Iberdomide, daratumumab, and dexamethasone in relapsed or refractory multiple myeloma with Professor Lonial

0:00 This is an AI-generated transcript Hello, and welcome to In Conversation With, a podcast from The Lancet Oncology. My name is Dr. Cheryl Reeves. This month, I'm delighted to be joined by Professor Sagar Lonial from the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University in Atlanta, USA.

0:21 He's going to talk to us today about his paper on ibredamide plus daratumumab and dexamethasone versus daratumumab, bortezomib, and dexamethasone in patients with a relapsed or refractory multiple myeloma, an open-label randomized controlled phase 3 trial, which is published in our November issue. What makes this drug combination important to research in relapsed or refractory multiple myeloma?

0:54 Well, I think, uh, what's really interesting and important about the EXCALIBUR relapsed/refractory trial is that we know that triplets, which are combinations of either IMiDs, the older class, or proteasome inhibitors with an anti-CD38 have traditionally been a standard. But they have certain toxicity and limited efficacy based on where we are in the modern world.

1:21 And while certainly bispecifics and CAR T-cells are very exciting, they're not necessarily available to everybody. And so having more effective, better tolerated approaches that are in a triplet combination really is one unmet medical need. And it was that unmet medical need that led the FDA to creating a new class of drugs called CELMoDs, which iberdomide is the first approval in that class.

1:49 So, um, can you explain the main findings of your trial? So the EXCALIBUR relapsed/refractory myeloma trial was a randomized phase three trial that had a two-stage design. Stage one was trying to identify the optimal dose, and then stage two was looking at efficacy. And the second unique portion of this trial was the fact that it had a dual primary endpoint, and one of them was MRD.

2:17 Uh, this was the first trial to use MRD as an approval endpoint by the US FDA. And the second was progression-free survival. And what we, uh, nicely demonstrated was that MRD was roughly double in the group that got iberdomide compared to the control arm. And the VGPR or better, so 90% reduction, was also, uh, significantly higher, as was the complete remission rate.

2:43 So speaks to that potency comment that I was making earlier regarding the CELMoD class of drugs. Okay. So can you provide some clinical context to aid interpretation of the findings in practice, particularly as you're only reporting at the moment the results of the minimal residual disease negative complete response, not the progression-free survival results?

3:05 So what we know about MRD, particularly at between nine and 12 months when it's measured, is that it does predict for improved progression-free survival and improved overall survival. That was the work of the I-squared team, uh, with a number of folks, uh, working on that. What I think is important is that anybody that you were thinking about a triplet combination on, this one is clearly superior, at least as measured by MRD.

3:33 So dara-pom-dex is one of the most commonly used triplet salvage regimens in the US. Iber-dara-dex should replace it because the MRD negative rate is significantly higher, and we know that that's a surrogate for outcomes. You say in the paper that most myeloma care occurs outside of academic centers.

3:53 Is this considered a problem in the treatment of patients? And is the field designing trials for patients it actually treats? Yeah. So, you know, I think that the structure of hematology care in the US is a little bit different than it is in Europe perhaps, where oftentimes patients with heme malignancies will go to a heme specialist and who's equipped to handle lots of different things.

4:16 In the US, uh, about 80% of cancer care is delivered in the community by people that see both oncology and hematology and benign hematology. So they're sort of doing a little bit of everything. And so the level of support and care in those centers is not quite the same as it is in a, in an academic center.

4:38 So I think having treatments that are easily accessible and have good efficacy really is an important need. So what are the limitations of the study? Is, is that one of them? Well, I, I, I don't know that that's necessarily a limitation in the sense that I think the results are e- you can extrapolate that to any clinical situation.

4:59 I think we know that there are patients who are good candidates for a CAR T, and certainly nobody would argue that that should be a good choice for them. There are patients that are good candidates for a bispecific. There are also patients who are not good candidates for either of those, and now we have an improved efficacy triplet combination to offer them clinical benefit.

5:20 So what are the challenges that you foresee that still lie ahead? Well, I think from a safety perspective in the trial, the one signal that did come up, and it's on target, so it's not unexpected, was neutropenia. And so helping clinicians to appreciate that the dose adjustment and modification and support are different than they were with the older IMiD class.

5:44 In that class, you had so many different doses that you could just make adjustments, and it was, it, and the dose, and it was okay. For the cell mods, uh, because they've been optimized in their dose, that wasn't the strategy used in the trial. In the trial, the dose was held and/or G-CSF was added. That's a subtle nuance, and it's different, but I think it allows you to maintain dose intensity and get the kind of results we saw in the EXCALIBUR trial.

6:11 Thank you so much, Professor Lonial. It's been a real pleasure chatting with you today. Thank you for listening to this episode of In Conversation With. Remember, the full article is now available online on the Lancet Oncology website, and you can subscribe to In Conversation with The Lancet Oncology wherever you usually listen to your podcasts.