ASH 2025 MajesTEC-3 supports teclistamab–daratumumab for relapsed/refractory multiple myeloma

medwireNews: MajesTEC-3 trial results show a significant improvement in progression-free survival (PFS) with use of teclistamab plus daratumumab (TD) for patients with heavily pretreated multiple myeloma compared with daratumumab plus dexamethasone with pomalidomide or bortezomib (DPd/DVd).

The primary efficacy and safety findings of the phase 3 study’s first interim analysis were reported simultaneously at the 67th ASH Annual Meeting and Exposition in Orlando, Florida, USA, and The New England Journal of Medicine.

“With the advent of ciltacabtagene autoleucel and teclistamab–daratumumab offering immunotherapy-based options with plateauing survival curves, we may be entering a new era of resetting survival expectations in a cancer that has been historically described as incurable,” say presenting author María-Victoria Mateos (Hospital Universitario de Salamanca, Spain) and colleagues.

Teclistamab–daratumumab boosts survival

The study included 587 patients (55% male, median age 64 years) who had received between one and three prior lines of treatment for multiple myeloma, including a proteasome inhibitor and lenalidomide, and experienced progression on or after their last regimen.

After a median 34.5 months of follow-up, the primary endpoint of 36-month PFS rate was 83.4% for the 291 patients who were randomly assigned to receive the bispecific anti-CD3/BCMA antibody teclistamab plus the anti-CD38 monoclonal antibody daratumumab.

This was significantly higher than the rate of 29.7% for the 296 patients who were treated with daratumumab–dexamethasone and investigator’s choice of DPd or DVd. The hazard ratio for disease progression or survival was a significant 0.17 in favor of TD, and this benefit was found across all prespecified and clinically relevant subgroups, say Mateos et al.

The researchers also report that TD was associated with a significantly higher rate of complete response or better than standard therapy (81.8 vs 32.1%) and overall response (89.0 vs 75.3%), as well as the rate of continuing response at 36 months (88.5 vs 36.4%).

In addition, next-generation sequencing showed that patients given TD were significantly more likely to achieve minimal residual disease negativity (10^-5) than those given DPd/DVd, at 58.4% versus 17.1%.

Finally, the 36-month rate of overall survival was 83.3% with TD versus 65.0% with DPd/DVd, again a significant difference. “The overall survival curves crossed at approximately 10 months of follow-up, primarily owing to early deaths from infection in the teclistamab–daratumumab group,” the authors explain.

Infection risk ‘ameliorated’ with treatment protocols

Overall, grade 3 or 4 adverse events (AEs) occurred in a comparable 95.1% of patients given TD and 96.6% of those given DPd or DVd. The most common AE at this severity in both arms was neutropenia (75.6 vs 78.6%), followed by anemia (20.5 vs 17.2%) and thrombocytopenia (19.4 vs 23.4%).

“Infections of any grade were common in both groups,” the investigators say, with grade 3 or 4 AEs in 54.1% of the TD and 43.4% of the DPd/DVd groups. Fatal infections occurred in 4.6% and 1.4%, respectively, but the investigators emphasize that 12 of the 13 deaths in the TD group occurred within 6 months of beginning treatment and “before the implementation of reinforced protocol-specified immune globulin treatment,” as well as the introduction of infection prevention guidelines adopted during the Covid-19 pandemic.

They therefore conclude: “The use of this combination was associated with a risk of adverse events that can be ameliorated with the use of established protocols.”

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67th ASH Annual Meeting and Exposition; Orlando, Florida, USA: 6–9 December 2025
N Engl J Med 2025; doi:10.1056/NEJMoa2514663