EHA 2026 | Tec-Dara in patients with R/R myeloma: analysis of MajesTEC-3 based on cytogenetic & functional risk

So as all of you are well aware, the MajesTEC-3 published the results from the New England Journal of Medicine paper, by Costa and colleagues last December, show that Tec-Dara, teclistamab plus daratumumab, dramatically outperformed standard therapies in early relapsed myeloma, meaning in patients with one to three prior lines of treatment who were randomized to Tec-Dara, meaning teclistamab at BCMA by specific antibody, T-cell engager, plus daratumumab, the standard CD38 monoclonal antibody, versus conventional treatments, the Tec-Dara arm had better PFS, so were in remission for longer, better overall survival, they lived longer, and better MRD negativity and quality of life. 

What we wanted to look at was the patients who have historically been left behind by these, you know, innovations in relapsed myeloma are the ones with high risk anything. And those are the ones we really wanted to focus in on. Historically, almost every study talks about high risk cytogenetics, right? Patients with deletion 17P, you know, 14;16, et cetera, et cetera, where historically they often have done worse in the setting of transplant. We looked at that, including gain 1q and amp 1q, which are emerging features of high-risk cytogenetics in multiple myeloma. What I’m really excited about and why I really asked to lead this project, we also looked at functional high-risk myeloma. The whole point of all of our cytogenetic risk factors is to predict patients at risk of early relapse with standard treatments. Functional high risk is early relapse, meaning the patients who unexpectedly have a relapse much earlier than expected. With a triplet induction regimen that is defined as 18 months from start of treatment or transplant to relapse. For a quadruplet induction, that’s 36 months from start of treatment or transplant to relapse. And so historically, these patients have done terribly thereafter, right? A lot of studies, including ones that we’ve led, show that these patients often, their overall survival is only two years afterwards. After that first relapse, whatever is wrong with their disease biology keeps accelerating and they have more and more and more relapses. We need to break that cycle. And the question was, can MajesTEC-3 do the trick with Tec-Dara? 

And short answer is absolutely, not just do the trick, but beyond surpassed expectations. For patients with cytogenetic high-risk abnormalities, for example, again, the ones that we typically think about, but also the 1q abnormalities, Tec-Dara dramatically outperforms standard therapies. Again, hazard ratio in the 0.12 to 0.17 range, very similar to the overall hazard ratio for PFS from the whole study. Tec-Dara shouldn’t just be for high-risk patients. On the other hand, I will highlight that of the patients with standard cytogenetics, so if you take all the normal high-risk features and gain 1q, amp 1q, and take them out, everybody else, their three-year PFS was 90%. So three years out, 90% of them are remaining on Tec-Dara in remission, basically functionally cured with a plateau on that curve, which is phenomenal. 

And moving to my personal passion project, functional high-risk disease biology, again, these are only the subgroup of patients, the MajesTEC-3, who had one prior line of treatment and went on straight to the study, either Tec-Dara or conventional investigator’s choice, either Dara PD or Dara VD. Of the patients was, and I should add, the study was not powered for those patients at all. For the patients with functional high risk who went on to get Dara PD, Dara VD, 36-month PFS was 0%. Not a single patient made it three years without a relapse or death thereafter. Highlighting historically how poor their prognosis had been for these patients. With the Tec-Dara arm, that number was 77% at three years. Night and day, the difference. Same for MRD negativity. So not a single patient with functional high-risk disease biology who went on to get standard treatment at the second line achieved MRD negative CRs. For the patients who got Tec-Dara, that number was 33%. 

So basically, where do we take with this? Tec-Dara, I would argue, is a great equalizer of relapsed myeloma. We know that some patients historically have been left behind by all the advances with PIs and IMiDs and all of that. Tec-Dara is starting to close that gap. Indeed, of the patients with functional high-risk disease biology, the curves for the functional high-risk patients and the non-functional high-risk patients were both plateauing almost parallel to each other. Tec-Dara is coming tantalizingly close to closing the gap for these patients. And I would argue that now, for some of the functional high-risk disease biology, they really should be preferentially getting CAR-T or Tec-Dara at first relapse. But obviously, it’s not just for the high-risk patients. The standard-risk patients, again, 90% PFS at three years is phenomenal and speaks to how these regimens are setting us down a path that we’ve never seen before in myeloma, a path where people are probably on their way to a functional cure.

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