The combination of teclistamab and daratumumab has demonstrated encouraging efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma, according to preliminary results from the TRIMM-2 trial presented by Paula Rodriguez-Otero, MD, PhD, from the Department of Hematology at Clínica Universidad de Navarra in Pamplona, Spain.
Strong Response Rates Across Dose Levels
In the phase 1b multicohort study, 37 patients with heavily pretreated multiple myeloma received the combination therapy. The patient population represented a challenging treatment scenario, with a median of 5 prior lines of therapy. Notably, 76% of patients had been previously exposed to anti-CD38 monoclonal antibodies, 60% were refractory to anti-CD38 monoclonal antibodies, and 54% were triple-class refractory.
The overall response rates ranged from 70% to 100% across the different doses and schedules of teclistamab evaluated in combination with approved doses of subcutaneous daratumumab. "The combination of teclistamab and daratumumab with this preliminary efficacy suggests a promising ORR that could be even higher as compared [with] the efficacy of teclistamab as a single agent," Rodriguez-Otero noted.
Deep and Rapid Responses Observed
A particularly encouraging finding was the high proportion of patients achieving deep responses, including very good partial responses or better. The responses occurred quickly, manifesting within the first month of treatment and continuing to deepen over time, though Rodriguez-Otero acknowledged that follow-up remains relatively short for this study.
Mechanistic Rationale and Safety Profile
The combination's rationale stems from preclinical data showing that daratumumab, an anti-CD38 monoclonal antibody, may lead to synergistic clinical efficacy when combined with teclistamab, a bispecific antibody targeting BCMA. "Daratumumab monotherapy [leads] to T-cell expansion and enhanced T-cell cytotoxic potential and preclinical studies showed that the addition of daratumumab may enhance the teclistamab mediated lysis of myeloma cells," Rodriguez-Otero explained.
From a safety perspective, the combination was well-tolerated with no new adverse effects compared to the safety profiles of the individual drugs as previously reported.
Comparative Effectiveness Data
Supporting evidence for teclistamab's efficacy comes from the MajesTEC-1 trial, which compared teclistamab monotherapy against real-world treatments using data from the Flatiron Health multiple myeloma database. The analysis included patients who had received at least 3 prior lines of therapy and were triple-class exposed to a proteasome inhibitor, an anti-CD38 monoclonal antibody, and an immunomodulatory agent.
After adjusting for baseline imbalances using inverse probability of treatment weighting, teclistamab demonstrated significant improvements in key efficacy endpoints. The treatment improved progression-free survival with a hazard ratio of 0.43 (95% confidence interval 0.32-0.59; P<0.0001) and time to next treatment with a hazard ratio of 0.42 (95% CI 0.31-0.58; P<0.0001) compared to real-world treatments.
Phase 3 Development Underway
The promising preliminary data from the TRIMM-2 trial has provided the foundation for the ongoing phase 3 MajesTEC-3 study (NCT05083169), which is further evaluating the combination of teclistamab plus daratumumab in patients with relapsed/refractory multiple myeloma. The study design included patients who had received at least 3 prior lines of therapy or were double refractory to a proteasome inhibitor and an immunomodulatory drug, with treatment continuing until disease progression.
