In a phase I/II study that involved patients with relapsed or refractory multiple myeloma, a once-weekly subcutaneous dose of a bispecific antibody, teclistamab that mediates T-cell activation and subsequent lysis of myeloma cells expressing B-cell maturation antigen (BCMA) induced responses in 63% of the patients, including a complete response in 39.4%. The overall depth of response was highlighted by the observation that 26.7% of the patients were found to have no minimal residual disease (MRD) at a sensitivity level of 10−5; these patients made up 82% of those in whom MRD could be evaluated. Side effects were common but were mainly of low grade and reversible. The findings of the MajesTEC-1 study are published by Prof. Philippe Moreau of the Hematology Clinic, University Hospital Hôtel-Dieu in Nantes, France, Dr. Saad Z. Usmani of the Memorial Sloan Kettering Cancer Center in New York, NY, US and study colleagues on the 11th of August 2022 issue of The New England Journal of Medicine.
The authors wrote in the background that BCMA represents a promising new target for treatment of multiple myeloma with 3 BCMA-directed therapies being approved for the treatment of patients with multiple myeloma who have received immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies. These approved BCMA-directed therapies are belantamab mafodotin, an antibody-drug conjugate, and two chimeric antigen receptor T-cell (CAR-T) therapies, idecabtagene vicleucel and ciltacabtagene autoleucel.
Teclistamab is a bispecific antibody that targets both CD3 expressed on the surface of T-cells and BCMA expressed on the surface of myeloma cells, thus mediating T-cell activation and subsequent lysis of BCMA-expressing myeloma cells. In phase I of the multicohort MajesTEC-1, the study investigators identified the recommended phase 2 dose of teclistamab as a weekly subcutaneous injection of 1.5 mg per kilogram of body weight. At this dose level, teclistamab showed promising efficacy in 40 patients, with 65% of patients having a partial response or better. Now, the study team reports the efficacy and safety results from the pivotal phase I/II portion of MajesTEC-1 involving 165 patients with triple-class–exposed relapsed or refractory multiple myeloma. Included in the report published in The New England Journal of Medicine is an assessment of pharmacokinetics, immunogenicity, and biomarkers of response and progression. The primary endpoint was the overall response defined as partial response or better.
Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease with median of 5 previous treatment lines. With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no MRD; the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI] 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI 8.8 to 17.1).
Responses were consistent across clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities or penta-drug refractory disease with the exceptions of those with extramedullary disease, stage III disease, and the presence of at least 60% plasma cells in the marrow. The latter two subgroups were small and had results with wide CIs. The lower response rate in patients with extramedullary plasmacytomas probably reflects the poor prognosis in this population, which is historically challenging to treat. In addition, subgroup analyses suggest that patients who have received no more than 3 previous treatment lines may have a better response rate than those who have received more than 3 lines, a finding that supports the use of teclistamab in earlier lines of treatment.
Common adverse events included cytokine release syndrome (CRS) in 72.1% of the patients (grade 3, 0.6%; no grade 4), neutropenia in 70.9% (grade 3 or 4, 64.2%), anaemia in 52.1% (grade 3 or 4, 37.0%), and thrombocytopenia in 40.0% (grade 3 or 4, 21.2%). Infections were frequent in 76.4% (grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell–associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2).
The authors commented that although comparisons across clinical studies are challenging to interpret due to differences in study design and patient populations, the response rate of 63% observed with teclistamab compares favourably with belantamab mafodotin, which has an overall response rate of 31% in patients with triple-class refractory disease. Overall response rates of 67% to 83% have been observed with approved CAR-T in patients who have undergone apheresis. However, CAR-T requires that patients have access to specialised care centres and can wait the minimum 4-week period for production. Teclistamab is readily available and has been associated with rapid onset of response after a median of approximately 1 month of treatment. They also commented that lower-grade profile of CRS with teclistamab supports the potential for outpatient administration.
In an accompanied editorial Sham Mailankody of the Memorial Sloan Kettering Cancer Center in New York, NY and Ola Landgren of the Sylvester Comprehensive Cancer Center, University of Miami in Miami, FL, US wrote that MajesTEC-1 establishes teclistamab as the first bispecific antibody that is active in patients with relapsed or refractory multiple myeloma. BCMA-directed therapies mark a major advance in the treatment of relapsed or refractory multiple myeloma. However, most patients will eventually relapse and need new treatments. An important emerging question is the potential role of alternate BCMA-directed therapies in patients who have a relapse after previous BCMA-directed therapy. Little is known about mechanisms of resistance. If the resistant cells continue to express BCMA, using that target to expose the cells to other effector mechanisms may still be feasible. Alternatively, additional T-cell–engaging therapies that target other novel antigens like GPRC5D and FCRL5 are emerging with promising early results.
The study was supported by Janssen Research and Development.