Longitudinal mechanisms of response, resistance and relapse to teclistamab in multiple myeloma: results from MajesTEC-1

Previous studies have shown that response to teclistamab, the first approved B-cell maturation antigen (BCMA)-directed bispecific antibody for the treatment of triple-class-exposed relapsed/refractory multiple myeloma, was associated with baseline immune fitness, while nonresponders had profiles suggestive of immune suppression and T-cell dysfunction. Here, we correlated longitudinal peripheral and tumor microenvironment immune profiles and BCMA antigen expression with teclistamab clinical response, resistance, and relapse in MajesTEC-1 (ClinicalTrials.gov Identifiers: NCT03145181/NCT04557098). Bone marrow and peripheral blood samples were collected at baseline, on treatment, and at disease progression. Teclistamab responders exhibited greater T-cell margination, recovery, and increased T-cell activation compared with nonresponders in the periphery. After teclistamab treatment, nonresponders generally exhibited trends for elevated and sustained expression of checkpoint markers on CD4+ and CD8+ T cells, suggestive of persistent T cell activation, and higher, sustained proportions of immunosuppressive regulatory T cells longitudinally, which could contribute to resistance. At relapse, higher proportions of peripheral and bone marrow CD4+ and CD8+ T cells expressing markers associated with T-cell dysfunction and impairment (eg, CD39 and CD57) and higher proportions of regulatory T cells were observed compared with baseline. Finally, a reduction in BCMA receptor density was observed on bone marrow tumor plasma cells at relapse. Our data highlight the importance of understanding mechanisms of response, resistance, and relapse to teclistamab to optimize T-cell and bispecific antibody activity, advance dosing and sequencing strategies, and inform further evaluation of teclistamab combinations with other anti-myeloma agents and use in earlier lines of treatment to improve patient outcomes.