iwMyeloma 2025 | Clinical trial updates in myeloma: anti-CD38 mAbs, ADCs, treating smoldering myeloma & more

Rafael Fonseca:

Hi we’re here at the iwMyeloma meeting in beautiful Miami, Florida, so thank you very much to our host Dr Landgren. We had a very good session just now looking at updates of what’s happening with the agents that are already available for the treatment of patients in the clinic and also what’s coming through the clinical trials. So, to start us off, Dr Martin, can you please tell us a little bit about updates that you think are key regarding the CD38 monoclonal antibodies?

Thomas Martin:

Yeah, we had a lot of data presented on the C38 antibodies. We have two very good antibodies, daratumumab and isatuximab, and both have been used in frontline setting with transplant eligible and transplant ineligible patients. And I think what it is these days is CD38 therapy is gravitating to frontline therapy. The question is, is what do you combine it with? Most of the data shows that CD38 plus the quadruplet of either VRd or KRd results in very high overall response rates, MRD negativity rates, and likely longer PFS. And those things are driving our use in the frontline setting.

What Dr. Fonseca brought up actually during the session was that one of the things with older patients and new patients in general is the proteasome inhibitor bortezomib is associated with some neuropathy. And so in some patients, is it okay to use a triplet using a CD38 plus Rd versus the quadruplet? And I think that’s an individual preference and that’s something that will talk to patients. My general strategy has been to use quadruplets for both transplant eligible and transplant ineligible patients and to actually use maintenance-based therapy with a CD38 plus lenalidomide as maintenance. We also discuss what is the best maintenance. Is it just Len? Is it CD38 plus Len? Is it a triplet in people that have high risk disease? And so I think those are also practice patterns that we’re developing over time. But certainly, quadruplets to start, transplant if you’re transplant eligible, and then maintenance therapy, which I prefer a doublet, a CD38 plus lenalidomide.

Rafael Fonseca:

Yeah, there’s no question that’s where the field is moving. And exciting developments, obviously, we’re going to have the development of subcutaneous administration, too, of isatuximab. One of the things that was notable in PERSEUS is, when you look at patients who were treated with DaraVRd versus VRD, there’s a greater discontinuation because of adverse effects with three drugs, which makes no sense because you’re adding a fourth drug, which actually leads us to believe that, you know, patients feel okay and like what they’re seeing with the results, right? For those who are not as familiar, what is the tolerance to CD38 antibodies in the clinic?

Thomas Martin:

Well, CD38s, especially when given by subcutaneous injection, are extremely well tolerated. There is a small chance, really 10% chance, that they have a mild reaction. And often that reaction occurs 2 to 12 hours after the initial subcutaneous injection. And it’s mild. People can take acetaminophen or diphenhydramine for those symptoms, and those symptoms readily go away. Other than that, things that have been reported, potentially some mild fatigue, there’s also an increased risk of infections. There’s no doubt about that. In all of these studies, there’s a 15 to 20 percent chance of pneumonia. And I think what we need to know about that is we have to follow patients for symptoms. If they do have symptoms of myeloma, we have to diagnose it and we have to treat them readily for the pneumonia. That wouldn’t just say to me that I don’t use a CD38 because there’s an incidence of pneumonia. We just have to be aware of it.

Rafael Fonseca:

Yeah, thank you. Thank you. Well, speaking of antibodies, Dr Rossi, we have other antibodies. We have ADCs and bispecifics, which have upped the ante, right? We’re seeing even higher levels of response. Would you mind giving us a little bit of an update? Let’s start with belantamab mafadotin. Where are we and where do you think that’s going?

Adriana Rossi:

So, you know, belantamab is sort of the only ADC in the BCMA space, which is getting increasingly crowded with the bispecifics and CAR-Ts. And I think, sadly, we’ve not had it available in the market for a while, but that has given us time to accumulate a lot of data. And I think you had pointed out to us today, you’ve shared the DREAMM-7, DREAMM-8, DREAMM-9, DREAMM-10, like the DREAMM keeps getting bigger and really gives us practical data for different combinations. So when we do get to use it again, I think it’ll be a very flexible drug. It partners well with so many of the other available drugs and it would allow us to use it through the spectrum, the continuum, right? And I think one of the important things also pointed out is, which patients? So we’re all sort of spoiled to be in academic centers where we have a number of different options, but maybe in different parts of the world, different patient populations who may not have such easy facility, that’s a really big population that we could be reaching. And one of the things that led to good discussion, I think, is as with many other drugs, we’ve sort of repeated things we’ve done before, like thou shalt treat myeloma weekly, and we’re learning that that’s really not the way. And we’ve probably over-treated a lot of patients along the way. And by learning to modify the dose and the schedule, we can probably minimize the toxicity, especially the ocular toxicity, as we reviewed not generally a severe impairment and generally reversible. I know I certainly had a number of patients back when we did have it available who I wanted to stop because they met criteria on a study and the patients themselves were very happy to continue to be dosed. And so the bigger interval with less toxicity and really no loss in response.

Rafael Fonseca:

Thank you. Thank you. You know, it’s very important to get into the nuance and the details because I think we were all worried, that there were different doses, different schedule. From what we can tell, it’s a much better tolerated product now. So hopefully that transforms itself into benefits for even more patients. By the way, if you work at GSK and you work on belantamab, you’re set to be part of the DREAMM team, right? So that’s what they say. Now let’s move on to bispecifics. Tell me a little bit about bispecifics. Lots of exciting data. And what do you think, predict the future will be with that?

Adriana Rossi:

Yeah, now that’s a much more complicated, right? We have different targets, different schedules, different doses, I think again, got sort of caught up in overdosing. In today’s session, we were specifically looking at early use, so maybe instead of waiting for myeloma, can we treat smoldering patients? And maybe again, limited dosing, limited time, limited schedule, all of which I think needs to be elucidated as we’re allowed, because precedent sets forth how we acquire our new data. But the bispecifics, again, in the BCMA space, we now already have quite a number of them. We do have the approved GPRC5D bispecifics. So, so many different places to use them in combination with other drugs, in combination with the naked antibodies. So I think that’s a question that could keep us going for most of the day.

Rafael Fonseca:

Yeah, and we’ve seen at the recent ASH meeting, some early peek into the use in frontline and even in consolidation, which I think everyone said at the panel that might be a part of the future, likely will be a part of the future.

Dr Langren, lots of areas to talk to you about, but let’s start, you talked a little bit about smoldering and you’ve actively participated in those trials. So what do you think is gonna happen in the smoldering field in the next few years?

Ola Landgren:

I do think that this year, 2025, will be one of the big milestones for smoldering myeloma because the daratumumab, the AQUILA trial, that was published in New England Journal of Medicine in December last year is now being reviewed by ODAC, the Oncology Drug Advisory Committee for the FDA. And we are anticipating in the spring of 2025 that ODAC probably will give the FDA thumbs up to go forward and approve the drug. So ODAC will advise, and FDA will make the final decision themselves. Most likely the data looks very promising. We probably will have daratumumab as the first approved drug for the treatment of high-risk smoldering myeloma. That’s what I think. That’s a big step forward for the field.

Rafael Fonseca:

And lots of questions, of course. I think you were among the first to say, we may even have to reclassify the disease, right? Move on from this, you know, MGUS, smoldering and myeloma, and we’re understanding more and more, in part through your work and Francesco’s as well, too, some of the similarities between the genetics of smoldering and multiple myeloma. So I think the world is going to change pretty rapidly for that.

Ola Landgren:

Yeah, I think the more we think about what is multiple myeloma with all the newer technologies, I think it gets more and more complicated. So myeloma is sort of a clinical syndrome, the way it is. It used to be broken legs and holes in the skeleton by imaging or kidney failure or things like that, hypocalcemia. But now, for the past 10 years, we have even recognized biomarkers, but there are more and more sophisticated biomarkers like genomics. We can pick up alterations using whole genome sequencing or other type of abnormalities. And if you compare newly diagnosed patients with a subset of the smoldering patients, there is a subset of the smolderers that look genomically the same as the patients that have multiple myeloma. And if we follow them, so Francesco has been part of our team for a long time, he’s now moved back to New York and we have looked at it and we see that if you have those signatures, you will develop this clinical syndrome within say 24 months. So why are we waiting for that? Why don’t we act? So maybe myeloma needs to be redefined. I think probably that will happen.

Rafael Fonseca:

Yeah, we need to have those conversations. Many of our mentors, when they cared for patients, it was like Sarah Newberry, published in the 1800s, right? With those broken bones and people who practice in the time of melphanoprednisone and urethane, nobisphosphonates, that was a sad reality for myeloma patients, so we’ve come a long way.

Let me finish on a congratulatory note, and that is you gave us a presentation of, I’m gonna call it the saga that you went through to present all of the data to ODAC so that we get a recommendation towards being able to start using MRD as a surrogate endpoint, both for traditional and accelerated approval for our drugs. So that was really commendable work. Thousands of patients, a lot of phone calls, I’m sure. So where do you think we’re going with implementation of MRD now in the clinic?

Ola Landgren:

The work that I pioneered when I was at the NCI started over 15, 16 years ago now. And I was told so many times that it will never work, it’s not a good idea, but we never stopped. And we delivered it and the FDA voted through ODAC last year, exactly a year ago, and they voted 12-0 in favor of using MRD as an early endpoint for accelerated approval. So I think myeloma is the only disease that has this early endpoint with MRD, which basically gives patients access to therapies more than 10 years faster than without MRD. Otherwise, you have to wait for the clinical endpoints. So I think the implementation will be that all the trials we now have, they already have MRD implemented based on this vote by ODAC last year. So we will see drugs being developed much, much faster. Patients get access much, much faster. The field is going to change faster also. So we who work in the field, we really need to get used to this new high speed. We’re going from 20 miles per hour to 200 miles per hour, which is good. So I think a lot of change will happen. I also think that MRD will, with the blood-based tests, and I’m sure you agree with that, with blood-based MRD tests will also be part of decision making. So all the work we did with the FDA is to get MRD into the approval pathway for getting drugs approved. But there is the other side of using MRD. That’s the daily work in our clinics so we can use MRD to tailor therapy. I think you can decrease the intensity. You can probably forego steps. People have talked about if you’re MRD negative, could you forego, could you harvest your stem cells and maybe have a delayed transplant or have different opinions on these things? Or could you give more cycles of therapy or fewer cycles? Different opinions there as well. Could the duration of maintenance be shorter or longer? I think two years, two drugs, and then maybe one drug if you’re MRD negative. So I think we will see more and more of MRD-driven decision making. That’s where I see the field going.

Rafael Fonseca:

You know, a couple of things. First of all, Tom gave us an example of how, in a clinical trial, if had we had the criteria that we can apply now for a possible design of trials, we would have saved seven years. So seven years of early access to patients, that’s huge. But I was thinking of a story that’s so relevant to you because I found this story, and I think it was in the book of Sid Mukherjee about cancer, where I think it’s the first use of MRD in cancer ever. And that was from a physician who was NCI when they started using methotrexate for the treatment of choriocarcinoma. Everyone was celebrating, but it turns out everyone was relapsing. And Min-Ching Liu, who was an oncologist there, noticed that you had to treat beyond. You had to make sure the HCG became negative. And if you treat it until then, those were the patients that were cured. Now, as happens in history, he was thought to be a maverick and fired, so he went to Memorial Sloan Kettering. But I think history has proven that when it comes to cancer, we have to finish the job, as I say, right? So I think this is a great example. So again, thank you for your advocacy, for your comments. I think this wraps up pretty nicely, sort of a summary of the panel we had, and I look forward to seeing you at the next one.

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