IMS 2026 | MajesTEC-3: teclistamab + daratumumab improves survival and disease control in R/R multiple myeloma

Here at 2026 International Myeloma Society meeting in Glasgow, we had a chance to present an expanded analysis of the MajesTEC-3 trial with emphasis on the components of progression for survival and how they affect overall survival. So just a recollection, this is a trial that took patients with lenalidomide-exposed, mostly lenalidomide-refractory disease, PI-exposed, who either were naive to daratumumab or they received that class of drug, but they were not considered to be resistant. And those patients were randomized between Dara-containing triplets, either DPd or DVd, or dexamethasone-free, total immunotherapy, teclistamab, daratumumab combo. This trial was presented about nine months ago and subsequently published, showing a fantastic improvement in progression-free survival with a hazard ratio of 0.17, and also an improvement in overall survival. The motivation to do this analysis that we present here is we hematologists oncologists when we look at that PFS curve we read that as a direct assessment of the drug efficacy because we assume most of the events are progression but it turns out that with teclistamab that was very few progressions to the point that progressions or death without a progression seems to have very similar contribution to the progression for survival which is a composite endpoint so what we did here was we separate those two components using a not so complicated methodology called competing risk analysis to better isolate the disease control effect and the potential toxicity signal that would emerge with a higher non-relapse mortality. And what we saw was quite striking. When you isolate cumulative incidence of progression, we see a reduction in the hazard of progression of 90%. So we can say, you know, the Tec-Dara reduces the risk of progression by 90% compared to a Dara-based triplet. When you look at non-relapsed mortality, there was some concern because there was some early deaths associated with infection on the teclistamab data then non-relapse mortality would be higher but we have to keep in mind that because patients are exposed to the treatment a lot longer because it takes longer for them to progress and the vast majority didn’t progress at all they are at risk for non-relapse mortality for longer so the best way to compare this is not a crude percentage, you know, is a time-to-event analysis like we did. And when you do that, there is no difference in non-relapse mortality with a rate of non-relapse mortality at three years of about 10% with Tec-Dara and about 8%, 9% with Dara-based triplets. Now, when you look at the overall survival analysis, we have what we call non-proportional hazards. In other words, the curves don’t uniformly separate. They stay together until 10 months, and then they separate. And then we’re trying to understand what happened there. And what we saw is that the first 10 months, there’s an equal number of deaths in both arms, 29. Those deaths are predominantly due to toxicity in teclistamab data, but predominantly due to progression in the Dara-based triplet. In other words, while there are some deaths that we would like to avoid in the future by better infection mitigating strategies on the Tec-Dara that is more than balanced by excessive deaths due to progression in the Dara-based triplet. But beyond 10 months, then the hazard of death drops by over 80%, by near 80%. So the hazard ratio goes down to 0.22, 78% in the risk of death beyond 10 months, really driving the message that really the biggest killer in myeloma is not the toxicity of the treatment, is the disease itself. When it has such a dramatic disease control as we have with Tec-Dara, that essentially drives this behavior, say, you know, viral survival. We believe this data could look even better if we’re able to better mitigate those initial infections. Remember that in this trial, most of those fatal infections happen in the first six months. And when patients transit to those six months, it was before implementation of measures that we now consider standard to prevent infection. But nevertheless, with the data as it is, there’s never a period of time during the study where the risk of death is higher with Tec-Dara, and the non-relapsed mortality, that is something that is increasingly one of our concerns, is no difference between the arms.

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