Dr Costa on Teclistamab Plus Daratumumab vs Daratumumab-Based Triplets in Relapsed or Refractory Multiple Myeloma

“The decision [between these regimens] ultimately comes down to a shared discussion between the patient and the [hematologist] about what [type of] therapy they choose. Some patients are willing to [accept] the small, but well documented, risk of long-term neurotoxicity and secondary malignancies associated with CAR T-cell therapy in exchange for a one-time treatment and the possibility [of achieving] cure.”

Luciano Costa, MD, the Mary and Bill Battle Professor of Multiple Myeloma and a professor of medicine at The University of Alabama at Birmingham School of Medicine, as well as director of the Multiple Myeloma Research and Treatment Program at the University of Alabama at Birmingham O’Neal Comprehensive Cancer Center, reviewed the clinical relevance of the first reported results from the phase 3 MajesTEC-3 trial (NCT05083169) presented at the 2025 ASH Annual Meeting,

MajesTEC-3 evaluated teclistamab-cqyv (Tecvayli) plus daratumumab (Darzalex) vs investigator’s choice of daratumumab and dexamethasone combined with either pomalidomide (DPd) or bortezomib (DVd) in patients with relapsed or refractory multiple myeloma. Costa explained that this trial enrolled patients who had received 1 to 3 prior lines of therapy who were largely proteasome inhibitor– and lenalidomide-exposed, with most patients being lenalidomide refractory and not refractory to prior CD38-directed antibody therapy. In this clinically relevant population, the teclistamab and daratumumab combination demonstrated a striking improvement in progression-free survival compared with the established DPd and DVd regimens, he stated.

According to Costa, the magnitude of benefit observed was unexpected and suggested the potential for durable disease control in a meaningful subset of patients, he noted. Costa also highlighted that, at the first interim analysis, an overall survival advantage favoring the teclistamab-based regimen was observed.

The MajesTEC-3 results, Costa noted, meaningfully shift perceptions around the role of T-cell–engaging therapies in earlier lines of multiple myeloma management. The depth and durability of responses observed in MajesTEC-3 suggest that T-cell engagers such as teclistamab have meaningful efficacy in this population, he reported.

Costa emphasized that direct comparisons between bispecific antibodies and CAR T-cell therapies remain challenging due to differences in trial design, eligibility criteria, and patient populations. CAR T-cell therapy offers the advantage of a single infusion with the possibility of long treatment-free intervals but carries recognized risks for acute and long-term neurotoxicity, as well as secondary malignancies, he said. In contrast, teclistamab-based therapy allows for immediate treatment initiation without manufacturing delays, has not demonstrated long-term neurotoxicity to date, and avoids the logistical complexity of CAR T-cell production, he added. However, this approach requires continuous administration and ongoing supportive care, including regular intravenous immunoglobulin to mitigate infection risk, he concluded.