Good day. Welcome to the educational KOL webinar. All participants will be in listen-only mode. Should you need assistance. Please signal a conference specialist by pressing the star key, followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on a touch your phone. To withdraw your question, please press star and then two. Please note this event is being recorded. I would now like to turn the conference over to Leah Gibson, Vice President of IR and Corporate Communications. Please go ahead.
Good morning. Thank you for joining our educational webinar to discuss the multiple myeloma landscape including the role of IKZF1/3 degraders in the emerging profile of cemsidomide. We will be making forward-looking statements today and slide two contains our legal disclaimer on this matter. Those presenting on today's call are Andrew Hirsch, our President and CEO, Nisha Joseph, Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and Len Reyno, our Chief Medical Officer. Andrew will begin with opening remarks and then hand it over to Dr. Nisha Joseph, who will go over the multiple myeloma landscape and IKZF1/3 degraders foundational biology. Len Reyno will discuss cemsidomide's potential best-in-class profile. We will end today's call with a Q&A session. Andrew, over to you.
Thank you, Leah. Good morning, everyone. Thank you for joining us. As you know C4 Therapeutics is a leading clinical stage biopharmaceutical company advancing the novel modality of targeted protein degradation to treat patients with cancer as well as inflammatory, neuroinflammatory, and neurodegenerative diseases. Our lead asset, cemsidomide is a next generation IKZF1/3 degrader in development for relapsed refractory multiple myeloma, where it has demonstrated a potential best-in-class profile in a phase I study recently presented at EHA. There has been exciting data recently presented on next generation IKZF1/3 degraders, bringing the importance of this mechanism in multiple myeloma into focus. As a next generation IKZF1/3 degrader, cemsidomide is designed to be highly potent and deliver a wider therapeutic index, which was reinforced by the updated data that we presented at EHA last week.
We're very excited to have Dr. Nisha Joseph on the call with us today an investigator on the cemsidomide program and a recognized expert in relapsed refractory multiple myeloma from Emory's Winship Cancer Institute. The multiple myeloma landscape has evolved rapidly with a focus on immune-directed agents like T-cell engagers and CAR-Ts across different lines of treatment with potential for various combinations. In our view, the question that many are asking, given this recent shift, is what anchors combination therapy and what therapies will remain relevant as the landscape evolves. Given that context, we felt it was critical to bring in a leading clinician to provide an independent perspective on how the landscape is evolving, what's resonating in clinical practice, and where IKZF1/3 degradation fits. Dr. Joseph brings deep experience in treating multiple myeloma patients and a strong understanding of IKZF1/3 degraders in clinical practice.
With that, I'll turn it over to Dr. Joseph to walk through the evolving landscape.
Thank you so much Andrew, and thank you so much for the kind invitation to speak to you all today. To get going here, I thought I'd start by walking you through really what is myeloma and talk you through a little bit about the very rapidly evolving treatment landscape in multiple myeloma and specifically relapsed and refractory myeloma. For those of you who are not as familiar, multiple myeloma or myeloma is the second most common hematologic malignancy. Even though it's overall a rare disease, it's still the second most common heme malignancy that we see. It is classified or defined as a clonal proliferation of plasma cells, and that manifests clinically in the patient's body with four main symptoms. Elevated calcium, kidney dysfunction or renal failure, anemia, and lytic bone lesions.
In addition to these symptoms that patients can present with, they're also often prone to infection because they have a disorder of their immune system. They often have decreased antibodies in their system. It's very common for these folks to either present at initial diagnosis with infection or to develop infection along the way. That's a really important piece of myeloma therapy is to also make sure that we are supporting patients so they do not get life-threatening infections while we're attempting to treat their myeloma. Myeloma, we expect around 30,000-40,000 new cases of myeloma each year. Even though things are getting markedly better in terms of outcomes and survival. We still expect roughly 10,000-11,000 deaths in 2026. We still are seeing about 40% of patients that are not surviving beyond five years.
Even though we've had significant advancements in treatments, we have a lot of new treatments and classes of drugs. There's still a large chunk of patients who are not experiencing the significant benefit that some patients are. Sometimes these patients have high-risk disease. Whether that is defined cytogenetically, if there are genetic changes that we know signal more aggressive myeloma, sometimes we're able to detect that at the onset. Sometimes they develop or acquire some of these genetic abnormalities every time they relapse or the longer they have myeloma. There is also a class of patients who might not even have any of these high-risk features at diagnosis, but they are functionally high risk. They don't respond to therapies the way that we expect them to.
There's still an ongoing need to find safe and effective therapies for many myeloma patients who still relapse and need effective treatments in the relapse setting. Here you can see really the evolution of myeloma therapies across the last 70, 80 years. Long before I was treating myeloma, there really wasn't a lot happening. If you look there in the 60s and 70s and really into the early 2000s, there was a few drugs that we had, and patients had very limited survival. When I was in medical school, we learned that myeloma survival was two to three years. The therapies we had were toxic, and it was just not a diagnosis that you wanted. You fast-forward now in 2026 and looking ahead, we have so many effective and well-tolerated therapies.
Not only have we had now the proteasome inhibitors, bortezomib and carfilzomib, ixazomib. We have several monoclonal antibodies in daratumumab, in isatuximab, with elotuzumab. Now more recently, as I'm sure you're familiar with, we now have more of these T-cell redirecting therapies. There's two FDA-approved CAR T-cell therapies in myeloma, ide-cel and cilta-cel. Really, cilta-cel is the CAR T-cell therapy we have access to in the early relapse setting that targets something called BCMA or B-cell maturation antigen that's highly expressed on the surface of malignant plasma cells. We have several bispecific antibodies. We have several bispecific antibodies that target BCMA, linvoseltamab, teclistamab, elranatamab, and we also have one bispecific antibody that targets something called GPRC5D, which is also another antigen that's highly expressed on the surface of malignant plasma cells.
With that, there are other classes like selinexor, which is an XPO1 inhibitor and other drugs in clinical trial development that offer different mechanistic approaches to myeloma death. What we are learning is how to best sequence and combine these agents to be the most effective. Even though we have these drugs, patients will relapse. Vast majority of patients will relapse. How do we make sure that when they relapse, we still have really effective options for them that are safe and well-tolerated and how do we know which one to use and in what combination?
There's a real explosion of not only clinical trial activity with new classes of drugs that are still very much in need but also with the drugs that we already have, either in combination with each other or in combination with some of these novel therapies to try to make them even more effective at each line of treatment, at each time the patients relapse. Here you're looking at just examples of some of the drugs that we think about at each time point in the myeloma patient's journey. For a standard myeloma patient, when I meet a newly diagnosed myeloma patient. I tell them, "Unfortunately, we've not yet cured this disease. We're working on it. The silver lining is we've turned this into more of a chronic disease.
The natural history of this disease is we're going to treat you, we're going to try to get the longest remission possible. For most patients, this disease unfortunately will come back. My role as your physician is to make sure that I'm selecting the most appropriate treatment at each relapse to maximize your depth of response, which will correlate to your remission time. I want to take into account not only the disease factors, so that would be genetic factors, high risk factors, how the disease is presenting, but also what therapies that myeloma has seen previously because that'll affect how it will respond to this next line. We have to take into account patient-derived factors." For a vast majority of myeloma patients, the average age of diagnosis is 67-69. Many patients in my clinic are in their 70s and 80s.
They might have other health problems. They might have other comorbidities. They might have limited mobility, limited social support, transport. Many of the folks that I see in Georgia, in the Atlanta area, we have a large catchment area. They live very far from the center. A vast majority of my patients, I don't actually treat on a day-to-day basis. I check in with them, but they have local community oncologists several hours away that I coordinate with, and they receive their care there. I have to take all those things into account every time they relapse, every time we're selecting therapies. Here's an example showing you of some of the drugs that we use or classes of drugs that we use at each setting.
In the newly diagnosed setting, what really is standard of care for both transplant-eligible and transplant-ineligible patients is a quadruplet therapy with a monoclonal anti-CD38 antibody. That's either daratumumab or isatuximab, often in combination with what we call an RVD or a KRd backbone, so lenalidomide, bortezomib, and dexamethasone. You can see there, lenalidomide, which is a degrader here an IMiD, is very integral and very important, really in all lines of therapy but particularly in combination with PI. The combination of an IMiD with a PI and then adding that monoclonal anti-CD38 has really revolutionized responses in newly diagnosed myeloma. It's such an important component of that quadruplet regimen. When patients relapse, depending on how they relapse, the manner in which they relapse, the time at which they relapse, we start thinking about what would be best for them next.
For example, if I have a standard-risk patient, I treat them with a quadruplet. They have a transplant. They're on maintenance therapy. One year later, they relapse. That's not what we would expect, right? When we look at the PERSEUS Trial, patients who get Dara-RVd, transplant, and maintenance, we're expecting remissions. I don't know if I believe some of the projections of 17 years, but I would say it's reasonable to say over 10 years. That's very impressive. Again, that is clinical trial data. That is not real-world, and that's not what we see. I think it's an effective regimen, but we often have folks relapsing a few years after transplant. We start thinking about things like, should we do another medical therapy-based combo with some of our standard therapies? Using another anti-CD38, using it again daratumumab perhaps.
With another IMiD like pomalidomide or maybe lenalidomide, if they weren't on len maintenance-based therapies, should we combine that dara with carfilzomib? That's data from the IKEMA or the CANDOR trials looking at a monoclonal antibody with a proteasome inhibitor. Those are often regimens, particularly for folks who are in the community, that are very effective, because those are all drugs that community oncologists are very familiar with, and they're able to deliver them. They have a lot of experience with those kinds of drugs. We also have things like anti-SLAMF7, which is elotuzumab, the XPO1 inhibitor selinexor, and then the anti-BCMA antibody drug conjugate is belantamab mafodotin, which we have now access to in early relapse in combination with bortezomib.
That's also an option, I think that is reasonable in the community setting, but it still can be challenging with some of the ocular toxicity or eye toxicity that they're seeing with the drugs. I think for a community really, they have more familiarity with those combinations of a monoclonal anti-CD38 with either an IMiD or a PI. Certainly at an academic setting where I am, particularly after some of the data. Of course, with CAR T-cell therapy in early relapse, if you're familiar with the CARTITUDE-4 trial showing efficacy of cilta-cel in early relapse. Now the newest excitement in the myeloma world, particularly in the U.S., is the MajesTEC-3 data. Looking at teclistamab in combination with daratumumab or even as monotherapy in early relapse. That's certainly an interesting option to use T-cell engagers or bispecific antibodies and CAR T-cell therapies.
That's a small portion of patients 20%-30% of my patients who are able to receive those therapies with me here in an academic setting. Most patients we're thinking about even clinical trial, right? That's a smaller subset of the patients. Many of the patients we're talking about some of these other therapies that they can receive closer to home. As we look forward, what's on the horizon, certainly some cemsidomide, a novel class of drugs showing really high potency. Particularly what's really interesting about some cemsidomide in contrast to the IMiDs and even the CELMoDs is we're looking a lot at the post-BCMA. Many of the patients enrolled in the early trials had received BCMA and T-cell redirecting therapy. There's a novel class of drugs that I think are really interesting, the p300 inhibitors in development, really more in combination.
There is some single-agent activity but in combination with IMiDs. There is some development of allogeneic CAR T-cell therapies. I think there's been some limited efficacy there but certainly an interesting concept and being further explored. There's also, I think interestingly in the CAR T space, ongoing investigation of dual targeted CAR T-cell therapies. Looking at BCMA and GPRC5D or BCMA and CD19, which so far in early trials are showing really interesting efficacy. Of course, ongoing work looking at bispecific antibodies in late relapse. There is a bispecific, for example, called cevostamab, looking at FcRH5 and then trispecifics. We had bispecifics, now we have trispecifics, looking at CD3 and two targets on the myeloma cell surface.
A lot of really interesting and exciting novel classes of drugs that we absolutely need to make sure that all patients, no matter their disease type or no matter where they're being treated have access to really effective well-tolerated drugs. Not only are these drugs in clinical trial development, but they're in clinical trial development in combination with other drugs. Whether those are other novel agents or other standard myeloma therapy. Really a lot happening in the myeloma space. It's moving very rapidly, which sometimes can make these questions of sequencing and what to do challenging, but it's a good problem to have. Okay, now a little bit on some biology at a very high level. Why does IKZF1/3 degradation matter?
When we think about IKZF1/3 , what we're talking about are Ikaros and Aiolos, then subsequently IRF4, which is a downstream transcription factor. Basically all we're saying here, these are very important transcription factors or components of myeloma cell survival. They're needed to make sure that myeloma cell lives and lives and lives. When you cut those things off at the knees, when you degrade those proteins, you are enhancing myeloma cell death. Without those important transcription factors, the myeloma cell has a hard time surviving. That's why these drugs are so effective, whether it was done with IMiDs or CELMoDs. When you degrade these proteins, that's what cemsidomide can do or any of these degraders can do, they target these important transcription factors for destruction.
Once you start decreasing or destroying the amount of Ikaros and Aiolos in the cell, that leads to enhanced myeloma cell death. It's a very critical component of myeloma therapy using these types of drugs. Not only what we have learned with these classes of drugs, whether it's IMiDs or CELMoDs or cemsidomide, there's very interesting T-cell activation data as a byproduct. You're leading to Ikaros and Aiolos degradation. You have enhanced myeloma cell death. As a byproduct, you're actually seeing increased cytokine production. You're seeing less T-cell exhaustion. You're having T-cell stimulatory effects just by using the drug in the first place. It's not necessarily what's happening to the myeloma, but it's a nice side effect. It's a nice byproduct.
I think this becomes particularly relevant and important in a field where we're using so many T-cell redirecting therapies, or we're seeing so much T-cell redirecting use in clinical trial development. Not only can we potentially pair these types of drugs, the IKZF1/3 degraders with T-cell redirecting therapies to enhance their efficacy, I think that's one really important pathway, you can also use them in between T-cell redirecting therapies. That's another really interesting place to put them. For example, after someone receives a bispecific antibody you see a lot of T-cell exhaustion or dysfunction. It's challenging to move directly into another T-cell redirecting therapy. You need to give time for those T-cells to recover, essentially. Potentially, that's a space for these classes of drugs. They're T-cell stimulatory.
They don't require functional T- cells to work, but you see really nice efficacy a nice safety profile and you're positioning that patient well in case they do need a next-line therapy. Here is showing you examples of how IKZF1/3 degraders are incorporated across the myeloma treatment landscape. You can see here for patients in the second and third line, patients in the fourth and fifth line. You can see here there's multiple options in these spaces, but IKZF1 /3 degraders are integral in many different combinations. You can see them in combination with CD38s and proteasome inhibitors with monoclonal antibodies. Moving forward, we're seeing more and more combinations with those in clinical trial development in combination with bispecific antibodies or even as maintenance therapy or even before T-cell apheresis for CAR T-cell therapy.
They're really a critical component of relapse across every sector. From second to fifth line, we can use these in combination with our standard agents. We can use them in combination with our more novel T-cell redirecting type therapies, bispecific antibodies or CAR T-cell therapies, or we can use them in between. They maintain a really important role in the treatment of myeloma. As we look ahead to the future of multiple myeloma treatment. Again, things are changing and moving so quickly, but there's still a significant unmet need in the late-line setting, particularly not only for an effective, well-tolerated treatment. I'll point out, particularly in late relapse, these patients can be a little beat up.
They've seen a lot of therapy, it's important to have not only an effective therapy, but one that they can tolerate one that they can be consistent with and does not negatively impact their quality of life. I think another really nice aspect of these types of drugs is that they're oral. Particularly for older patients, particularly for patients who don't live near a large city or near an academic setting, having an oral option is really convenient and really allows them access to effective drugs they wouldn't otherwise have access to if they're all going to be T-cell redirecting therapies that have to be delivered in an academic setting.
The other thing we think about when we think about what to select in relapse is we want to make sure, there is a known attrition in myeloma therapy, meaning as you look at first-line patients, second-line patients, third-line patients, there's a drop-off. Even though patients are doing better, there's a drop-off. There's side effects, there's ability to continue with treatment, et cetera. We really want to make sure at each relapse, we're using absolutely the best, most effective therapy that we have, the most potent. We want to use that early, we want to use that in combination in a way that's effective and, again, safe for these patients. We're seeing a huge shift in these novel immune therapies into earlier lines of therapy. These therapies are not curative. Even though we're using these therapies earlier, the vast majority of patients are relapsing.
They often have T-cell dysfunction or exhaustion, it's important to still have regimens that are effective for those patients. As we think about CAR T- cell therapy, I think that's another really important unmet need, and how do we make CAR T- cell therapy even more effective? How can we add maintenance therapy? There's ongoing trials not only with maintenance post-CAR T but even using these types of drugs that have T-cell stimulatory effects in patients who might have an exhausted T-cell phenotype to use these drugs prior to apheresis. There's a lot of work and I think interesting ideas about how can we use these important class of drugs to make CAR T- cell therapy even more effective, to help with persistence and help with duration of response.
I think what I've tried to talk about in the last few minutes here is this is a really effective class of drugs, it might be easy to think that moving forward, we have all these novel immunotherapies. Is there a role for these therapies? There absolutely is. The therapies that we have that are using T-cells, the bispecifics, the CAR T- cell therapies, they're not curative. There is room for improvement. These drugs can potentially fill that space. We're seeing, in its predecessors and in some of the early data, there's a real mechanistic advantage to combining these classes of drugs with other standard myeloma therapies and some of the new novel therapies. We're seeing enhanced potency, enhanced myeloma cell death, without a significantly worse safety profile. We're seeing that we can use these drugs across multiple different treatment lines.
Again, in combination, in between, in really each setting, there's a specific role for these drugs to make sure that we're getting good myeloma depth of response and long-term remissions. So, I think, it's a really important class of drugs, and I'm really excited about the clinical trial data that we're seeing. I'm looking forward to seeing more data as we start to combine these drugs with some of the T-cell redirecting therapies and novel therapies in our field. With that, I will conclude. I thank you so much for your attention, and I'll turn it over to Len, C4 Therapeutics Chief Medical Officer to discuss cemsidomide's profile.
Thank you, Dr. Joseph, for the excellent summary, we appreciate you joining us today. With the context just outlined, I'm excited to discuss cemsidomide's potential best-in-class profile as a next generation IKZF1/3 degrader for multiple myeloma. To start, it is helpful to understand how IKZF1/3 degraders have evolved over time. IMiDs, CELMoDs, and cemsidomide all have the same mechanism of action. Lenalidomide and pomalidomide were first-generation IKZF1/3 degraders i.e., IMiDs, they have been clinically relevant for over 20 years. However, when IMiDs were developed their mechanism was not understood, there's a clear need for next generation IKZF1/3 degraders because of the limitations in terms of potency, selectivity, and durability. Mechanistically, these original drugs primarily block proliferation and do not drive multiple myeloma cell death, which ultimately allows resistance to emerge. They did very effectively establish the importance of the pathway.
Next-generation agents, iberdomide, mezigdomide, also known as CELMoDs, and cemsidomide, were designed to address these limitations by not just inhibiting proliferation, but actively driving myeloma cell death and overcoming resistance. Importantly, cemsidomide is built on novel chemistry with a well-understood and validated mechanism, and we believe it is uniquely positioned as a potential best-in-class IKZF1/3 degrader as we move into later-stage development. Let's think about cemsidomide as a molecule and its potential for best-in-class in multiple myeloma. Cemsidomide was designed from the bench up as a highly potent and selective IKZF1/3 degrader. In this regard, it has uniquely highly targeted specificity. It does not degrade off-target neo-substrates, including CK1α and GSPT1. Important for patient care, where 50% of patients with myeloma have some degree of renal impairment, cemsidomide has no renal clearance.
It also has low protein binding, which maximizes the availability of free circulating drug to deposit deep in the tissues, including the bone marrow. In patients, cemsidomide has a two-day half-life. This two-day half-life is important because it sustains free drug at therapeutic concentrations while maintaining efficacy and allowing neutrophils to recover during a break in dosing. In this regard, cemsidomide is uniquely dosed on a 14-day on, 14-day off dosing schedule. This break in dosing allows the potency of cemsidomide to maintain anti-myeloma control, but also enabling full neutrophil recovery. These features make cemsidomide an ideal backbone for combination regimens. We've taken this information and launched it into a differentiated label-enabling strategy from other IKZF1/3 degraders. We are particularly focused on how to incorporate the potency of cemsidomide with its class-leading safety and efficacy into the evolving multiple myeloma landscape.
Now let me take a moment to walk you through the data that has demonstrated cemsidomide's potential for a best-in-class profile from our first-in-human phase I trial. This phase I trial, which is schematically illustrated on this slide, completed enrollment in September of 2025, and last week, we presented further analysis from the trial at the European Hematology Association. In total, 73 patients were enrolled on the study across multiple dose levels, including safety and expansion cohorts. 100 micrograms was declared as our RP2D. Patients enrolled on this trial were extremely heavily pre-treated with 7 median prior lines of therapy. Important in the current evolving context, 75% of these patients had prior CAR T or T-cell engager therapy.
The fact that we've been able to show an impressive response rate in this population confirms that the mechanism of action of targeting IKZF1 and three remains foundational regardless of prior treatments. Cemsidomide was extremely well-tolerated across the dose levels tested. There were no discontinuations related to cemsidomide and minimal dose reductions. Well-tolerated safety profile also included manageable neutropenia. It should be noted that all drugs in this class require a break in therapy to allow neutrophils to recover. On this study, grade 3 to 4 neutropenia rate was 22%, and the grade 4 neutropenia rate was 36%. But more importantly, there were very low rates of neutropenic complications. Including low rates of febrile neutropenia across all dose levels, with only 4% at grade 3 and 1% at grade 4. Equally importantly to patient care, there were also incredibly limited grade 3 or 4 non-hematology side effects.
It's also important to note the risk of neutropenia did not increase over time on this study. There was limited G-CSF use. In fact, there was minimal impact of the neutropenia on the patient's clinical experience, and patients did not come off drug for side effects of cemsidomide. Across all doses, only 45% of patients ever received G-CSF. In fact, most of the neutropenic events occurred in the first two cycles, where in later cycles when the disease was controlled, the patients enjoyed excellent tolerability. The exciting safety profile of cemsidomide is supported by an equally and more exciting evidence of anti-myeloma activity. On this slide, we summarize reductions in serum free light chain levels across the doses tested in the first-in-human study.
What you can clearly see on the graphic that we had deep degradation of serum free light chains across all doses, but most especially at the two highest doses. Of course, serum-free light chains is a prerequisite to demonstrate IMWG responses. On this slide, you can see that our highest dose level, 100 micrograms, that in 19 patients, we had a 53% response rate. We had two patients who achieved this stringent CR, and the CR also achieved MRD negativity. From a drug development point of view, it's also important to note that the drug is active at all doses studied. In fact, we had a 40% response rate at the next lowest dose level. In fact, over all dose levels interrogated for cemsidomide plus dexamethasone, the response rate was 36%. It's important to put this anti-myeloma activity for cemsidomide in context.
On this slide, we compare the phase I results of cemsidomide against the other next generation IKZF1/3 degraders currently in development. Let's first consider the population studied. The populations are not the same in that the cemsidomide first-in-human study enrolled patients where 75% of the patients received prior BCMA-directed therapy. 12% of patients had BCMA-directed therapy for mezigdomide, and none of the patients had BCMA-directed therapy on the iberdomide first-in-human study. Notwithstanding these differences in the pretreatment populations, cemsidomide across all dose levels has the highest overall response rate of 36%. At the dose level of greatest interest, the RP2D, our response rate of 53% compares favorably with mezigdomide, and is almost double the response rate of iberdomide. As you can see from the available data, cemsidomide has the potential to be a foundational treatment across multiple lines of multiple myeloma therapy.
Based on this emerging profile, we've designed a development strategy that is both differentiated and aligned with how the treatment landscape for multiple myeloma is evolving. First, in the late-line setting, there remains a clear unmet need for safe and effective therapies, highlighted by our phase I trial that despite new emerging therapies, patients are still progressing and seeking disease-modifying care. We're enrolling the phase II MOMENTUM Trial now with the potential for accelerated approval. This is a setting where other IKZF1/3 degraders, including next generation degraders, are not currently pursuing label-enabling strategies. Second, in the earlier line setting, we're focused on combination strategies. Our initial development strategy is in a combination with a BCMA. The rationale for this combination to combine cemsidomide T-cell activation with deep anti-myeloma activity, which should drive higher and more durable responses.
We've initiated a phase I-B study with elranatamab with plans to advance into a phase III trial. This phase III trial has the potential to support accelerated approval based on MRD negative CR rates, as well as confirmatory for the broader program. Third, we're exploring ways to include cemsidomide as a possible broader IMiD replacement strategy. These activities include a phase I-B trial with a proteasome inhibitor and CD38. The trial is expected to initiate in the first half of next year. The goal here is to establish a consistent, predictable dose of cemsidomide that can be combined with agents that are used frequently to treat multiple myeloma in standard-of-care regimens. We are currently not planning to use this data to embark on a registrational trial, but rather to increase the body of knowledge of how to combine cemsidomide safely with other drugs.
Overall, these three strategic paths are designed to maximize both near-term and long-term value by addressing unmet need in late-line disease while building toward broader use in earlier settings. With that, I'll turn it over to Andrew for closing remarks.
Thank you, Len and Dr. Joseph, for this highly informative session regarding the evolving multiple myeloma landscape. As you heard this morning, despite the rapid emergence of new therapies, IKZF1/3 degradation remains a foundational mechanism that continues to underpin treatment across lines. At the same time, the limitations of first-generation agents create a clear opportunity for next-generation degraders that can deliver improved tolerability, deeper and more durable responses, and better address resistance mechanisms. Based on the data we've generated to date, we believe cemsidomide is well-positioned to deliver on that opportunity with the potential to be a best-in-class IKZF1/3 degrader. Our goal is to establish cemsidomide as a foundational backbone therapy across multiple lines of treatment and believe cemsidomide is well-positioned to play an important role in the future multiple myeloma treatment landscape. We're encouraged by the progress we've made and remain focused on advancing this program through later-stage development.
This year, we plan to provide additional commentary on how our phase I-B trial with elranatamab is progressing, and data is expected mid-2027. Our phase II MOMENTUM Trial is on track to complete enrollment by the end of Q1 2027, with initial ORR data expected in the second half of 2027. With that, we're happy to open the line for Q&A.
We will now begin the question and answer session. To ask a question, you may press star then one on your touch-tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star and then two.
Our first question comes from Tyler Van Buren with TD Cowen. Please go ahead.
Hey, guys. Thanks very much for the presentation. I thought it was very well done. A couple for you all. The first is, as we think about the higher 75 and 100 microgram doses, what do you think median PFS and median duration of response might be trending towards? For the second question, just can you discuss the significance of the SUCCESSOR-2 data at ASCO for the class, as well as how we should benchmark the control arm for the SUCCESSOR-1 trial reading out some months from now, which could be even more important for the class?
Yeah. Thanks Tyler, for those questions. I'll have Len address both of those.
Thanks, Tyler. They're good questions, yet they're difficult to answer. Let's start with first principles, though. We have small cohorts right now at any given dose level, they do not represent anything remotely as a randomized comparison. I would say the following. We know overall in the population that we have a PFS that's around four months, that's irrespective of response rate and irrespective of dose you received. We also showed in the webinar you just saw that as you increase the dose, you get deeper degradation of the transcription factors and better response rates. One would anticipate that we have an opportunity at the highest two dose levels in particular to improve on that.
I think it's really difficult and would be pure conjecture to try to say what the size of that improvement is. I would suggest that overall, the data supports that we have a compelling signal to start with as we optimize our dosing of patients at the RP2D and one dose reduction if necessary, I think we'll see improvements there.
The second piece of the puzzle that you allude to in terms of the SUCCESSOR-2 data, just to align with everybody on the call, that represents a randomized trial where mezigdomide was added to a 2-drug regimen has an incredibly compelling hazard ratio. We are really happy to see that hazard ratio because it provides an initial read-through on the class, meaning a potent degrader can be done in a global phase III trial safely and successfully, can be associated with a high efficacy signal. We congratulate the patients who enrolled on the study and BMS for conducting it. However, what we also see there is an important read-through for how it fits to cemsidomide. What's unique perhaps about this class of drugs, IKZF1/3 degraders, is how well early first-in-human data predicts future outcomes.
If we think about where mezigdomide was at the time of its original first-in-human data, which we summarized briefly in the webinar, we're at there or better, the part where we're better is actually on not having fewer dose reductions and less need for supportive care. Why does that matter? They have a positive study. Because in that positive study, what's really important to note is it was positive despite the fact that 40% of patients had dose reductions, we don't know what they were dose reduced to. In addition, there was evidence in the study that some patients on study, their cause of death was actually not myeloma, but we don't know details for. We think cemsidomide can do at least as well or better in that.
Finally, your next question with respect to the SUCCESSOR-1, which is comparing a three-drug regimen and swapping pomalidomide for mezigdomide. We would anticipate it as a positive study. I would anticipate the effect size is smaller because you're actually just augmenting a class of drugs, and we wait to see that data with interest.
Yeah. I'll just add, I think, the two comparator points we can point to for what that kind of POM Kd arm is going to look like or there's a study called the SELECT study of 52 patients where there was an 11.1 month PFS. If you look at the comparator arm to the MajesTEC-9 study, which is a very similar patient population, we saw that have about an eight-ish month PFS. That's another way to handicap SUCCESSOR-1 to see what is that POM triplet arm going to do versus the doublet that was in SUCCESSOR-2.
Thank you.
The next question comes from Bradley Canino with Guggenheim. Please go ahead.
Hey, great. Thanks for the question and for the overview this morning. Question for me is how do you think about the ability for these next generation IKZF1/3 degraders to be more effective than pomalidomide in earlier lines of therapy? Really the question behind the question I'm thinking about is why a T-cell engager combination in second, third-line therapy might be better with a drug like cemsidomide instead of a generic drug like pomalidomide? Thanks.
Thanks, Brad. Nisha, I'm actually going to ask you to address that.
Sure. Hi, everyone. Happy to be here this morning. I think the question was why would we think that cemsidomide might be more potent with T-cell engagers than the classic IMiDs that we have currently. Is that correct?
Yeah.
Yeah, roughly. Yeah.
I think we don't have the data, but my answer to that would be an extrapolation from what we're seeing in the late line. When we look at pomalidomide in this, if we looked at that in this combination, or we looked at CELMoDs in this late relapse population, the cemsidomide data looks more potent. The depth of response, we're not supposed to do cross trial comparisons, but we do all the time. The depth of response, particularly in a much more heavily pre-treated population, looks so much better. When we compare them, we're expecting to see some better efficacy than the IMiDs that we have currently. I think it's encouraging the data that we see with IMiDs, that we use IMiDs in combination, with bispecific antibodies, both on trial and really in the real world practice all the time.
We see those pre-clinical effects in patients all the time. Those immune stimulatory effects able to really deepen the responses that we see with bispecific antibodies in late relapse and even in early relapse, in several clinical trials that we have here. For me, again, we have the phase I-B open here looking at elranatamab in combination with cemsidomide, we're enrolling the first patient on Tuesday, looking forward to see that data. For me, it's just a very simple answer of it looks more potent than the late relapse. We're seeing that efficacy with IMiDs, we would expect to see, at the very least the same, I would imagine improved efficacy given what we're seeing in the late relapse population.
Thanks, Nisha. If I could add to that, Brad, just one other point that is embedded in what Nisha said. It's not different, just as more illumination, if you will, is for us, our starting dose with our ELR combination is 75 micrograms. What's unique about that dose is we obviously know it has T-cell enhancement features, that's great, that dose has a 40% response rate. If you think about the first two cycles. In particular, when you're giving a BiTE, you're trying to get the patient into response. We're hoping, the data will be the data, I want to make sure I'm clear on it, I'm hypothesizing.
At the end of the day, we're hoping what cemsidomide can bring, because we can give it at a dose that has its own independent anti-myeloma effects, that it will really help drive getting the patient into a really clinically important response quickly, as well as the T-cell enhancement effects, sort of supporting the back end for long-term durability and increasing depth of response over time. We're really excited about the trial. Certainly, we have great investigators participating on it.
I'll add one other comment is what's really also important is the selectivity of cemsidomide. When you think about the first-gen, no one knew the mechanism, so they can't be selective. They degrade a number of other neo substrates like GSPT1 and CK1α. When you think about combining them with a BiTE, you really want to do the safest most tolerable one because there can be overlapping toxicities, and BiTEs alone have some toxicities. To be able to maximize the anti-myeloma effect and give the maximum dose possible, you want the cleanest sort of drug on target and really based on the data that's out there, that's really cemsidomide.
Yeah. On that aspect, it'd be good to hear Dr. Joseph's perspective on how much TCEs can actually get out into the community and penetrate that patient population over time as the community continues to learn how to give them. Then also the feasibility of combining with a drug like cemzi and the potential for overlapping neutropenia. Is that going to be a challenge, or can that be administered there as well? Thank you.
Yes, of course. Happy to address those, and I think really good questions. I think at least in our region of the country we have been seeing bispecific uptake in the community, at a slower rate maybe than other regions, but it's definitely happening. I think what's also been really helpful recently is TEC3 and TEC9. I think it's kind of becoming unavoidable that community physicians need to become familiar and learn how to give bispecific antibodies, and they want to, right? They want to keep patients. What they don't want to do is having to send patients to us often, right? Even with CAR T-cell therapy, they don't want to lose the patient, and they're worried that if they come to an academic center, they won't get the patient back. They want to be able to give BCMA therapy. They have belantamab.
That can be a trickier one for them to give because of some of the ocular toxicity. They want to be able to give a drug in their clinic that's effective, and they can keep their patient. I think given some of this data looking so effective in early relapse, I really think we're going to see even more shifts. I think another thing that we've been working on here at Emory, and we've been doing this now across the country, is how do we make administration more feasible for the community practice. Right now what we're currently doing is we do the ramp-ups for them. There's a lot of anxiety about CRS and ICANS, but we've also started, I'm sure you've heard, and we've started doing this in clinical trial practice now is just routinely using prophylactic tocilizumab. Many folks have published on this.
It markedly reduces the rates of CRS, we're not seeing a lot of ICANS. It's really a lot of education that we all do about the role of prophylactic tocilizumab, how to use it, and how limited those effects are into the first cycle in terms of CRS and ICANS. I think that is getting better. I think community doctors are becoming more comfortable. At the very least, we do the ramp-up, and we send it back. It won't be forever, but that's what we're doing. I'm seeing more people comfortable picking up with cycle two. I do think that's going to continue to shift just because it has to. Bispecifics are coming in earlier line. Trispecifics are coming. They just are going to have to start making this shift.
This is becoming standard of care for myeloma patients in early relapse, and it's going to become. I think, standard in newly diagnosed at least for certain populations. That's just an inevitability, I think. In terms of the feasibility piece about neutropenia in combination with cemsidomide, and again, let's see the data. Certainly, when we look at CELMoDs in combination with bispecifics, we saw a good amount of neutropenia, with some dose findings, that certainly improved. I think the thing you have to remember is even with community docs who are giving these regimens, they are hematologists. There are side effects that are not good, that we really can't tolerate, and then there are side effects that we can, and those tend to be hematologic. Hematologic, even with significant rates of neutropenia, that's very familiar for our community hemonc.
Giving G-CSF, holding drug or doing dose reductions, I'm not particularly worried about that. I think it's on us to make sure we find a dose that's appropriate and that we're not seeing high rates of febrile neutropenia or opportunistic infections and things like that. Outside of that, I think it's quite manageable, certainly for academics, but even for the community.
Okay, the next question comes from Etzer Darout with Barclays. Please go ahead.
Great. Thanks for taking the question and conducting this webinar. A couple of questions for Dr. Joseph. Just, again, if these data hold, would love to hear your thoughts around how you would use cemsidomide, and would you use it ahead of other IKZF1/3 degraders, IMiDs or CELMoDs. Also, are you seeing patients that have progressed on BCMA modalities and how you're currently treating these patients, and maybe the success or lack thereof you're having with those patients? Thank you.
Sure. Happy to. I'll start with the last one first. The question about are you seeing post-BCMA and how those patients doing. That's the most rapidly growing population in our practice, is post-BCMA. We're giving so much more cilta-cel in early line. We're starting to give more bispecifics. Not only are we seeing a post-BCMA population, we're seeing a post-GPRC, growing post-GPRC5D population, and that's going to grow as we start using trispecifics and other dual-targeted CAR T-cell therapies in early line, which are coming also. In terms of how they do or what I do currently, that depends certainly on the case, but I think that really highlights the efficacy or the role of these classes of drugs. Because often coming off, certainly of a bispecific antibody, as you know, we tend to have a dysfunctional T-cell phenotype.
Going to another bispecific isn't going to work. Going into CAR T-cell therapy is usually not the ideal. I think that's a role for these types of drugs. In current practice, outside of clinical trial, if someone was coming off of CAR T-cell therapy, I might consider a BiTE, but if someone's coming off of a BiTE, I'm trying to scramble to find some other regimen that I think would be effective. If they haven't had carfilzomib or even maybe selinexor, we're kind of limited outside of clinical trial in that space. On clinical trial, we go for things like this C4, cemsidomide. Excuse me, or other p300 inhibitors, things that don't require T-cells. I think that's one space that these drugs are very helpful. In terms of how they do, it just depends. If this is an early relapse patient, I think there's so many options.
If this is a late relapse patient, it does get harder and harder for these patients to find options. I'm sorry?
Okay.
I'm sorry?
No, no one interrupted. Just keep going.
Okay. All right, I'm sorry. I think the other question was, how do I see using cemsidomide? Is that correct? Forgive me.
Yeah.
That's correct. If the data holds.
Yeah, I think, again, I guess I just addressed this. I think the role of these types of drugs are either in a post T-cell redirecting space, where you don't need functional T-cells and you have this potential immune stimulatory effect, or in combination. We've talked about MajesTEC-9. I'm sure you all are familiar with CAR T data. I referenced this in the talk. These drugs are effective, but they're not curative. There's significant room for improvement. To be able to not only improvement, but improve safety, which was referenced early, and we're moving towards fixed duration also. To be able to give bispecifics forever and ever is really not feasible. We saw the infection data in MajesTEC-3.
If we can try to get deeper, more durable responses early and then back off on the bispecific, and maybe continue an oral drug or whatever, there's so much to learn there. There's a significant room for improvement in terms of efficacy, duration of response and safety. In the current landscape, if you gave me cemsidomide right now. I'd probably be using it in a post-BCMA space. That would be the approval, but post-CAR T or post-bispecific, in between bispecifics. I think there's a lot of potential as we learn about how to combine with bispecifics and other standard therapies, as you heard about. I would imagine it coming earlier in terms of what would I do with CELMoDs versus cemsidomide. That's all very hypothetical.
I think certainly we see activity with cemsidomide in the post-CELMoD space, and the CELMoDs are going to move up, and everything's moving up. It's hard for me to wax poetic on what's going to come. Ultimately, the best drug wins. The most potent drug, the safest drug for patients. I think particularly when you talk about an oral agent that we're going to be giving in the community more, safety matters, the amount of dose reductions matter, how much supportive care matters. Community oncologists, I see 20 myeloma patients a day. They see one to five every six months. We have to find drugs that are effective and easy to dose. I hope that answers the question.
Great. Thank you.
The next question comes from Derek Archila with Wells Fargo. Please go ahead.
Hi, this is Jacob on for Derek. Good morning, and thanks for taking our question. Just thinking about dex step-up dosing, G-CSF usage, and other approaches to mitigate some of the safety issues with this class in BCMA bispecifics, can you talk a little bit about the differences between your study with Elra and then those of Iber and Messi? How might these differences affect the dosing intensity and reductions compared to the CELMoDs? Thanks.
Well, I'll have Len answer and address that one.
Yeah. The data that precedes us with Elra, in particular with iberdomide, which was seen at ASH, if you remember that presentation, there was a learning curve, if you will, during that study, vis-a-vis how to give the Elra, and in fact how to even define DLTs. We've been able to learn from how that trial was actually designed, and try to mitigate the risks that we will get into a situation where we're caught off guard by unexpected findings. We have proceeded to start the study with Elra, which is in the dose of administration, the way it was finessed in that study. We've redefined the DLTs carefully and made it very clear how to use supportive care, in particular in the safety evaluation period, to make sure patients all get maximum supportive care if needed.
Also, a key feature is that, of course, we don't start cemsidomide during the step-up dosing. The step-up dosing obviously is a unique set of risks related to BiTE therapy, to Elra therapy, and we want to make sure the patient gets through that safely so that we don't contaminate our ability to understand any safety issues, before we introduce cemsidomide. The trial is very well designed, and it benefits from the knowledge that's been gained before us. We're super excited about it, and as I said, it's open and recruiting. We have benefited from being second with this combination, actually.
Yeah. Thank you.
This concludes our question and answer session. The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.