Key Clinical Summary:

• Design/Population: The phase 3 MajesTEC-3 trial was the first randomized study of a bispecific T-cell engager in multiple myeloma, enrolling patients previously exposed to proteasome inhibitors and immunomodulatory drugs, with 86% lenalidomide-refractory disease. Patients were randomized to teclistamab plus daratumumab versus standard daratumumab-based triplets (DaraPd or DaraVd) in the second to fourth line setting, with median follow-up >35 months.
• Key Outcomes: Teclistamab + daratumumab significantly improved progression-free survival (Hazard ratio [HR] 0.17)—the lowest hazard ratio reported in a randomized myeloma trial—and showed an overall survival benefit (HR 0.46). The 3-year PFS exceeded 84%, with an apparent plateau after 6 months, suggesting durable disease control. Benefits were consistent across older patients, high-risk cytogenetics, and extramedullary disease. 
• Clinical Relevance: MajesTEC-3 establishes off-the-shelf BCMA-directed T-cell redirection with teclistamab plus daratumumab as a highly effective, scalable early-line strategy, delivering unprecedented durability and survival benefit without chemotherapy or steroids. 

Luciano Costa, MD, University of Alabama at Birmingham, Birmingham, Alabama, presented early results from the phase 3 MajesTEC-3 trial, the first randomized study of a bispecific T-cell engager for multiple myeloma, which found teclistamab plus daratumumab significantly improved outcomes when used as early as second-line therapy.

These results were presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition in Orlando, Florida.

Dr Costa concluded, “This is as good as any treatment we have seen in myeloma.”

Transcript:

Hello, my name is Luciano Costa. I'm a multiple myeloma physician in University of Alabama at Birmingham. I'm here at the 2025 ASH Annual Meeting. We're going to be sharing some very exciting data from the first analysis of the Majestec-3 trial. I'm 1 of the co-lead investigators along with my colleague Dr. María-Victoria Mateos. Maria is presenting a late-breaking session; it is the very last abstract being presented ASH on Tuesday morning. We're going to have a simultaneous publication on the New England Journal of Medicine. Everybody's going to be able to look at a full data set on Tuesday.

This is the very important trial, is the first randomized trial with bispecific T-cell engagers in myeloma, and it's going to be the trial that brings teclistamab, the first BCMA-directed T-cell engager, to earlier lines of therapy. This trial was designed to take a patient population that was exposed to proteasome inhibitor, any immunomodulatory agents. 

With the majority of patients, 86% of the patients, having lenalidomide refractory disease. A small subset of patients could have been exposed to CD8 monoclonal bodies so long as they were not refractory. The patients were randomized between receiving a standard regimen, which could be DaraPd or DaraVd, which are 2 acceptable triplets, dara-based in that appropriate for second-, third-, or fourth-line therapy or to receive daratumumab in combination with teclistamab (tec-dara).

There are some nuances of this design. One of them is that teclistamab was not used as approved for later line, which is weekly at 1.5 milligrams per kilogram. You actually follow a scale that mimics the daratumumab, which is weekly for the first 2 cycles, then every other week at a higher dose, 3 milligrams per kilogram, and then once every 4 weeks going forward. Patients were followed with the primary end point being progression-free survival, several secondary end points for efficacy and certainly safety and also overall survival.

The results that we are showing here have a median follow-up more than 35 months. It is a highly positive study with a hazard duration for progression or death of 0.17, which is the lowest we have seen for any randomized trial in myeloma, which is pretty impressive. We also, in the first entering analysis, we also saw an improvement for overall survival with a hazard rate of 0.46 favoring teclistamab and daratumumab. Now we can say T-cell redirecting therapy with teclistamab in combination with daratumumab has better progression-free survival and overall survival as early as second line of therapy.

This is all very exciting data. We expected this trial to be positive, but I don't think the most optimistic among us expect some of the details that we saw. One of them is the very high PFS rate at 3 years follow up. The progression-free survival is more than 84% essentially parallel to the overall survival, and that's the highest ever reported for similar population or even for last treated population. 

When you look at the curves, there seems to be a plateau at the curve. There are some drops in the first few months, particularly in the first 6 months. Some unfortunately were due to toxicity, leading to death, and perhaps some few for very aggressive disease. But the vast majority of patients are fine, and the rate of progression beyond that 6 month is incredibly low. Imagine that some of those patients might never require another line of therapy through the remaining early lifetime.

The other part that was also surprising is we had an impression from early data in later lines with this combination that infection was going to be a problem and to the testament to the conduct of the study. That infection signal, which really started in the 19 20, 21, 22 at the peak of the pandemic, was acted on very promptly and patients were directed to receive what we now consider standard prophylaxis for infections with IVIG replacement pneumocystis prophylaxis and acyclovir. 

What we saw is there were a few more deaths related to infection on the tec-dara arm, at 13 out of near 300 patients, which is more than I think 6 or 7 in the control arm. Overall, the rate of discontinuation due to toxicity was actually very low and similar between the 2 arms. Of course, the discontinuation due to progression was far less on the tec-dara arm.

After those measures had been implemented, most patients were already beyond 6 months. After that, there was a single death related to infection telling us that those measures that are relatively simple are actually quite effective. This progression-free survival and overall survival advantage that we saw are noted in every single subset that was preplanned, including older patients, including patients with high cytogenetic risk, including patients with extramedullary disease.

This dataset changed the landscape of relapse refractory myeloma in many ways. One it proves that we now have a scalable T-cell redirecting therapy off the shelf, steroid-free, accessible to all sorts of populations that have a deep and lasting impact in progression-free survival. Second, I think it's changes a little bit of how we think about this therapy compared to others, including CAR T-cell therapy. When you see results like this, it's hard to say they're second to anything. It kind of elevates the idea off-the-shelf bispecific T-cell engagement in the priorities of therapies. Patients should be treated with this therapy that won't feel like they're getting a second choice treatment or a compromised treatment. This is as good as any treatment we have seen in myeloma.

Source: 

Mateos MV, Bahlis N, Perrot A, et al. Phase 3 randomized study of teclistamab plus daratumumab versus investigator’s choice of daratumumab and dexamethasone with either pomalidomide or Bortezomib (DPd/DVd) in patients (Pts) with relapsed refractory multiple myeloma (RRMM): Results of majestec-3. Dec 6-9, 2025; Orlando, FL. Abstract: LBA-6