focus a lot more on the direct binding of cereblon in the tumor cell, but the immune effects of the CELMoDs even more so than len or pom or even thal, is even more potent. In fact, those compounds were engineered to really do more T cell activation and NK cell activation, as you nicely showed in that cartoon there. Yet it is the same target. It is cereblon binding upregulates IL-2 and downregulates other transcription factors in T cells and NK cells that makes them more active. When you think about this from a therapeutic perspective, how do you all position the new CELMoDs?

Dr. Gay: I think from a therapeutic perspective, it is extremely important the combination where we think about the synergistic effect with the immune system. I showed the dara combination, for instance. If we think about combinations with bispecific or potential use of this drug after treatment with CAR T cells to maintain the effectiveness in the long-term, is one of the most appealing uses of these new drugs in the context of the novel therapies. Particularly because they have a high potency, they can be effective in terms of immunomodulation, even at low doses, so we can reduce the potential toxicity and have a good immunomodulatory effect that can potentiate the activity of these drugs.

Dr. Ramasamy: I want to make a couple of points from Francesca's presentation. I think one of the things that we should all recognize is particularly that quite a lot of the biology data was generated when lenalidomide was largely used for early relapse or multiple relapses followed by in a pomalidomide, but we are all now using lenalidomide for a number of years in the newly diagnosed setting. This really presents us with a very high bar and challenge.

This is really where I see CELMoD role . Often, we are seeing patients 4 or 5 years on lenalidomide therapy. We never saw that when we were giving it at early relapse or even in later relapses. The additional biological changes, some of which that Francesca touched upon, is going to be incumbent on us to develop those combinations using CELMoDs with the different biology that the CELMoDs bring in, to induce higher response rates.

The way I look at CELMoDs is, is it giving me more efficacy? Is it giving me better tolerability? Is it giving me a more options for combinability? The way I am reading it right now is that it possibly gives me all three of these. This is why I am most excited about utilizing CELMoD as a platform drug where we can potentially add all the other effective immunotherapies that we increasingly keep identifying to be able to drive those deep remissions.

Dr. Lonial: I fully agree, and to me, I think many of you may have heard me say this before, I think of the CELMoDs as cappuccino for T cells. You get exhausted T cells, and you need a little something to wake them back up. You saw that very nicely on the graphic there. You also saw that in patients taking the treatment. It is not like it is an in vitro phenomenon. It actually happens in patients who are taking the drugs. I think that makes it a great partner for all of the immune therapy-driven drugs that you mentioned here.

There is a question from the audience about modalities of MRD, which is more likely to become the dominant one. I do not think this is going to end up being expert opinion. I think it is going to be adjudicated through trials that are comparing these different modalities head-to-head. My sense is that in the US, NGS is probably the dominant methodology right now. I think in Europe, flow is probably the dominant methodology. There are lots of reasons, but at the end of the day, it is less about the test and more about the predictability and the sensitivity, I think, but I do not know what you all do.

Dr. Gay: I think in Europe, there is a wider use of flow. What we have that is really helping is the two technologies are one of them is that there is a great correlation between the two technologies shown in several trials. It makes it almost one or the other as equivalent in the ability to detect the level of MRD that is predictive of outcome. I think both of them.

Dr. Ramasamy: I think the equivalence is the key word here, because there is no data suggesting that we are looking at different biological states between flow and NGS. This is why in the UK, as you know, all of our studies use flow cytometry because that has been the standard way of us doing it.

Increasingly, there is some genetic adoption happening, so maybe down the line we will have both NGS and NGF, but right now predominantly is flow-based tech.

Dr. Lonial: Thank you again for the wonderful discussion so far. I am going to spend the next few moments really going over available data, and as I said, maybe give you a little bit of a teaser into what may be coming very soon.

Patient Case 1: 51-Yr-Old Woman With Fatigue and Frequent Infections

Let us start off with a 51-year-old patient with fatigue and frequent infections. She had no past medical history. Hemoglobin was 11. Light chains were about 32, with a ratio of 89. She had no pet positive lesions and had about 18% plasma cells in the bone marrow, but did have 1q amplification, or gain, sorry, and 17p deletion at initial presentation.

Lambda light chain smoldering myeloma was initially diagnosed, but then she progressed to symptomatic myeloma with a rising free light chain ratio and with the development of anemia. Initially treated with D-VRd induction therapy, followed by high dose therapy, and achieved a VGPR, and then was noted at that time point to be MRD positive at 10 to the minus three level, following consolidation therapy.

Unfortunately, this is a patient that, at least from what we know now, is not going to necessarily have a great outcome. In 2024, she started dara len as maintenance therapy. In June of 2025 had rising light chains with increase in plasma cell numbers, and recurrence of the same genetic abnormalities. At this time point had extramedullary disease in the liver with multiple FDG-avid sites in the bone marrow as well.

For whatever reason, and I do not know what the answer to that reason is, CAR T was not an option for this patient at that time. Started on bela bortezomib dexamethasone and quickly achieved a VGPR, but just a few months later had light chains rising again while on bela monotherapy given every six weeks.

Pretest 2

In this 51-year-old patient with heavily pre-treated and high-risk myeloma, particularly extramedullary disease, which CELMoD has demonstrated activity in this advanced relapsed refractory setting, based on latest clinical trial data?

1. Cemsidomide is one choice with modest response rates in early phase;
2. Iberdomide with activity in relapsed refractory;
3. Mezigdomide with activity in heavily pre-treated patient populations;
4. Iber and cemsidomide with equivalent response rates;
5. Cemsidomide and mezigdomide with identical efficacy profiles.

This is the pre-test. We do not expect you to know the answer to this.

A fair number of you were on target there, in terms of mezigdomide, and I am going to cover a little bit of that as we go forward as well.

Pretest 3

In terms of the next pre-test, which of the following patients with relapsed, refractory myeloma might be eligible for SUCCESSOR-1, an ongoing Phase 3 trial evaluating mezigdomide plus bortezomib and dexamethasone?

1. Transplant eligible newly diagnosed only;
2. Post-primary therapy for newly diagnosed with greater than a PR;
3. Relapsed refractory myeloma with one to three prior lines of therapy;
4. Post-primary therapy for newly diagnosed with greater than a PR and relapsed refractory with one to three prior lines; or
5. Transplant eligible newly diagnosed myeloma and relapsed refractory with one to three prior lines of therapy.

Take a moment to answer. It is a good mix.

Initial Proof of Activity

We are going to talk a little bit about these three agents, iberdomide, which is also known as CC-220, we are going to talk about mezigdomide, previously known as CC-92480, and then we will talk a little bit about cemsidomide, which was CFT7455.

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

Just to give you a little bit of sense, let us start with the CC-220-MM-001 trial. This was the original Phase 1 trial of iberdomide, where iber was given alone or in combination with dexamethasone. Then you can see a number of additional expansion cohorts on the right. We are going to talk about some of those, as well as some of the other cohorts looking at iber plus dara, iber plus bortezomib, or iber plus carfilzomib, to evaluate the potential synergy in these combinations.

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

One of the things that I want you to look at, particularly in cohort D, this is an expansion cohort of over 100 patients with six prior lines of therapy who received iber plus dex as salvage therapy. What I want you to notice is a difference in the adverse events. When I think about the CELMoDs, there are really three things that I think about, you have heard them from my colleagues already. The first is greater potency and greater binding affinity, the second is a better immune activation, and the third is a better adverse event profile.

Those are the three take-home messages I think about CELMoDs. This is one great example. You are going to see this in subsequent trial analyses where the grade 3/grade 4 adverse events that we typically associate with drugs like lenalidomide or pomalidomide are significantly lower with the CELMoDs than we have seen with the previous IMiD category. That again represents a big step forward for patients because they are able to tolerate the treatment better.

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

If you look at that cohort D, these again, median of five six prior lines of therapy, median PFS was about three months, median duration of response was about 30 weeks. Again, this is a heavily pre-treated, all oral iber plus dex-based combination. This to me is proof of principle that this drug has activity, particularly in pom and len refractory patients, and again, sets itself up for a great partner with other agents.

There were, as I said, other combination cohorts that were looked at.

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

One of them, for instance, again is looking at Iber adverse events, particularly in the context of combinations. You will see cohort E and F and G, which were combinations with dara, bortezomib and dex. Again, look where I showed you that box before, of grade 3/grade 4 adverse events. You will see again, very little grade 3 grade 4 adverse events with the dara combination, with bortezomib combination or with carfilzomib combination. Again, keeping in line with that message that I gave you earlier.

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

If you begin to look at responses, you will see this is the iber plus dara cohort. This is cohort E response rate of about 50%. Here, remember, about 40% were dara refractory and about two-thirds were actually pom refractory. Coming into this, many patients had been on pom dara prior to coming into this expansion cohort as well.

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

It was these initial hints of activity that led to the EXCALIBER Relapsed/Refractory Randomized Phase 3 of iber dara dex versus dara bortezomib dex ,or the CASTOR study, basically, so comparing iber dara dex versus the treatment arm, the experimental arm of CASTOR.

This randomized Phase 3 trial completed enrollment over a year ago. Many of you may have seen a press release that it hit its primary endpoint of MRD negativity. That is all we know at this time point. We are hopeful very soon because the FDA has greenlighted potentially [?] date of August of 2026. We are hopeful that by August of 2026, we will see the full dataset and will, in fact, potentially have our first CELMoD FDA approved.

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

At same time, CC-92480, or mezigdomide plus dex, was being evaluated in an early Phase 1 study for relapsed and refractory myeloma. This study was a little bit more complicated than the iber study I showed you before, in that they were looking at different doses and schedules. The question of 21 on seven off was being questioned with mezigdomide, is it 7 on, 7 off? Is it 14 on, seven off? Is it 14 on 14 off? What is the best cycle to use for mezigdomide? It turns out we should have kept it simple. 21 on 7 off was ultimately chosen as the right schedule for giving mezigdomide.

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

Again, what I think you will notice here on that right in that box is that the grade 3 grade 4 adverse events are significantly lower than what we see with len or pom in a heavily relapsed and refractory Phase 1 patient population. Again, I think this speaks to those three messages that I gave you earlier about messages that I think carry what the CELMoDs really bring to the table.

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

If you begin to look at response rates, you will see in all patients, 40%, and in patients with prior anti-BCMA, it was about 50%. This cohort in the middle is the one that I think is most interesting, because one of the weaknesses of the IMiD class, for as long as I have been taking care of myeloma patients, is that they do not have great activity in the context of extramedullary disease.

What we see with mezigdomide is that it does, in fact, have about a 30% response rate in extramedullary disease. In fact, that 30% response rate is not just because it is more potent, but it actually penetrates into the plasmacytoma. They measured mezigdomide in the actual plasmacytoma, which we have not seen with any other drug that binds CELMoDs.

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

Now, this was the Phase 2 study looking at mezigdomide in combination therapy. Mezigdomide plus bortezomib or carfilzomib. These were initial dose escalation studies and then went on to expansion cohorts.

CC-92480-MM-002: Dose Escalation- Efficacy

What you will see is median PFS plus bortezomib of about 20 months, and if you look at the median PFS with carfilzomib, again, it was about 11 to 13 months. Very different patient populations, median of four prior lines of therapy. Many of these patients were PI-resistant when they came into the study overall.

CC-92480-MM-002: Mezigdomide + Vd Dose Expansion - Efficacy

This again just gives you a sense of that dose expansion cohort. You can see that patients were having ongoing responses when combined with bortezomib, with an overall response rate of about 81%. This was an earlier line of therapy for this expansion cohort.

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

This ultimately led to two trials. The first is SUCCESSOR-1, which was mezigdomide plus bortezomib plus dex versus PVd, pom bortezomib dex, in one to three prior lines of relapsed and refractory myeloma. What we know about SUCCESSOR-1 is that I think, is completed enrollment. We are waiting on results of this randomized Phase 3 trial, but this is certainly a triplet versus a triplet that we hope will help support the FDA label for mezigdomide as well.

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

Now, we also do know that SUCCESSOR-2, which was mezigdomide plus carfilzomib and dex versus carfilzomib and dex, had a press release that was put out a little while ago that it had met its primary endpoint. I think we have seen some preliminary data that this will be presented in the next few weeks at a meeting in Chicago and potentially in EHA, and this hopefully will get to see again, first-line data of mezigdomide plus dex in the SUCCESSOR-2 trial, which is a little bit later than the SUCCESSOR-1. SUCCESSOR-1 was one to three. This was a little bit later. Again, the control arm here was carfilzomib and dexamethasone.

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

Now, the other drug that is really making a bit of a splash in this space is cemsidomide. This is CFT7455. At our center, we have treated a large number of patients with this drug as well as with mezi and with iber. This was initially a Phase 1 study looking at cemsidomide alone, and then cemsidomide plus dexamethasone, based on the synergy associated with the combination of a CELMoD or a cereblon binding agent with dexamethasone.

CFT7455-1101: TEAEs With Cemsidomide + Dex

What again, I think you will see is there were some adverse events, fewer grade 4 adverse events. We know that all of these drugs have neutropenia and hematologic toxicity as a potential side effect. That is an on-target effect of binding cereblon. That is not an off-target effect. That is, in fact, an on-target effect, and finding that therapeutic window is really important with all of these drugs, particularly when you begin to combine them with other agents as well.

CFT7455-1101: Efficacy With Cemsidomide + Dex

This gives you a sense of the therapeutic efficacy. If you look again, these are relatively small cohorts, but as you get to the 100 microgram cohort, you will see that the overall response rate was about 50% in that expansion cohort. In aggregate, cemsidomide plus dex, had an overall response rate of 34, but that used a number of different cohorts that you can see on the left side, going all the way down to 37.5 micrograms of dosing given daily.

Posttest 2

Here is the first post-test question. The same patient, the 51-year-old with extramedullary disease, which CELMoD, has demonstrated activity in this advanced relapsed refractory setting, based on the latest clinical trial data. Remember, this patient had liver extramedullary disease and had been exposed to a number of different agents, including bortezomib, pomalidomide, as well as lenalidomide and CD38 antibodies. Take a moment to re-answer this question. A, B, C, D, or E.

It looks like more of you got this. We can talk about this during the discussion, but certainly based on what I showed you before, mezi clearly has activity in this patient population, particularly in patients with extramedullary disease.

Posttest 3

Let us do the other post-test. Which of the following patients with relapsed, refractory might be eligible for SUCCESSOR-1? This was the triplet versus triplet, mezi bortezomib dex versus PVd. Is A, B, C, D, or E the correct answer?

I think that is a winner. I do not know if you did well or I did well, but overall, everybody got that one.

CELMoDs in NDMM

Let us switch gears just a little bit and talk about the CELMoDs in the context of newly diagnosed myeloma, because there are some emerging datasets that I think are really interesting, and speak to Karthik's point that he brought up earlier along about moving these very active agents into earlier lines of therapy.

Patient Case 2: 63-Yr-Old Man With Fatigue and Back Pain

This is a 63-year-old gentleman with fatigue and back pain. A workup showed an IgA Kappa myeloma with PET-positive lesions in the rib and the spine. RISS 1 MM FISH was hyperdiploidy. No significant past medical history. Received dara VRd induction, followed by high dose melphalan and autotransplant DVRd consolidation with no significant adverse events. MRD testing on the bone marrow was negative at 10 to the minus five, and the PET was complete metabolic response.

Pretest 4

In this 63-year-old with newly diagnosed myeloma, who has completed induction therapy, which investigational CELMoD has shown activity as post-transplant maintenance.

1. Cemsidomide is maintenance after a transplant;
2. Iberdomide is maintenance after transplant;
3. Mezigdomide as maintenance after transplant;
4. Iberdomide and mezigdomide as maintenance after transplant, or
5. Cemsidomide and mezigdomide as maintenance after transplant.

CC-220-MM-001: Iberdomide for NDMM (Cohort K)

Then we are going to get to the other - let me show you some data. This is cohort K from that initial Phase 1 study. This was iber for newly diagnosed multiple myeloma.

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

This was iber plus dara dex in newly diagnosed multiple myeloma. Again, if you look at the adverse events, what I think you will see again is those typical lenalidomide-associated adverse events were significantly lower, particularly in the grade 3 grade 4 perspective. If you look at both the right and the left graphs here, suggesting that what I told you in the late relapse setting is panning out in the newly diagnosed setting as well.

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

In fact, if you look at the efficacy, it was about 94% of patients had an overall response rate. The CR rate was about 68%. If you look at MRD negativity at 10 to the minus five and 10 to the minus six, you can see it is quite substantial. In fact, if you indirectly compare this to what was seen with MAIA, which used dara len dex, the CR rate is almost double, and the MRD negativity rate is almost double as well.

Now, again, those are not head-to-head comparisons, they are not randomized trials, but certainly suggest that potency argument I have been making before is likely to hold up when we look at this in the newly diagnosed context as well.

EMN26: Iberdomide Maintenance After ASCT in NdMM

Now, at the same time, Niels van de Donk was doing an EMN26, iberdomide maintenance after transplant. This is the only CELMoD study that has been done in the maintenance setting to date. This was looking at different doses of iberdomide as maintenance. We know that with lenalidomide, we do not use 25, we use 10 typically or even lower, depending upon the adverse events.

EMN26: Safety in Cycles 1-12

In this, they explored multiple doses and actually demonstrated, in terms of adverse events, that again, this was a very well-tolerated maintenance approach for patients.

EMN26: Response Improvement

In fact, a significant fraction of patients had improvement in their depth of response with the use of iberdomide in the maintenance setting. This is being evaluated in terms of PFS right now for a short term for a smaller study.

EMN26: Progression-Free Survival

This ultimately, and here is that PFS curve you can see with early follow-up. This is relatively short. Certainly, it looks like the 0.75 mg dose, which is the lower dose, has at least numerically the better PFS. Again, not statistically significant, but certainly suggests that you do not need full-dose iberdomide in the maintenance setting, which is also very important to consider.

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

In fact, 0.75 is the dose being used in the randomized Phase 3 trial of lenalidomide versus iberdomide head-to-head in the EXCALIBER maintenance trial. This trial has either just completed enrollment or will complete enrollment in the next week or two. Then we will wait for the follow-up to see whether iber continues to be superior, as I suspect it will be, both in terms of adverse events and efficacy over time.

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

At the same time, the GEM21 study is looking at iber plus isa plus bortezomib for transplant-eligible patients. You can see the schema here. Iber, isa Vd versus isa RVd versus RVd, randomized to different maintenances as well. Looking at iber, isa, or just len dex in the maintenance phase as well.

Practical Considerations: How Do the Safety Profiles for CELMoDs Compare With Each Other and With IMiDs?

This trial is beginning to enroll as well. When we think about the CELMoDs, it is important to think a little bit about safety profiles and how do they compare with each other and IMiDs. Again, as I mentioned, the hematologic toxicity is an on-target effect of binding cereblon. The higher the potency, perhaps the more hematologic toxicity you are going to put yourself at risk with.

Certainly, the use of G-CSF a couple of times or three times a week, depending upon what the patient needs, is not really a big concern. Infection risk mitigation, I think, is something we have all gotten used to in this era of immune therapy. This is something that I think we are all relatively comfortable using in general, overall.

Potential Role of CELMoDs in the Future Treatment Landscapes of MM in Earlier Lines of Therapy.

As we begin to think about potential role of CELMoDs in future treatment, and we likely have some time for questions and certainly discussion from the panel, iberdomide is associated with fewer non-heme adverse events, potentially looking at it in induction or in maintenance therapy. We have a trial at our center looking at iber in high-risk smoldering myeloma as a single agent, and one of the patients actually said to me, you told me there was no placebo in this trial, I do not feel like I am taking anything. We had to reassure them that they were, in fact, taking the iberdomide. Certainly, that gives you a sense for what the adverse event profile looks like.

Mezigdomide activity in a high-risk disease, extramedullary disease, and later relapse again, a partner in the context of relapsed disease, and cemsidomide is an investigational agent now launching a large Phase 2 expansion cohort, as well as looking at combinations of cemsidomide with other commonly used antimyeloma drugs as well.

Posttest 4

We are almost done and ready for discussion. Let us do the post-test four. Which investigational CELMoD has shown activity in post-transplant maintenance?

1. Cemsidomide;
2. Iberdomide;
3. Mezigdomide;
4. Iberdomide and mezi; or
5. Cemsidomide and mezi.

I do not know whether again you won or I won, but everybody won because that is, in fact, the right answer.

Q&A

We will get to our question and answer session now. I want my colleagues to perhaps start off with a couple of comments about presentation in general.

Dr. Gay: First of all, great presentation, as usual. Now I have a question for you. I was thinking about the mezigdomide data that were super interesting, particularly if we think about the extramedullary disease. You know that we have also the problem of efficacy of immune therapies in extramedullary disease. They may have a suboptimal efficacy. What are your thoughts in combining mezigdomide with bispecifics, for instance, in extramedullary disease?

Dr. Lonial: To me, that is that is really exciting. We have seen data from MagnetisMM-30 looking at elra plus Iber as a combination cohort, and the data looks very interesting. It was presented first at ASH, and I think we will be updated in the coming meetings. There is also data plus elra and mezi in the MM-1 study that also looks really interesting.

I think, when we consider these patients with extramedullary disease, high-risk features by any measure, we knew that patient was going to have a rough course just based on their initial genetics, I think combination strategies make sense, and finding a way to combine with not just one, but perhaps two bispecific or trispecific, really makes a lot of sense.

Dr. Ramasamy: I think what you brought to the fore is the fact that we have these CELMoD agents, and the way to think about it is tolerability because we have had huge experience with len and pom, and really the T cell activation and the redirection. If we use those central concepts, then how do you place them in combination, and what activity do you look particularly for in those trials that you have highlighted to people around infection signal, activity signal, and durability of response in those patients becomes increasingly more important. Very nuanced, but I think we need those nuanced understanding now to think about how we put CELMoDs in combination with very effective immune therapies.

Dr. Lonial: I fully agree. To me, I think an interesting question is when you think about T cell engagers, what is the better partner? We have seen really compelling data for an anti-CD38 as a partner for T cell engagers. Can CELMoDs match or exceed that? What is the adverse event profile look like between those two trials? I think that is a question we as a field are going to have to really evaluate in the coming years.

Dr. Gay: You were talking about tolerability combinations. What about the elderly people? Because the tolerability is very good. We have iberdomide in the maintenance setting, and we were commenting before that our experience is as yours is like - not like placebo, but the tolerability is very well. What are the data specifically in the elderly, in the subgroup analysis? Do we have something?

Dr. Lonial: I do not think we have that right now with the existing trials, but hopefully, from many of the European groups that are doing these studies, we will get more data on that.

I think we can take questions. There are a couple from the web. The first is what is the clinical comparability to len and pom? I think I showed you, there is really two trials, or at least one trial head-to-head that is looking at that. That is the EXCALIBER maintenance where len and iber are going head to head against each other.

Then the GEM trial is also looking at replacing lenalidomide with iberdomide as part of the induction, as well as part of the consolidation and the maintenance. We will see some data from that sense as well.

Do we now need studies examining sequencing of CELMoDs between BCMA and GPRC5D if response rates are improved following progression? To me, and again, I am curious what my colleagues think, as we begin to think about getting to limited-duration therapy. Can you use short bursts or even shorter bursts, rather than five years of continuous therapy, can you get away with two to three, which allows you to recycle the target and potentially allows you to recycle the CELMoD as well? So that you do not have to necessarily say, well, I have used up one, now I need to go to the other. How do we think through that? Or how do you all think through that?

Dr. Ramasamy: I think for me, when we look at durations of therapy, there are two concepts. One, is my clone really low, like MRD negative, like 10 power minus six. The second is, have I primed the immune environment to put the immune brakes on for this clone to escape? That is really how I am thinking about CELMoD combinations and potential durations of therapy, because what I really want is really low tumor, that is not measurable using the standard MRD test, be it NGS or NGF. Then I need to have the ability to activate those T cells to put the brakes on, is what it is.

Taking that concept, I certainly want to run a combination which is decent enough to prime the adaptive immune environment for a period of time. I would not go too short. I would probably go two to three years, particularly in the newly diagnosed setting, for me to establish that level of adaptive immune control in those patients.

My concern, obviously, with the data that, albeit is from very genomically unstable fourth line, fifth line patients showing BCMA biallelic loss and mutations and GPRC5D loss, hopefully less of that we will see in the newly diagnosed setting, but I am still concerned that we are going to generate those subclones, as I was trying to describe from an unmet need perspective. What we do not want to see is six years down the line, we sit here and then look at longer duration, bi specific therapy and potentially challenging biology downstream emerging. We do need to use CELMoDs in a more effective manner in combination.

Dr. Gay: I totally agree. I think the key point is again, to go back to MRD and sustained MRD negativity, to keep the disease under control for a sufficient time. That probably is predictive of long-term outcome. In this regard, a fixed duration but not so short, probably two to three years, I would agree, of immunomodulation after can help.

Dr. Lonial: Another question that has come up here is what if CARTITUDE-5 and CARTITUDE-6 show maintenance may not be needed? Certainly in CART-6, they are using maintenance for at least two years in both arms. If we end up not needing to do anything else because CARTITUDE-6 tells us we have cured everybody, that will be a great problem, but let us cross that bridge when we get there, is what I would say.

Then are there already data about long-term toxicity, such as secondary malignancies? I do not know if you all want to address that one.

Dr. Gay: We have some data in the frontline setting in the EMN26 trial, where we are approaching now the three to four-year follow-up, the rate is comparable with what we saw with lenalidomide is very low. The follow-up is still short to have this long-term data. I think we will come up with the data in the future years, and in the relapsed setting, of course, this is relapsed is always difficult to really understand what is the impact of the last line of therapy in heavily pre-treated patients rather than all the other treatments?

Dr. Ramasamy: I think that is an interesting question, but I do want to remind, I know this was a central debate that we were having 10 years ago as to whether it was causative with us using immunomodulating drugs. It is increasingly important that, even in the non-maintenance like CASSIOPEIA, there are SPMs in the newly diagnosed setting. Please do not look at this as causative. I think it is disease biology, and host biology is probably what we are looking at.

Dr. Lonial: I was going to reference that a little bit as well in the analysis that Jonathan Kaufman from our group has done in the exceptional responders, so far greater than 10 years on RVd induction transplant and risk-adapted maintenance, in those almost 20-something percent that at 10 years are still in remission, of those patients, the SPM rate is no different at 10 years than it was for the people who relapsed earlier. What that tells me is that, if it is causative and I do not know, I am not going to wade in that in that debate, but if it is causative, one year is enough. Saying you are on two years or three years or four years does not necessarily increase your risk. That risk is 2.7%. It is still relatively low compared to the benefit in PFS that you see.

Any other questions from the audience? I cannot quite tell. This light is really bright. I know we are already a little bit behind time. We have got one or two more minutes if there is another question. Otherwise, any final comments from my colleagues?

Dr. Ramasamy: I think it is critically important because we are at that inflection point with going from bispecific to trispecific, going from single antigen CAR T to dual antigen CAR T, is the platform for improved survival has really come from immunomodulatory drug use in multiple different combinations, either with the proteasome inhibitor, as you showed with the MeziKd type approach, or with daratumumab, like in the EXCALIBER approach. That is what has taken survivals, particularly in the Western world, from like five years to 10 years.

It is important to build on that platform is critically important, and not necessarily thinking that going after more surface antigens with a T cell redirection strategy is the absolute holy grail. It is important, hopefully, that folks have heard from your presentation today that all of those trials are going to be increasingly practice-informing for us moving forward in different setting in our clinical practice. I think that is very important.

Dr. Gay: I think that to add to that, we have now a good experience in managing all the adverse events with the immune therapies, and we have the possibility with combination or sequencing, if we think about maintenance, to have other drugs that can be added with a good safety profile. This means improving overall the quality of life of our patients.

Dr. Lonial: I will just wrap up, as well saying, we are asking the immune system to do a lot with our current therapeutic approaches. Anything we can do to improve their health, improve their responsiveness, help them be better partners for bispecifics, trispecifics and CARs, I think, is really important. This clearly has single-agent activity, but also has the added benefit of that immune-enhancing effect as well.