Longitudinal Correlative Profiles of Responders, Nonresponders, and Those with Relapse on Treatment with Teclistamab in the Phase 1/2 MajesTEC-1 Study of Patients with Relapsed/Refractory Multiple Myeloma

Introduction: Teclistamab (tec) is the only approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody with a personalized, weight-based dosing schedule for the treatment of triple-class exposed relapsed/refractory multiple myeloma (RRMM). In the phase 1/2 MajesTEC-1 study (NCT03145181/NCT04557098), tec demonstrated deep and durable responses. To better understand mechanisms of resistance and relapse in MajesTEC-1, we assessed longitudinal BCMA expression and immune profiles. Methods: Patients (N=165) with RRMM received subcutaneous tec 1.5 mg/kg weekly after step-up doses of 0.06 and 0.3 mg/kg, with the option to switch to every-other-week dosing if they achieved at least a partial response after ≥4 cycles of therapy in phase 1 or a complete response or better for ≥6 months in phase 2. Bone marrow and peripheral blood samples at baseline, on treatment, and at disease progression (PD) were analyzed by flow cytometry for BCMA expression and immune cell populations. Bone marrow aspirates were analyzed by cytometry by time of flight (CyTOF) for immune cell populations. Soluble BCMA (sBCMA) was analyzed in serum samples by electrochemiluminescence ligand binding. Results: Patients who responded to tec had a greater recovery of CD3+ T cells in the periphery and bone marrow during the first treatment cycles, which was sustained over time compared with nonresponders. Greater activation during the first cycle was observed in responders, indicated by a transient increase in CD38 on CD8+ T cells. In contrast, an exhausted T-cell phenotype in the blood and bone marrow was observed longitudinally in nonresponders vs responders, indicated by increasing and sustained levels of activation and exhaustion markers including persistence of CD38+ T cells and expression of LAG-3, PD-1 (Figure 1A), PD-1/LAG-3, and PD-1/TIM-3 on CD4+ or CD8+ T cells. Higher levels of immunosuppressive regulatory T cells (Tregs), including CD38+ Tregs, were also sustained in the periphery in nonresponders compared with responders. BCMA expression and sBCMA levels were assessed in a subset of patients who initially responded then relapsed on tec, who had matched baseline and end-of-treatment/PD samples. There were no significant changes in the frequency of BCMA+ plasma cells, BCMA receptor density, or sBCMA levels at PD relative to baseline, suggesting BCMA loss was not a mechanism of relapse in these patients. In contrast, higher proportions of peripheral CD4+ and/or CD8+ T cells express