Miami Myeloma MRD 2025 | Ongoing research at the MMRF: Horizon Clinical Trials Program

George Mulligan

Hi, welcome to the Miami Myeloma MRD meeting. We’re here with a group of folks in Miami discussing the application of MRD and we just completed a session where we describe the MMRF’s adaptive trial program. I’d like to turn it to you, Dr Cho, maybe to describe what the foundation is doing at this point in time.

Hearn Jay Cho

Sure, thanks George. So we had a discussion about the MMRF’s Horizon Platform Clinical Trials Program. We just launched Horizon 1, which is in relapsed/refractory multiple myeloma. We are in the process of launching Horizon 2, which is in high-risk, newly diagnosed multiple myeloma. Dr Varga and Dr Mailankody are both playing important roles in those programs, respectively. The point that we were making is that this program grew out of the MMRF’s long history of running clinical trials in multiple myeloma through the Multiple Myeloma Research Consortium. And that this represented the next step in the evolution of our research program to develop better and ultimately curative therapies for patients with multiple myeloma.

George Mulligan

So, Dr Varga, maybe you could explain the initial Horizon 1 study and where that’s at and what you think is most intriguing about that?

Cindy Varga

Absolutely. So, you know, this is part of a big platform where you have one control arm and then you have multiple investigational arms or substudies, so to speak. And for Horizon 1, this is for specifically for relapsed and refractory patients. The control arm in this situation is monotherapy teclistamab. As we know, teclistamab is a very good drug in relapsed disease. And patients will be randomized to either the control arm or any investigational arms that are open at the time. And patients need to have relapsed/refractory disease. They need to have been exposed or refractory to one of the classes, or each of the classes, rather, of proteasome inhibitor, immunomodulator, and anti-CD38. And these patients can also have exposure to anti-BCMA therapy by antibody drug conjugate or CAR-T as long as they’ve had a six-month or more washout period. So the inclusion criteria is quite relaxed. I think it’s a great, great opportunity for patients with relapsed disease to get on trial and get access to amazing combinations of drugs that they might not otherwise have access to.

George Mulligan

And that study is now up and running?

Cindy Varga

It is up and running.

George Mulligan

Completed discussions with FDA?

Cindy Varga

Yes, it’s up and running. It’s open to enrolments. I believe there are four patients on trial.

Hearn Jay Cho

Six?

Cindy Varga

Yeah, six. Great.

George Mulligan

Okay, thank you. So, Dr Mailankody, maybe you can comment on the next wave, our Horizon 2 study, and some of the unique aspects of that.

Sham Mailankody

So, very much along the same lines, I guess, obviously, if there’s Horizon 1 for relapsed/refractory, we have Horizon 2 for newly diagnosed multiple myeloma, these same treatments that have so much promise, CAR T-cells, bispecific antibodies, we’re all very excited to bring them to the frontline setting to patients with newly diagnosed myeloma. I think one of the opportunities and challenges there is we already have pretty effective treatments for patients with newly diagnosed myeloma. The quadruplets that we’re now using as part of induction, we have patients do very well for many, many years. But I think there is about 25, 30% of patients who get diagnosed with newly diagnosed myeloma have high-risk disease based on genetic markers that we identify, but from their bone marrow biopsies, let’s say at baseline. And these patients tend not to do very well with standard of care treatments. We think the opportunity is the highest to enrol these patients in a clinical trial for newly diagnosed myeloma that incorporates novel therapies that can build on the successes of quadruplets that we already have in place. So that’s the idea behind Horizon 2. The design is very similar. It’s a multi-arm platform study. There’s multiple arms, including one would be considered as a standard of care, highly effective quadruplet treatment for patients with high risk newly diagnosed multiple myeloma. But then there are these multiple other arms that will incorporate novel therapies bispecific antibodies either as part of the initial induction or consolidation, maintenance or all three. And there will be multiple arms over a period of time that will open and enrol patients across different sites. We are going to allow for patients who have received one or two cycles of standard of care treatments before because that is another challenge. These patients progress very quickly. So we don’t want patients to be waiting for a very long time to get enrolled on the study or get referred to the study. So patients who’ve gotten any standard of care treatment for one or two cycles will still be eligible and able to participate in this study. And historically, there’s been very, very few studies that are dedicated to high-risk myeloma. This is, you know, there’s one or two studies overall globally so far. So I do think that this is both a challenge and an opportunity. and with the new treatments we have with MRD as an endpoint and with these innovative platform designs, we should be able to address this question for our patients in the next three to five years.

George Mulligan

You described though that there’s 20 to 30% of newly diagnosed. So how do you grapple with those challenges of a subset enrolment?

Sham Mailankody

Yeah, so it becomes critical therefore that we do this collaboratively as multicenter number one. We keep the eligibility as broadly eligible as possible. We don’t exclude patients unnecessarily. And we have the flexibility, for instance, I mentioned allowing patients to go into the study after one or two cycles. So let’s say a patient was seen in the community, gets started with treatments there for his first cycle or his or her first cycle, then is identified to have high risk. As you know, these cytogenetic results can take one or two weeks to come back. So by the time the patient is recognized as high risk, they may already be on treatments. But that does not [inaudible] from going on this study. They can still be referred to, there’s enough time for them to come to one of the sites that has this platform study open and enrol on and benefit from these treatments. So I think we would require that kind of flexibility and that kind of enrolment criteria to allow for the broadest possible number of patients to go on a study so that we’re not enrolling these studies for five, seven years. We’re enrolling them in a timely fashion and getting the results in a timely fashion to then move on to the next questions we need to ask for these patient populations.

Cindy Varga

And I wanna highlight that because I think a lot of high-risk patients, it’s very hard to do high-risk studies because a lot of patients, even if you know they’re high-risk, they don’t have the time to wait for screening and whatnot. And so allowing a cycle or two, you’re gonna capture a lot more high-risk patients onto this trial. So I love that design.

George Mulligan

Dr Cho, maybe you can address the status of the high-risk study, timelines, that would be helpful.

Hearn Jay Cho

Yeah, so the MMRC, the MMRF, through the Multiple Myeloma Research Consortium will be the sponsor of the study. In order to do that, we have to get approval for what’s called an Investigational New Drug Application. So we’re actually cross-referencing the INDs from our pharma partners for their approved agents, and then incorporating that as part of the application process. So we have a master protocol draft written. We have the the control sub-protocol draft written, with Shams help, and we have a investigational protocol, sorry, Shams is co-writing the investigational sub-protocol. So we’re gonna go to the FDA with a master protocol, the control and the first investigational sub-protocol. So that submission’s probably gonna happen later this month, in April of 2025. We are on a track to have a meeting with the FDA to review their responses to this material. And ultimately, the goal is to get this study open by the fourth quarter of 2025. So not long. It’s a very aggressive timeline, but we did it for Horizon 1, and the goal is to get these treatments available for patients as soon as possible.

George Mulligan

So a collaboration across many different institutions to get this going. Maybe a bit about the interest on the biopharma side, critical partners to do any of this.

Hearn Jay Cho

Absolutely. We appreciate the commitment of pharma partners to pushing back the frontier, to not only know what their agents can do now, but can they be better? Can they be better applied? Can they be more safely applied? And ultimately, can we cure the disease with the right treatment design? So we are very appreciative of the pharma partners who have committed to Horizon, and we are always open to further collaboration to bring the best treatment strategies into the platform.

George Mulligan

So maybe just if you could reflect, the conversations today are very much about subsets, correlative endpoints, MRD, and others. So how do you put today’s discussions in context for this particular trial?

Cindy Varga

Well, if we’re talking about MRD, we are definitely integrating MRD into the designs of the trial. So for example, for Horizon 1, we have that teclistamab control arm. Already there’s MRD testing in that, so we’re doing MRD testing to confirm CR, and then we’re doing it at 12 months, and then 24 months and 36 months. So we are checking MRD. We’ll be able to see sustained MRD that way. And then at the end of the control arm, there is the opportunity where some patients, if they’ve achieved a deep enough response, can be randomized into three different arms. One where we continue teclistamab every four weeks, one where we deescalate to every 12 weeks, or one where we stop. And that will also be really important to look at MRD, right? Are we losing MRD as we follow these patients? So I think it’ll be a very interesting design, and we’ll see how long we can sustain MRD. And maybe we’re overtreating patients, and maybe even when we de-escalate, if they achieved a good enough response, we might still sustain MRD. It’s yet to be seen.

George Mulligan

Your thoughts, Dr Mailankody?

Sham Mailankody

I mean, similar. I think one of the, it’s important to do these studies and do these studies in a timely fashion so we get the clinical answers. But often the clinical answer is not the end of the story. In other words, these treatments work well for some patients, not for others. So part of our responsibility is also to try and understand why things work when they do and why they don’t when they don’t. And so I think one of the strengths of the Horizon platform is that we do have a pre-planned collection of biospecimens, bone marrows, blood samples, at regular time points. That’s going to be uniform across the study. And that will allow us, and I think we now have technologies not only to detect minimal disease, but also probably characterize what minimal disease that is left over using circulating DNA, other technologies that are research-grade at this point that can look and see if you have a small level of disease left over, is the biology of that small level of disease different from all the disease that you managed to eliminate. And so that will help us answer those patients that are really refractory to these treatments or do not benefit as much. Why are they not benefiting as much? And then one of the concerns with incorporating these treatments early on is, are we going to affect the T-cell health in a way that would preclude these patients from receiving other treatments in the future? How much time do you need from one T-cell engaging treatment to the next one? So again, I think the strength of this platform would be that we would collect serial samples that will allow us to dynamically assess T-cell fitness, health, exhaustion, other parameters to answer this question, not only in the context of this study, but also the patient’s future treatment options.

George Mulligan

Yeah, that is exciting.

Cindy Varga

And some of these sub-studies, you know, we’re using drugs that are FDA approved, we might just be using them differently and sequentially. So I think those are also very exciting.

George Mulligan

I’m just excited to see the way that bringing together the clinical team that can do the studies with a similar team of physician scientists who are doing the correlative work and have that track record. So I think you can see it’s really been a great session here at the Miami meeting and we’re really seeing the way technology and new drugs are having an enormous impact on patients. So thank you for joining.

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