ASH 2025 | ReKInDLE: a Phase II trial of iberdomide, carfilzomib, daratumumab, & dexamethasone for R/R myeloma

So the ReKInDLE study is sort of an important study. It’s a phase two single-arm study. We did this with a quadruplet therapy regimen built on an iberdomide backbone. Iberdomide is a CELMoD. It’s a cereblon E3 ligase modulator. And it’s been in development for quite some time, but these drugs seem to be active and effective in settings where IMiDs, the prior sort of generation of drugs, are ineffective or where patients develop resistance. 

And so what we decided was that in the very early relapse setting where most patients relapse with a lenalidomide refractory state, most of the IMiD-based therapies that are available are suboptimal, you know, aside from being able to use BCMA-targeted therapies, which is kind of a developing field. So in this setting, we said, maybe we can use a quadruplet therapy with an iberdomide backbone to try to recapture deep responses and then to help facilitate patients to de-escalate back to monotherapy, which is a very nice place to be for quality of life purposes. And so the ReKInDLE study is re-induction with carfilzomib, with iberdomide, daratumumab for long-term efficacy – ReKInDLE. 

And so eligible patients had one to three prior lines of therapy, prior exposure to CD38-directed therapy, and carfilzomib was allowed as long as patients weren’t refractory to those agents. And patients would enroll, 32 of them, enroll to get eight 28-day cycles of the combination of IberDKd with iberdomide dosed at one milligram, 21 out of 28 days. And after eight cycles of therapy, patients would then go on, would undergo a bone marrow biopsy with MRD testing as well as a PET scan. And the MRD testing we’d either do via next generation sequencing with adaptive Clonoseq or with multi-parametric flow cytometry. And that was the primary endpoint to get MRD negativity at the end of those eight cycles of therapy. Now, regardless of the response, though, patients would then deescalate to up to three years or 36 cycles of iberdomide monotherapy. 

And so at this time, all patients have accrued. So all 32 patients have enrolled. They’ve all gotten at least one dose of study drug. 18 patients have actually already deescalated. They finished their eight cycles, and they went on to get monotherapy, which they are currently on. Five patients have come off study. One patient withdrew very early for social reasons, and the other four were either progression or toxicity. 

And generally speaking, the results have been pretty remarkable. Top line, so the overall response rate so far is 100%, so all patients have responded. And for the primary endpoint, the 10 to the negative 5th MRD threshold, our rate is 71% for 24 assessable patients so far. So 71% is remarkable, mostly because compared to other drugs and other combinations utilizing IMiDs in this setting, it’s much, much lower, depending on the trials that you cherry pick from, could be anywhere in the 10 to 20% range. 

And then in terms of safety, we also did quite well. So the nice thing about CELMoDs, iberdomide specifically, is that compared to the prior generation of IMiDs, the side effect profile is a lot nicer and friendlier for patients. So very little fatigue, diarrhea, rash, and no thromboembolic events. So pretty well-tolerated regimen, and no patients discontinued therapy because of toxicity. Speaking to further toxicity, hematologic toxicity is sort of an issue, especially with the combination of these four drugs together. And so we did see a lot of neutropenia, which patients don’t feel, but obviously can be dangerous. We didn’t see that much of an infectious signal, which is great, but the rates of neutropenia did have us dose-reduce iberdomide relatively frequently. But still, because of the good tolerability, we’re able to maintain dose intensity compared to prior IMiD-based studies. So overall, the regimen seems to be quite tolerable. There’s no new safety signals compared to what we’ve seen with either single-agent use of the drugs, now that this is a quadruplet combination. And it does seem to be very active in a lenalidomide-refractory setting. 

So, you know, this is a very evolving field. There’s a lot of new T-cell redirecting therapies, but this still does look like it might have a place either before T-cell redirecting therapies or in between T-cell redirecting therapies. And we’ll be excited to report the rest of the results as soon as they come in.

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