Teclistamab/SC Daratumumab Potential New SOC in 2L R/R Multiple Myeloma

Data from the phase 3 MajesTEC-3 trial (NCT05083169) yielded significantly improved overall survival (OS) and progression-free survival (PFS) with teclistamab-cqyv (Tecvayli) plus daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) compared with standard daratumumab-based regimens for patients with relapsed/refractory multiple myeloma who have previously received 1 to 3 lines of prior therapy. The results were presented at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.

The 36-month OS rate was 83.3% with the bispecific BCMA-directed CD3 T-cell engager teclistamab plus subcutaneous daratumumab (Tec-Dara) vs 65.0% with patients receiving investigator’s choice of subcutaneous daratumumab plus dexamethasone and either pomalidomide (DPd) or bortezomib (DVd).Tec-Dara reduced the risk of death by 54% vs DPd/DVd (HR, 0.46; 95% CI, 0.32-0.65; P <.0001).

At a median follow-up of 34.5 months, the median PFS had not been reached with Tec-Dara vs 18.1 months with DPd/DVd, translating to an 83% reduction in the risk of disease progression or death (HR, 0.17; 95% CI, 0.12-0.23; P <.0001). The 36-month PFS rates were 83.4% vs 29.7%, respectively.

The depth of response was also greater with Tec-Dara. The median duration of response was not yet evaluable for Tec-Dara compared with 23.5 months with DPd/DVd. Further, 81.8% of patients receiving Tec-Dara achieved a complete response or better compared with 31.1% of patients treated with DPd/DVd (P <.0001). Among evaluable patients, the MRD negativity rate (10^-5) was 89.3% vs 63.0%, respectively (P <.0001).

MajesTEC-3 Trial | ©Sabrina Serani/MJH Life Sciences using AI

“MajesTEC-3 showed unprecedented efficacy, supporting a new second line and later standard of care with broad potential across academic and community settings,” said lead study author María-Victoria Mateos, MD, PhD, Hospital Universitario de Salamanca, Salamanca, Spain.

Safety Profile in MajesTEC-3

The safety profile for Tec-Dara showed that all cases of cytokine release syndrome were grade 1 (44.2%) or grade 2 (15.9%) and all cases were resolved.The rate of immune effector cell-associated neurotoxicity syndrome was low with Tec-Dara at 1.1%. The most common hematologic adverse event (AE) with Tec-Dara was any grade neutropenia at 78.4% vs 82.8% with DPd/DVd. The most common nonhematologic AEs were infections, which occurred at grade 3/4 rates of 54.1% vs 43.4% in the Tec-Dara vs control arms, respectively.

Mateos noted that the rates of infections were much higher with Tec-Dara vs the control arm during the first 6 months; however, “beyond month 6, the incidence [of infections] was comparable, and what’s especially important is that the overall incidence of infection declined over time.”

Explaining the reason for the decrease in infections over time, Mateos said, “The study was initiated before the approval of teclistamab, when we did not yet have any peer-reviewed guidelines for the management of patients with bispecific monoclonal antibodies. When we observed this rate of infections, especially during the first 6 months, the trial protocol was amended and it was reinforced that investigators should use immunoglobulin replacement therapy and antimicrobial prophylaxis.”

At the time of the study analysis, 71% of patients remained on Tec-Dara. Fewer patients discontinued Tec-Dara at 4.6% vs 5.5% who discontinued DPd/DVd in the control arm. Fewer patients died in the Tec-Dara arm at 15.9% vs 33.1%, respectively.

MajesTEC-3 Study Design

The phase 3 MajesTEC-3 trial enrolled patients with R/R multiple myeloma who had received 1 to 3 prior lines of therapy including a proteosome inhibitor and lenalidomide (Revlimid). Patients who had received only 1 prior line had to be lenalidomide refractory per IMWG criteria, and all patients had to have an ECOG performance status of 0 to 2. Patients were not eligible to enroll if they had previously received BCMA-directed therapy or if they were refractory to anti-CD38 monoclonal antibodies.

Overall, 587 patients were randomized from October 22, 2021, to September 29, 2023. The median patient age was 65 years (range, 25-88) and the median number of prior lines of therapy was 2 (range, 1-3). There were 291 patients randomized to Tec-Dara and 296 patients randomized to DPd (n = 269) or DVd (n = 27).

Following the approved step-up dose schedule, patients in the experimental arm received teclistamab at 1.5 mg/kg weekly in cycles 1 and 2 followed by 3 mg/kg every 2 weeks in cycles 3 to 6 and 3 mg/kg every 4 weeks in cycle 7 onward. The cycles were 28 days. Subcutaneous daratumumab was administered at 1800 mg every week for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and every 4 weeks for cycles 7 onward. In the control arm, patients received investigator’s choice of DPd or DVd according to the approved schedules of the regimens.

Commenting on the Tec-Dara regimen, Mateo said, “It's important to note that the combination of teclistamab plus daratumumab is a subcutaneous administration with a convenient monthly dosing after cycle 6, and the combination is free of steroids after cycle 1 day 8, and [this is all] extremely important from the patient perspective.”

The primary end point was PFS per IRC. Secondary end points included OS, response, MRD negativity, symptom score/quality of life, safety, and pharmacokinetics/immunogenicity.

Teclistamab is currently approved by the FDA for the treatment of adult patients with R/R multiple myeloma who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.²

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 (DPd/DVd) in patients (Pts) with relapsed refractory multiple myeloma (RRMM): Results of majestec-3. Blood. 2025;146(suppl 2): LBA-6. doi:10.1182/blood-2025-LBA-6
2. FDA approves teclistimab-cqyv for relapsed or refractory multiple myeloma. FDA. Published online October 25, 2022. Accessed December 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma