ASCO 2026 | SUCCESSOR-2 trial: mezigdomide, carfilzomib & dexamethasone (MeziKd) versus Kd in R/R myeloma

SUCCESSOR 2 trial was the first randomized phase 3 data generated with the novel CELMoD mezigdomide. This compared mezigdomide, carfilzomib, and dexamethasone to the active control of carfilzomib and dexamethasone in relapsed/refractory myeloma patients who had to have received and or become refractory to lenalidomide And also, and this is most important, had to also have received CD38 monoclonal antibody therapy and or be refractory to it. So this was a uniquely vulnerable population. And the important aspects of the trial were several, actually. One, that it had been one or more prior lines, but the range was one to nine. Our median was two. Second, this included a two-stage design. The stage one was the dose optimization exercise pursuant of guidance from the FDA for Project Optimus, and at the same time, then a large randomized three to two randomization of either mezigdomide, carfilzomib, and dexamethasone, or carfilzomib, dexamethasone as control. Mezigdomide was dosed at one milligram daily, three weeks on and one week off. Carfilzomib was traditionally dosed at 56 milligrams per meter squared twice a week, basically three weeks on, one week off, or 70 milligrams per meter squared days one, eight, and 15 every 28 days. This change was made subsequent to the ARROW data being approved in August of 2023. For the control arm, to ensure equipoise, the carfilzomib dosing could be maintained at full intensity throughout the course of the patient’s course on treatment. In contrast, for the mezigdomide, carfilzomib dex arm, after 12 cycles, the carfilzomib was dropped by design to just twice a month from three times a month. So there was a deliberate move to try and decrease the intensity of carfilzomib for the experimental arm. In terms of the patient disposition and patient demographics, they were very well balanced across both arms. It’s important to note that we had over 25% of patients who were aged 75 or over. And I think very importantly, in terms of the distribution of lines of therapy, at least a quarter of our patients were either four or more lines of prior treatment in the relapsed refractory setting. Otherwise, the arms were very well balanced for risk features, high risk features, extramedullary disease, prior therapies, and so forth. I think the punchline really, with SUCCESSOR-2 was the progression-free survival benefit was striking. 18 months for the experimental arm compared to 8.2 months for the control arm with a hazard ratio of 0.48. So this was really, I think, very encouraging. What was also most important was each pre-specified subgroup, age, number of prior lines of therapy, refractoriness, cytogenetics, high risk or otherwise, and importantly, extramedullary disease. For all of those key pre-specified endpoints, the hazard ratios was firmly in favor of mezigdomide, carfilzomib, and dex. Then I think what was exciting was the response data. We saw response rates in excess of 80% for the MeziKd arm compared to around 54% for the KD control. And the quality of responses was significantly superior for the meziKd arm. I think in that spirit, the duration of response was significantly better for meziKd. And moreover, if you looked at PFS2, and this is a very important endpoint, this was strikingly in favor of meziKd compared to KD with a hazard ratio of 0.53. So with all of that put together, we’re very confident that we’ll see a survival benefit actually emerging from this trial, or very hopeful, I should say, that we’ll see survival benefit emerging from this trial. With a follow-up of around 11 months, the survival data are still a little premature, but even at this stage, the hazard ratio is 0.7. So with that in mind, I think we’ll be seeing a survival benefit over time because there’s no crossover of the curves. So that suggests we won’t have competing risks from toxicity. And in the spirit of analyzing toxicity, we are very pleased to report that there were no unexpected safety signals. Neutropenia, which is an expected side effect of mezigdomide and is an off-target effect in terms of neutrophil differentiation from the cereblon and E3 ligase modulation that underpins how mezigdomide works, was remarkably manageable with growth factor support and, when needed, dose reduction and so forth. But the most important thing is that the dose intensity of mezigdomide in the study was preserved at 83%. So whilst there was some dose reduction, it certainly wasn’t enough in any way to impact upon the efficacy of mezigdomide overall. The other thing which was very reassuring was we did see some infections, but the rates were low. The rates of opportunistic infection were extremely low, and fatality was low. The treatment-related mortality was very low, and in fact, in terms of the number of treatment-related deaths on study, almost two-thirds were due to progressive disease rather than actual attributable toxicities. So this, I think, was very encouraging. And then in terms of long-term outlook or next steps, obviously with this striking PFS advantage, this trend in survival benefit, and this manageable tolerability profile, we’re very much hopeful that this will provide a platform for FDA approval, if not later this year, certainly by early next. There is the SUCCESSOR 1 trial coming, which is comparing mezigdomide bortezomib and dexamethasone to the active control of pomalidomide bortezomib and dexamethasone. And we expect to read out from that study early next year. So putting it all together, I’m very hopeful, Tom, that we’ll see mezigdomide in combination achieve regulatory approval and access then for patients across the board. A few sort of closing comments. One, that what was so exciting was to see the benefit of the drug in different settings. I think that’s a very important construct. Its value is a community-based option because it’s obviously oral. And I think what’s really interesting is if you look at its use in early relapse, the median PFS for that group of patients has not been reached. And as we sought to sort of contextualize these results, we presented data, for example, from the SELECT trial, which was Carfilzomib, pom, dex. the median progression-free survival there was just 11 months, so we were way north of that, recognizing the caveats of cross-trial comparison. But if you look at two similar populations and match them for CD38 refractoriness and LEN refractoriness, you look at, say, KarMMa-3 or CARTITUDE-4. In KarMMa-3, the ide-celmedian PFS in that particular study was 13 months in the similar group of patients, which I think is very interesting. And then second of all, for CARTITUDE-4, the medium PFS in a similar group of patients is 19 months. So I think when you think about the landscape, I think these data are very promising. They’re recognizing the real power of bispecifics and the very exciting data around, for example, MajesTEC-9, I think, nonetheless, this provides a really important option for patients who, and let’s face it, bispecifics are not for every patient, or least of which because of the potential significant complications, especially in the area of its infection. So I think we are very pleased to be able to offer mezigdomide to our patients in a variety of settings and therefore confer, hopefully, significant clinical benefit.