Teclistamab, a B-Cell Maturation Antigen (BCMA) x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Correlative Analyses from MajesTEC-1

Introduction: Teclistamab is an off-the-shelf, B-cell maturation antigen (BCMA) bispecific IgG4 antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells. The multicohort, open-label, phase 1/2 MajesTEC-1 study is investigating safety/efficacy of teclistamab in patients with relapsed/refractory multiple myeloma (RRMM) who previously received ≥3 lines of therapy. In phase 1, the recommended phase 2 dose (RP2D) of teclistamab was identified as a weekly subcutaneous (SC) dose of 1.5 mg/kg preceded by step-up doses of 0.06 and 0.3 mg/kg. Initial results from patients treated at the RP2D in phase 1/2 (no prior exposure to a BCMA-targeted treatment) demonstrated that teclistamab was well tolerated, with encouraging efficacy. Here, we report translational research data from the pivotal RP2D and active dose cohorts of patients in the MajesTEC-1 study. Methods: Baseline or on-treatment whole blood and bone marrow aspirate samples from pivotal RP2D patients (SC) were analyzed by flow cytometry for BCMA expression or immune populations. Serum samples were analyzed for soluble BCMA (sBCMA) using an electrochemiluminescence ligand binding assay and for cytokines using MSD or Luminex assays. Whole blood from active dose cohorts (intravenous/SC) was analyzed by cytometry by time of flight (CyTOF). Results: Analysis of pivotal RP2D patients demonstrated that the baseline expression of BCMA on bone marrow plasma cells was prevalent and highly variable among patients with RRMM but was not associated with clinical responses to teclistamab. Higher sBCMA levels at baseline were associated with lower response rates and high-risk disease characteristics (higher revised International Staging System stage, high bone marrow plasma cells [>60%], and presence of extramedullary plasmacytoma). Nonresponding patients had lower peripheral CD8 T-cell counts, higher frequency of regulatory T cells (Tregs) and CD38+ Tregs, and higher overall frequencies of T cells that express markers, such as PD-1, TIM-3, and CD38, in both peripheral blood and bone marrow at baseline. Additional analysis at baseline using CyTOF showed the enrichment of memory CD8 T cells expressing PD-1, LAG-3, TIM-3, CD38, and HLA-DR and a higher number of natural killer (NK) cells in nonresponders, as well as an enhancement of a naïve phenotype in T cells in responders. A higher frequency of baseline T cells expressing PD-1, TIM-3, CD38, CD25, as well as PD-1/TIM-3 and PD-1/CD38, was observed in the blood and bone marrow of patients with high bone marrow plasma cells (>60%) and those with high composite tumor score (based on plasmacytosis ≥80%, serum M-spike ≥5 g/dL, and serum free light chain ≥5000 mg/L). Worse progression-free survival (PFS) was associated with higher frequencies of peripheral PD-1+ CD8, CD38+ naïve CD8, CD38+ effector memory CD4, and Tregs at baseline. A higher frequency of baseline CD25+ CD4 and CD38+ CD4 T cells in bone marrow was also correlated with decreased PFS after adjusting for tumor burden. Such a T-cell profile associated with worse clinical outcome likely reflects a dysfunctional and exhausted T-cell phenotype. Consistent with this hypothesis, a lower induction of interferon-gamma and PD-1+ CD8, CD25+ CD4, and CD38+ CD4 T cells was observed with teclistamab treatment in nonresponding patients. Furthermore, teclistamab-mediated induction of peripheral PD-1+ and PD-1+ CD38+ CD8 T cells was lower in patients with high tumor burden. Finally, occurrence of cytokine release syndrome was associated with higher CD3 T-cell frequency and lower baseline sBCMA, TIM-3, and PD-1/TIM-3 expressing CD4 T cells in the periphery. Conclusions: Analysis of baseline correlatives for pivotal RP2D patients suggests an emerging profile for non-responders of unfavorable immune characteristics at baseline, including lower T-cell numbers; higher frequency of T cells at baseline expressing markers such as PD-1, TIM-3, and CD38; higher frequency of Tregs and CD38+ Tregs; and lower proportion of naïve T cells and more NK cells. These data support clinical combinations of teclistamab with agents such as daratumumab or checkpoint inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal