For patients with previously treated multiple myeloma, the greatest risk reduction yet achieved in a phase III clinical trial was reported with the BCMA-directed CD3 T-cell engager teclistamab-cqyv plus daratumumab and hyaluronidase-fihj. Treatment with this combination resulted in an 83% reduction in the risk of disease progression or death and a 54% reduction in death over standard daratumumab-based regimens in the MajesTEC-3 trial, with findings reported as a late-breaker at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition and simultaneously published in The New England Journal of Medicine.1,2
“MajesTEC-3 showed unprecedented efficacy, supporting a new second-line and later standard of care with broad potential across academic and community settings,” said María-Victoria Mateos, MD, PhD, Consultant Physician in the Hematology Department and Associate Professor of Medicine at the University of Salamanca, Spain. In a press briefing, she acknowledged this is “the best hazard ratio we’ve seen in a phase III clinical trial.”
María-Victoria Mateos, MD, PhD
Ajay K. Nooka, MD, MPH
Co-investigator Ajay K. Nooka, MD, MPH, Professor and Director of the Myeloma Program, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, told The ASCO Post, “The results of MajesTEC-3 are the best we had seen in early relapse myeloma…. These results rival those of [chimeric antigen receptor] CAR [T-cell therapy] studies in this space and are so compelling that this study might serve as a catalyst for broader adoption of bispecifics in the community.”
Teclistamab is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. As a result of the MajesTEC-3 findings, the combination was granted Breakthrough Therapy Designation by the FDA on December 9, 2025.
Key Findings
In MajesTEC-3, a total of 587 patients who were previously treated with one to three prior lines of therapy were randomly assigned to receive teclistamab plus daratumumab or the investigator’s choice of daratumumab plus either pomalidomide and lenalidomide (DPd) or bortezomib and lenalidomide (DVd). The subcutaneous dosing of teclistamab plus daratumumab aligned with the approved daratumumab schedule, with monthly dosing after the sixth cycle and steroid-sparing after the eighth day of the first cycle. Patients were not eligible to enroll if they had previously received BCMA-directed therapy or if they were refractory to anti-CD38 monoclonal antibodies. The primary endpoint was progression-free survival by investigator review.
At a median follow-up of 34.5 months, the median progression-free survival had not been reached with teclistamab plus daratumumab and was 18.1 months with DPd or DVd (hazard ratio [HR] = 0.17; P < .0001). The 36-month progression-free survival rates were 83.4% vs 29.7%, respectively. Overall survival, a key secondary endpoint, was also found to be superior with teclistamab plus daratumumab, with a 36-month rate of 83.3% vs 65.0% for DPd or DVd, representing a 54% reduction in risk (HR = 0.46, 95% confidence interval [CI] = 0.32–0.65; P < .0001).
The progression-free survival curves appeared to plateau after about 6 months, after which more than 90% of patients were progression-free; this benefit was sustained out to 3 years, Dr. Mateos said, “suggesting the potential for a function cure.” In a press briefing, she noted that the control arm performed even better than expected; in previous studies the mean progression-free survival for daratumumab plus pomalidomide and dexamethasone was approximately 1 year.
Dr. Mateos believes the benefit may be because of the synergy observed between these two agents. As she explained at a press briefing, “Daratumumab targets CD38 expressed on the surface of the plasma cells [and] has a direct antitumor effect, but in addition, all immunosuppressive cells in the tumor microenvironment also express CD38. This means that daratumumab primes the microenvironment and depletes the immunosuppressive cells, resulting in the enhancement, stimulation, and redirecting of CD8-positive T cells.”
Depth of response was also found to be greater with teclistamab plus daratumumab. The median duration of response was not yet evaluable with this combination and was 23.5 months with DPd or DVd. Further, 81.8% of patients who received teclistamab plus daratumumab achieved a complete response or better compared with 31.1% of the control arm (P < .0001), and among evaluable patients, the rate of measurable residual disease (10-5) was 89.3% vs 63.0%, respectively (P < .0001).
Safety Profile
With teclistamab plus daratumumab, all cases of cytokine-release syndrome were grade 1 (44.2%) or 2 (15.9%), and all resolved. The rate of immune effector cell–associated neurotoxicity syndrome was reported to be low (1.1%), and all cases resolved. The most common hematologic adverse event with teclistamab plus daratumumab was any-grade neutropenia, at 78.4% vs 82.8% with DPd or DVd. Teclistamab plus daratumumab was found to be associated with lower rates of discontinuation (4.6% vs 5.5%) and death (15.9% vs 33.1%).
The most common nonhematologic toxicities were infections, which were grade 3 or 4 in 54.1% and 43.4% of patients treated with teclistamab plus daratumumab and DPd or DVd, respectively. According to Dr. Mateos, the infection rates were much higher with teclistamab plus daratumumab during the first 6 months; however, beyond that time, the incidence between the arms was “comparable,” and she added that “what’s especially important is that the overall incidence of infection declined over time.” She further explained that the initial increase occurred in the absence of guideline recommendations for preventing and managing infections; these guidelines are now in place, and infection risk has diminished. “The trial protocol was amended, and it was reinforced that investigators should use immunoglobulin replacement therapy and antimicrobial prophylaxis,” she said.
DISCLOSURE: Dr. Mateos has served as a consultant (including giving expert testimony) for AbbVie, Pfizer, Seagen, Amgen, Takeda, Oncopeptides, BMS/Celgene, Stemline, Janssen, Sanofi, GSK (formerly GlaxoSmithKline), AstraZeneca, Roche, Adaptive, Kite, and Johnson & Johnson; and has received honoraria from AbbVie, Pfizer, Amgen, BMS/Celgene, Stemline, Sanofi, AstraZeneca, GlaxoSmithKline, Kite, and Johnson & Johnson. Dr. Nooka has served on advisory boards and received honoraria from AstraZeneca, Blue Earth Diagnostics, Cellectar Biosciences, GlaxoSmithKline, Janssen, Kite, ONK Therapeutics, Opna, Pfizer, Perceptive Informatics, Premier Research, Sanofi, and Sebia; has received institutional grant or research support from Aduro Biotech, Amgen, Arch Oncology, BMS, Cellectis, Cellectar, Genentech, GlaxoSmithKline, Janssen, Opna, Karyopharm, Kite, Merck, Pfizer, Skyline Diagnostics, and Takeda; and has received grant or research support for investigator-initiated studies from Amgen, GlaxoSmithKline, Janssen, Merck, and Takeda.
REFERENCES
1. Mateos M-V, 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 in patients with relapsed refractory multiple myeloma: Results of majestec-3. 2025 ASH Annual Meeting and Exposition. Abstract LBA-6. Presented December 8, 2025.
2. Costa LJ, Bahlis NJ, Perrot A, et al: Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. December 9, 2025 (early release online).
EXPERT POINT OF VIEW
Noopur Raje, MD, Director of the Center for Multiple Myeloma at Massachusetts General Hospital, Boston, commented on the results of the MajesTEC-3 trial in an interview with The ASCO Post. “We saw really remarkable data with combining an anti-CD38 antibody with a bispecific [antibody]. Three years out, progression-free survival was robust, with a hazard ratio [HR] that is pretty incredible (HR = 0.17),” she said.
“But I do think one has to be a bit cautious,” Dr. Raje emphasized, noting several areas of concern with moving both teclistamab and daratumumab into earlier lines of therapy. “The beauty of this approach is to have an off-the-shelf treatment choice for the majority of our patients, but it’s not a slam dunk. People need to think through all the issues.”
Noopur Raje, MD
Infections remain a concern with bispecific T-cell engagers, she observed: “Grade 3 or 4 infections occurred in 54% of patients on teclistamab and daratumumab, and that is not a trivial number. There were also grade 5 events [13 deaths because of infection with teclistamab plus daratumumab]. The high rates were early-on [before the issuance of guidelines for managing infections], but one of my concerns is that this treatment entails continuous use of the bispecifics until progression.”
Dr. Raje also noted that the regimen was tested in an almost exclusively daratumumab-naive population. “Only 5% of patients had been daratumumab-exposed. In our clinical practice, we just don’t have that patient population anymore,” she said. Findings from the PERSEUS trial established daratumumab as a maintenance strategy in transplant-eligible patients, and many now receive it for up to 2 years, probably diminishing the sensitivity of their disease.1 “I think the degree of benefit with teclistamab and daratumumab is going to be substantially lower than what you’re seeing on MajesTEC-3,” she predicted.
Given the impressive magnitude of benefit seen with teclistamab plus daratumumab in patients who received just one prior line of therapy, the combination is now positioned as an alternative to chimeric antigen receptor (CAR) T-cell therapy, though CAR T-cell therapy will likely remain the preferred choice, Dr. Raje said. “I believe most academic clinicians will want to do CAR T-cell therapy first for the simple reason that when you give bispecifics indefinitely you’re causing damage to T-cell health,” she explained.
“I think it’s important as we move these bispecifics into patients with one to three prior lines of treatment to ask whether we should be giving bispecifics indefinitely to patients who have not had CAR T-cell therapy yet,” she stated. “I think our future is to get rid of indefinite treatment and to use fixed-duration treatment so that the sequence of therapies does not matter as much. Then we can do whatever is best for the patient at that point in their lives and not be burning bridges. I love the MajesTEC-3 data, but I think that’s one thing we may be doing here—burning the bridge for CAR [T-cell therapy].”
DISCLOSURE: Dr. Raje reported relationships with AstraZeneca, GSK, Genentech, Johnson & Johnson, Pfizer, Caribou Biosciences, Immuneel, Sanofi, BMS, and Kelonia.
REFERENCE
1. Sonneveld P, Dimopoulos MA, Boccadoro M, et al: Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 390:301-313, 2023.
