Teclistamab Plus Daratumumab Approved for Relapsed or Refractory Multiple Myeloma After MajesTEC-3

Luciano Costa, MD UAB Medicine | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• In the MajesTEC-3 trial, teclistamab plus daratumumab improved progression-free survival (PFS) outcomes versus standard triplet regimens in patients with relapsed or refractory multiple myeloma.

• Cytokine release syndrome (CRS) occurred in around 60% of patients treated with teclistamab plus daratumumab, however all events were grade 1 or 2.

• Prophylaxis with antibiotics, antivirals, and immunoglobulin and growth factor support should be implemented for all patients receiving teclistamab plus daratumumab.

• Teclistamab plus daratumumab may be more accessible compared with chimeric antigen receptor (CAR) T-cell therapies, although treatment is continual until progression.

Teclistamab Plus Daratumumab in Relapsed or Refractory Multiple Myeloma

On March 5, 2026, the FDA approved teclistamab plus daratumumab in adult patients with relapsed or refractory multiple myeloma after at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent. Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with the lead author of the MajesTEC-3 trial, Luciano Costa, MD, of UAB Medicine, to discuss the data that led to the approval. 

MajesTEC-3 Efficacy Data

MajesTEC-3 compared daratumumab plus teclistamab against either daratumumab, pomalidomide, and dexamethasone (DPd) or daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma with one to three prior lines of therapy. Patients with only one prior line of therapy were required to have lenalidomide–refractory disease. 

The median PFS was not reached (NR; 95% CI, not estimable [NE]-NE) in the teclistamab plus daratumumab arm versus 18.1 months (95% CI, 14.6-22.8) in the control arm (HR, 0.17; 95% CI, 0.12-0.23; P < .0001). The 36-month PFS rates were 83.4% versus 29.7%, respectively, according to the abstract. “This is the lowest hazard ratio reported on a phase 3 multiple myeloma trial. Honestly, I don’t think anyone was expecting this,” said Dr. Costa.

In the interim overall survival (OS) analysis with a median follow-up of 34.5 months, median OS was NR in either arm (HR, 0.46; 95% CI, 0.32-0.65; P < .0001). The 36-month OS rate was 83.3% with teclistamab plus daratumumab versus 65% with the control. Teclistamab plus daratumumab also improved the minimal residual disease–negativity rate at 58.4% versus 17.1% with control (OR, 6.78; P < .0001).

Teclistamab Plus Daratumumab Side Effects in MajesTEC-3

The most common any-grade treatment-emergent adverse events reported with teclistamab plus daratumumab were neutropenia, hypogammaglobulinemia, CRS, diarrhea, cough, COVID-19, upper respiratory tract infection, anemia, pyrexia, thrombocytopenia, pneumonia, lymphopenia, leukopenia, and COVID-19 pneumonia. Grade 1 CRS occurred in 44.2% of patients, grade 2 in 15.9%, and grade 3 or higher in 0%. The rate of infections was highest in the first 6 months, but decreased with transition to monthly dosing and with increased prophylaxis amended into the MajesTEC-3 protocol. 

Recommended prophylaxis when using teclistamab plus daratumumab includes antibiotics in month 1 and intravenous immunoglobulin starting month 2, as well as continuous pneumocystis jirovecii pneumonia prophylaxis and acyclovir. Growth factor support can also be used for neutropenia events, which most commonly occur during the first 2 cycles, said Dr. Costa.

Bispecifics Versus CAR-T

Previously, the International Myeloma Working Group recommended pursuing CAR T-cell therapies before bispecifics. However, that consensus was based on efficacy data in later lines of  therapy, and the findings from MajesTEC-3 support that teclistamab plus daratumumab carries similar efficacy as was reported for ciltacabtagene autoleucel (cilta-cel) in the CARTITUDE-4 trial, said Dr. Costa. 

Overall, teclistamab plus daratumumab requires less logistical burden before starting therapy, and may avoid the long-term toxicities that have been associated with CAR T-cell treatments. However, teclistamab plus daratumumab is an indefinite therapy whereas cilta-cel is fixed duration. Generally, teclistamab plus daratumumab may be more accessible for patients in the community, while access to CAR T-cell treatments may continue to require trips to specialized centers, Dr. Costa said.