Belantamab Mafodotin: The Comeback Drug in Multiple Myeloma

— Joseph Mikhael, MD, leads a discussion on the DREAMM-7 and DREAMM-8 trials


At the American Society of Clinical Oncology (ASCO) annual meeting, positive findings were presented on two phase III trials -- DREAMM-7 and DREAMM-8 -- testing belantamab mafodotin (Blenrep) in multiple myeloma. Belantamab mafodotin had received accelerated approval in 2020 but in 2022 was following a failed confirmatory study.

app brought together three expert leaders in the field for a roundtable discussion about multiple myeloma: moderator Joseph Mikhael, MD, is joined by Amrita Krishnan, MD, and Tulio Rodriguez, MD, all of City of Hope in Duarte, California. This final of four exclusive episodes focuses on the results of DREAMM-7 and DREAMM-8.

Click here to watch the other videos from this roundtable series on multiple myeloma.

Following is a transcript of their remarks:

Mikhael: Let's shift our focus to our final discussion point, which is the potential resurgence, reappearance, whatever phrase you want to call it, of belantamab mafodotin. As we know, belantamab mafodotin was approved on the accelerated approval path as a single agent in relapsed myeloma, and then when one of the confirmatory studies was done and did not demonstrate a significant benefit over pomalidomide and dexamethasone, it was withdrawn from the market. It is still accessible under certain restrictions -- I know I have several individual INDs [investigational new drug applications] for many of my patients. Many of them are still benefiting from belantamab.

But here at ASCO, arguably two of the most influential abstracts of the year are the first reports now published in the New England Journal of these phase III trials of using belantamab in earlier relapse and really going head to head with bortezomib [Velcade] and head to head with daratumumab [Darzalex] in the DREAMM-7 and DREAMM-8 studies.

So let's start with you, Amrita. What strikes you the most about these two studies -- DREAMM-7 and DREAMM-8 -- as to whether or not this is going to mean the return -- it sounds like a sequel -- the return of belantamab.

Krishnan: So you know what it reminds me of? I was thinking last night of the actor Robert Downey Jr. Everyone wrote him off and then he came back to win the Academy Award. So there you go.

Mikhael: You see why I want Amrita to do these discussions with us? She always has the best analogies. I love it.

Krishnan: I am the pop culture analogy, but same thing, two New England Journal papers, a drug that clearly in two phase III trials, and even more than that, I have to commend them that it was triplet-versus-triplet trials, and that is huge. And so absolutely no one can argue with those hazard ratios in terms of progression-free survival, and also overall survival.

Mikhael: And overall as well. Yeah, let's make that very clear, because that's pretty much unprecedented.

Krishnan: And also the subgroup analysis that's also going to be presented in this "functionally high-risk" group. Again, high-risk cytogenetics, lenalidomide [Revlimid]-refractory patients. So I think without a doubt, this drug needs to make a comeback.

Having said that clearly, again, let's talk about toxicity. In DREAMM-7, 25% of patients having grade 3 or higher blurred vision, and that can run a gamut. That's the problem, or it can be literally interfering with your ADLs [activities of daily living] to that point.

So that's a challenge, and I think it speaks to, again, in the real world, most of us are going to take other measures to reduce that risk of toxicity. Specifically in regards to the schedule of the drug, which in these trials was Q [every] 3 weeks, I would venture to say most of us won't give it at Q3 weeks.

Mikhael: And I think actually even in design and what was presented, was showing what was actually given. And of course there was the opportunity in DREAMM-8 -- of course, was started at Q4 to go out to Q8. I can tell you in the patients that I'm treating now that are on those individual INDs, because that's still available for them, most of my patients, I give them their first dose, I give them a second dose 4 weeks later, and then I plan the subsequent ones between 8 and 12 weeks later. I mean, I've teased one of my patients that she just needs to smell the bottle every ...

Because there's clearly a subset of patients that really benefit from this. But I think you're absolutely right. It goes back to the point I made earlier, which was every drug goes through an evolution in myeloma. We've gone from twice-weekly to once-weekly bortezomib, twice-weekly to once-weekly carfilzomib [Kyprolis], intravenous to subcutaneous daratumumab, selinexor [Xpovio] twice weekly to once weekly.

I think we're still optimally trying to find the right window for belantamab, but even despite that, we saw this incredible efficacy. And so I agree with you. I do think it's going to come back.

I think we still need to be able to tailor it more carefully to our patients. And of course, they're still going to continue to have their eye exams. But Tulio, what's your take on these two DREAMMs? Are they that dreamy?

Rodriguez: No doubt this drug is back. It was very striking to me that in DREAMM-7 there was a monoclonal on both sides, and then you have this conjugated [drug] antibody kind of working way better. Then we have better ... we have more experience now managing the toxicities than the side effects on DREAMM-8. It was started at every 4 weeks with a 2.5 per kilo, the following cycle deescalated to 1.9, not even waiting for side effects, and after that interval became a little bit more flexible. And they have shown that there's no progression of myeloma while waiting for the patient to recover for any possible toxicity.

So I think that the combination of a very well-designed trial in contrast to what I think happened with the initial studies and better management of toxicity, I think that this drug is back.

Mikhael: Yeah, I completely agree. I mean, I think it does speak to the challenge of doing research, right? You've got to design the trial correctly, and I commend them as Amrita did that going triplet versus triplet took some challenge. But that's the kind of trial we want to see. We do want to see that because inevitably -- not inevitably, but more often than not -- triplets versus doublets do better.

So to do that, and maybe as a final point I'll make, despite the fact that we love cellular therapy and we haven't even had time to talk about bispecific antibodies, can you believe that? That's how much is going on at ASCO right now. There is something very attractive about giving a drug that is easy to administer that's given over half an hour once a month or 2 months or 3 months, can easily be given in the community.

We don't have the concerns about cytokine release syndrome and potential neurotoxicity. Yes, we have the ocular talk as we've discussed, but there is something very attractive to that. And I do think that as we think about what both of you have said, from a biological and a pragmatic perspective, no two patients are the same with myeloma.

So I want choice. I want that "Cheesecake Factory" menu of choice -- you almost need a table of contents for that. And for one patient, it may be CAR T, another patient may be a bispecific, another patient, it may be the ADC [antibody-drug conjugate]. And then of course sequencing is another roundtable on that.

But let me thank both of you very much, Tulio and Amrita. I respect you both. I love the way you think about myeloma and how you care for your patients. So thank you for joining me today on this app roundtable discussion here at ASCO.

Thank you for joining us. I hope it's been helpful to you, provocative, to be excited about this new data and learn very pragmatic ways in which we can bring it to our patients. So thank you again very much for joining us.

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    Greg Laub is the Senior Director of Video and currently leads the video and podcast production teams.