A Look at the Multiple Myeloma Data Leading to Blenrep’s Withdrawal

In the DREAMM-3 trial, belantamab mafodotin (belamaf; Blenrep) did not improve progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma when compared with pomalidomide (Pomalyst) plus low-dose dexamethasone, failing to meet the phase III study’s primary endpoint.

Data from the study were presented at the recent American Society of Clinical Oncology (ASCO) annual meeting and led to the withdrawal of the therapy from the U.S. market late last year.

MedPage Today brought together three leaders in the field for a virtual roundtable discussion: Moderator Sarah A. Holstein, MD, PhD, of the University of Nebraska Medical Center in Omaha, is joined by Brea C. Lipe, MD, of the University of Rochester Medical Center in New York, and Monique Hartley-Brown, MD, of the Dana-Farber Cancer Institute in Boston. This first of four exclusive episodes focuses on the study results and what they mean for physicians moving forward.

Following is a transcript of their remarks:

Holstein: Hello everyone. My name is Dr. Sarah Holstein. I’m a professor at University of Nebraska Medical Center, and it’s my privilege today to be here with Dr. Brea Lipe, who is a professor at the University of Rochester Medical Center, as well as Dr. Monique Hartley-Brown, who is an assistant professor at the Dana-Farber Cancer Institute. And today we are going to be discussing some of the really exciting data from ASCO that was presented specifically in the disease space of multiple myeloma.

So our first topic has to do with a phase III study that I think everybody was really looking forward to getting a glimpse of the data in detail. And this is the DREAMM-3 study, which involved randomization of patients with relapsed/refractory disease to either belantamab or pomalidomide and dexamethasone. Dr. Monique Hartley-Brown, would you mind telling us more about the study?

Hartley-Brown: Thank you. I’ll go ahead and jump right into it. Basically the DREAMM-3 trial, as you mentioned, was a phase III trial that looked at belantamab mafodotin as a single agent versus pomalidomide and dexamethasone as a doublet. And the study was randomized 2:1 in favor of belamaf. And the usual doses of pomalidomide and dexamethasone were used for the doublet arm, the primary endpoint being progression-free survival.

We had over 300 patients — about 325 patients were enrolled. And these were patients that basically were all adults. There was a slightly increased amount of males — so about almost two thirds of the patients were males. And we were looking to see whether the belamaf would have a PFS comparable or favorable to pomalidomide dexamethasone.

As we all know, as of November of 2022, the belantamab failed to reach that endpoint. And so the updated information from ASCO this year looked a little bit more in depth into the outcomes of both arms.

We still see that the belamaf arm has a somewhat longer PFS even though it still has a ratio of 1.03, so it’s not going to reach its endpoint. But we do still see about an 11.2-month median PFS for the belamaf arm compared to the doublet arm of about 7 months.

So, there are still other trials that are ongoing looking at belantamab in combination with anti-CD38 monoclonal antibody therapy, as well as in combination with other PIs [proteasome inhibitors].

We do have the DREAMM-8 and DREAMM-9 — there’s some data that’s still pending on those. But the fact that this update is showing slightly increased benefit in terms of the PFS, even though it didn’t reach statistical significance, is telling, I think. And also when you look a little bit more into the duration of response, you see that the duration of response and the depth of response for the belamaf arm was somewhat deeper.

And so I think this is some interesting information, and I wonder how that’s going to read out in the combination of belamaf with other agents, especially with pomalidomide and dexamethasone as the triplet, which we do have some preliminary data that’s going on with the ALGONQUIN study. But I think we haven’t heard the last of belamaf, is what I’m taking from this.

Holstein: Thank you. Dr. Lipe, what were your thoughts when you listened to this presentation?

Lipe: You know, when I hear this data, I think it’s hard to envision a role for this moving forward — this drug in particular. We have more drugs coming to the BCMA [B-cell maturation antigen] space, and finding a role for a drug that has not the same level of activity that we’ve seen with some of these BCMA-targeted therapies, at least not in a randomized trial, but at least when you look at the response rates from the individual trials, I think it’s going to be hard to see what we do with that.

And when you take into account the toxicity and the ocular events, I think these results are sort of what we heard. It’s disappointing, and for me, I find it hard to find a future here.

Holstein: Interesting. Yeah, and this study did the every-21-day cycles, and I think a lot of the ongoing studies are trying to figure out if you space out the belamaf, whether that will result in less ocular toxicity. But I think some of the signals so far would suggest that the further you space it out, perhaps the lower efficacy. So it is a bit difficult to understand where this is going to fit in with all the bispecific antibodies that we’re going to be discussing a little bit later.

And there wasn’t much granularity in the presentation regarding how often patients did require dose delays. I know in my own experience, when this drug was approved for whatever period of time that was, that it was very uncommon to be able to keep patients on an every-3-week cycle, just because so many of them did experience ocular toxicity.

Hartley-Brown: I agree with what you both have said. I would argue that we’ve heard this story before. If you think back on the story of bortezomib, we really had significant toxicity when it came to the neurologic toxicity. And we had such high peripheral neuropathy rates when we first started with that drug, and we learned how to manage that. And I think all of the other therapies that are coming up in our discussion, many of those therapies, it’s going to take some time before we can apply them in the community oncology setting — which let’s be frank, most of our patients are treated in that setting. And they need something before they can access therapies at the tertiary care centers that have experience with the bispecific antibodies and the CAR-T [chimeric antigen receptor T-cell] therapies, and have the resources to allow patients to get those therapies safely and appropriately and in a timely fashion.

So that’s where I’m seeing belamaf and seeing it in combination. And I also agree that we have a lot of work to do in terms of defining the dosing and the interval of dosing because that’s how we are probably going to gain some momentum in terms of mitigating the toxicity, especially the keratopathy, but maintaining efficacy when we use this agent in combination with other agents. But we’ll see.

Holstein: Oh, excellent points, absolutely right. It is difficult for patients oftentimes in the community to be able to have access to therapies where inpatient monitoring for cytokine release syndrome and other toxicities is mandated.

Dr. Lipe, what are your thoughts, though, about sequencing and concerns about having patients receive belantamab in the community, but then perhaps not get as much benefit later with subsequent bispecific or CAR T-cell therapies?

Lipe: I think that’s my primary concern. I think those are great points that Dr. Hartley-Brown pointed out, and the community population is sort of the population I’m struggling most with. And the decisions that people have to make in terms of their life, what they’re willing to sacrifice for travel to get these new drugs, is often heartbreaking. And it’s personal and it’s real. But I think that rather than accepting that this is going to be hard and so we should have other agents that seem to be inferior, we need to push the envelope.

And it’s incumbent upon us to figure out how to give these drugs in a community setting. How do we make these drugs that are better acceptable and tolerable to our patients? Because I think we have some data coming out showing that you can get some responses after prior BCMA-directed therapy, including the ADCs [antibody-drug conjugates].

But the response rates aren’t the same, And we don’t have enough data yet to know about the durability of those responses. So why would we accept inferiority? We need to fix the problems, and we need to make these drugs accessible.

Holstein: Excellent point.

Lipe: In my pie in the sky, if I could fix the world …

Holstein: So I think we’re all going to be really curious to see how belantamab fits into the armamentarium of myeloma therapeutics moving forward. And I certainly do believe that we’re probably not done with it yet. There’s many ongoing studies, planned studies, and we’ll be keenly interested to see how all of those read out.