MajesTEC-1: teclistamab, an off-the-shelf BCMA bispecific antibody, in heavily pretreated myeloma
A ready-made antibody that pulls T cells onto myeloma cells produced responses in 63% of patients after a median of five prior therapies, without the wait for cell manufacturing.
MajesTEC-1 was a phase 1/2 single-arm study of teclistamab, a BCMA x CD3 bispecific T-cell engager given subcutaneously weekly after step-up dosing, in 165 patients with relapsed or refractory multiple myeloma who were triple-class exposed (median five prior lines). The overall response rate was 63%, with complete response or better in 39.4%; median duration of response was 18.4 months and median PFS 11.3 months. Cytokine release syndrome occurred in 72% (almost all grade 1-2) and neurotoxicity in about 14.5%, but infections were frequent (grade 3-4 in about 45%) and hypogammaglobulinaemia was near universal. Teclistamab received accelerated approval in 2022, the first bispecific for myeloma.
- 165 triple-class-exposed patients; median 5 prior lines.
- Overall response 63.0%; complete response or better 39.4%; MRD-negativity in 26.7% of all patients.
- Median duration of response 18.4 months; median PFS 11.3 months.
- CRS 72.1% (grade 3 0.6%); neurotoxicity 14.5% (ICANS 3%).
- Infections 76.4% (grade 3-4 44.8%); 5 COVID-19 deaths; hypogammaglobulinaemia common.
Teclistamab showed that an off-the-shelf bispecific can approach CAR-T-like response rates in late myeloma, giving patients who cannot wait for or access cell therapy a real option. It also exposed the price: prolonged T-cell engagement causes profound immunosuppression, so infection prophylaxis and immunoglobulin replacement are now routine. Less frequent dosing after response is being adopted to reduce this burden.
- Single-arm study; MajesTEC-3 later provided randomised evidence in earlier lines.
- Continuous weekly dosing until progression in the original protocol; optimal duration and schedule still being defined.
- Infection-related deaths were substantial; many patients were treated during the COVID-19 pandemic.
- Responses are shorter than with cilta-cel, and BCMA-directed sequencing (CAR-T then bispecific or vice versa) reduces subsequent efficacy.