Teclistamab Plus Daratumumab and Hyaluronidase Improves Survival in Relapsed, Refractory MM

In the pivotal, randomized MajesTEC-3 study (phase 3; NCT05083169), teclistamab-cqyv (Tec; Tecvayli; Johnson & Johnson) plus daratumumab and hyaluronidase-fihj (Dara; Darzalex Faspro; Johnson & Johnson; Tec-Dara) significantly reduced the risk of disease progression or death in patients with relapsed/refractory multiple myeloma (RRMM) as early as in the second line compared with standard regimens. The data were presented at the Late-Breaking Abstracts Session at the 67th American Society of Hematology Annual Meeting and Exposition and simultaneously published in the New England Journal of Medicine.^1-4

Tec-Dara Meets Key Efficacy End Points

The combination reduced the risk of disease progression or death by about 83.3% at 36 months of follow-up (HR, 0.17; 95% CI, 0.12-0.23, P < .0001). Remarkably, over 90% of patients treated with Tec-Dara who were alive at 6 months were also alive at 30 months, a major sign of long-term efficacy.^1-3

There were significantly higher rates of complete responses or better (81.8% vs 32.1%, respectively; OR, 9.56; 95% CI, 6.47-14.14), overall response (89.0% vs 75.3%; OR, 2.65; 95% CI, 1.68-4.18), and minimal residual disease (MRD) negativity (58.4% vs 17.1%; OR, 6.78; 95% CI, 4.53-10.15) observed with Tec-Dara (P < .0001), according to the investigators.^1-3

Compared with standard-of-care treatment, patients treated with Tec-Dara remained symptom-free significantly longer, underscoring the major improvements in patient-reported quality of life with the treatment. Furthermore, at data cutoff—at which 71.0% of patients remained on Tec-Dara—median treatment duration was twice as long as Dara and dexamethasone with either pomalidomide (DPd, Polymast; Bristol Myers Squibb) or bortezomib (DVd, Velcad; Takeda Oncology; 32.4 vs 16.1 months).^1-3

“We consider that this synergistic immunotherapy combination based on teclistamab and daratumumab is a new potential standard of care for [patients with RRMM] after at least 1 prior line of therapy, with broad potential across academic and community settings,” María-Victoria Mateos, MD, PhD, consultant physician in the Department of Hematology and associate professor of medicine at Hospital Universitario de Salamanca in Spain, said during the late-breaking presentation.¹

Background on Teclistamab and Daratumumab With Hyaluronidase

The MajesTEC-3 investigators evaluated the safety and efficacy of the combination of Tec-Dara vs DPd/DVd in patients with RRMM who had previously received 1 to 3 lines of prior therapy. Increasing rates of patient attrition and decreasing response durability with each line of RRMM therapy require novel, earlier approaches, they noted.¹

Teclistamab is a combinable B-cell maturation antigen–targeting bispecific antibody that redirects T cells and has shown efficacy in RRMM, inducing deep, durable responses. Daratumumab is a foundational anti-CD38–targeting monoclonal antibody that has shown significant improvements in overall survival in patients with newly diagnosed MM and RRMM. The bispecific regimen has shown significant efficacy as early as the second line, providing meaningful potential for future availability and proliferation of this treatment.^1,5,6

Safety Considerations Observed in MajesTEC-3

A notable safety trend was observed in a high frequency of grade 3 or higher treatment-emergent adverse events (TEAEs), although rates were comparable between the Tec-Dara and standard-of-care groups. Concurrently, any grade infections occurred in 96.5% and 84.1% of Tec-Dara and DPd/DVd patients, respectively; however, as noted by Mateos, new-onset grade 3 or higher infections decreased over time, which coincided with transitioning to dosing every 4 weeks.¹

“Infections were frequent in both arms; most of these infections were COVID-19, upper-respiratory tract infections, and COVID-19 pneumonia,” Mateos explained, noting that study protocol was amended to reinforce the diligent use of established prophylaxis and image-guided radiation therapy supplementation.¹ “MajesTEC-3 started recruiting patients during the COVID-19 pandemic, but especially when we had no specific guidelines for the management of bispecific monoclonal antibodies.”

Responding to the positive data, the FDA granted Johnson & Johnson a breakthrough therapy designation for the regimen, which is expected to expedite development and review. Accordingly, Johnson & Johnson submitted a supplemental biologics license application for the use of Tec-Dara as a combination treatment in RRMM. If approved, the treatment would represent the continuation of a paradigm shift in the treatment of patients with MM.³

“The combination of [teclistamab] and [daratumumab with hyaluronidase] offers remarkable efficacy, a well-characterized safety profile with robust infection management protocols,” Mateo said in a news release.³ “It has the potential to change the standard of care as a steroid-sparing combination regimen suited for outpatient administration on the familiar [daratumumab] schedule.”

REFERENCES

1. Mateos M, 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. Presented at: ASH 2025; December 6-9, 2025; Orlando, FL. Abstract LBA-6. https://meetings-api.hematology.org/api/abstract/vmpreview/304640

2. Costa LJ, Bahlis NJ, Perrot A, et al; MajesTEC-3 Trial Investigators. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. Published online December 9, 2025. Accessed December 9, 2025. doi:10.1056/NEJMoa2514663

3. Unprecedented results from the phase 3 MajesTEC-3 study support Tecvayli plus Darzalex Faspro as a potential standard of care as early as second line for patients with relapsed/refractory multiple myeloma. News release. Johnson & Johnson. December 9, 2025. Accessed December 9, 2025. https://www.jnj.com/media-center/press-releases/unprecedented-results-from-the-phase-3-majestec-3-study-support-tecvayli-plus-darzalex-faspro-as-a-potential-standard-of-care-as-early-as-second-line-for-patients-with-relapsed-refractory-multiple-myeloma

4. A study of teclistamab in combination with daratumumab subcutaneously (SC) (Tec-Dara) versus daratumumab SC, pomalidomide, and dexamethasone (DPd) or daratumumab SC, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (MajesTEC-3). ClinicalTrials.gov. Updated December 5, 2025. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT05083169

5. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478

6. Afrough A, Atrash S, Paul B, et al. Efficacy and safety of daratumumab, pomalidomide, and dexamethasone (DPD) compared to daratumumab, bortezomib, and dexamethasone (DVd) in daratumumab-naïve relapsed multiple myeloma. Cancers (Basel). 2023;15(19):4894. doi:10.3390/cancers15194894