Pharmacodynamic Profiles of Patients (Pts) with Newly Diagnosed (ND) Vs Relapsed/Refractory Multiple Myeloma (RRMM) Who Received Teclistamab (Tec) or Talquetamab (Tal) Plus Daratumumab (Dara) and Lenalidomide (Len) in the Phase 1b Majestec-2 and Monumental-2 Studies

Introduction: The first-in-class bispecific antibodies tec (targeting BCMA) and tal (targeting GPRC5D) have demonstrated deep, durable responses as monotherapies in pts with RRMM. Dara, an anti-CD38 monoclonal antibody, and len, an immunomodulatory drug (IMiD), have been shown to enhance T-cell cytotoxic activity against myeloma cells alone or in combination with other agents. We evaluated immune-cell profiles in pts with NDMM vs those with RRMM in the MajesTEC-2 (NCT04722146) and MonumenTAL-2 (NCT05050097) studies to identify differential immune signatures between pts with NDMM and RRMM treated with either tec-dara-len or tal-dara-len.

Methods: Pts in MajesTEC-2 received subcutaneous (SC) tec 1.5 mg/kg QW after step-up dosing (0.06 and 0.3 mg/kg) plus the approved schedules of dara 1800 mg + len 25 mg. In MonumenTAL-2, pts with RRMM received SC tal 0.3 mg/kg QW, and pts with NDMM received either 0.6 mg/kg Q2W or 0.8 mg/kg Q4W plus the approved schedules of dara 1800 mg + len 25 mg. Dexamethasone was given concurrent with the first 3 full IMiD-containing cycles. Peripheral blood and bone marrow samples were collected at baseline and post treatment at cycle 2 and/or 3 for evaluation of immune cells (CD3+, CD4+, CD8+, regulatory T cells [Tregs], and natural killer [NK] cells), T-cell receptor (TCR) sequencing, cytokine profiles, and assessment of activation/exhaustion markers by flow cytometry. Analyses include all pts for whom samples were available (MajesTEC-2: NDMM, n=11; RRMM, n=19 and MonumenTAL-2: NDMM, n=18; RRMM with ≥3 prior lines of therapy [pLOT] or 1–3 pLOT, n=20).

Results: Overall, pharmacodynamics following tec/tal-dara-len treatment revealed enhanced T-cell recovery plus an increase in effector memory T cells compared with tec/tal monotherapy and consistent with tec, tal, and dara mechanisms of action (MOA) and T-cell restimulation post len (including CD38 subsets), consistent with len MOA. While a reduction of immunosuppressive Tregs and of NK cells with tec/tal-dara (consistent with dara MOA) was observed, the addition of len resulted in increased numbers of NK cells. We sought to further assess whether a differential immune profile exists between pts with NDMM and RRMM treated with tec-dara-len or tal-dara-len. At baseline, pts with NDMM demonstrated a favorable immune fitness profile, indicated by higher absolute counts of peripheral T-cell numbers and NK cells and higher TCR diversity, higher proportions of T cells expressing CD38 (likely due to lack of prior dara exposure), and lower proportions of T cells expressing markers associated with T-cell activation/exhaustion compared with pts with RRMM. Longitudinally, pts with NDMM treated with tec/tal-dara-len showed greater recovery in number of peripheral CD3+ T cells compared with those with RRMM. With tec/tal-dara treatment, early induction of T-cell activation markers was greater in pts with NDMM than in pts with RRMM; specifically, len administration transiently restimulated T cells expressing HLA-DR. In addition, higher induction of pro-inflammatory cytokines such as IFNγ and sIL-2Rα, was seen in pts with NDMM compared with RRMM, suggesting a greater activation capacity in pts with NDMM with both tec/tal-dara-len. Tec/tal-dara-len led to a reduction of the proportion of CD38-expressing T-cell subsets in pts with NDMM and RRMM; the addition of len resulted in a transient upregulation of CD38 on T cells, but continuous dara dosing lowered the proportions of these cells. Further, reduction of NK cells with tec/tal-dara was observed in NDMM and RRMM, with minimal differences in NK cell recovery following the addition of len. Importantly, pts with NDMM exhibited higher T-cell clonal expansion capacity and a lower repertoire similarity post tal-dara-len compared with pts with RRMM, suggesting therapy-induced T-cell expansion.

Conclusions: This combined analysis was conducted to provide insights into the differential immune profiles in pts with NDMM vs RRMM treated with tec/tal-dara-len to enhance understanding of the therapeutic benefits and guide future treatment strategies, which are being evaluated in the phase 3 MajesTEC-7 study (NCT05552222). The more favorable immune profile observed in pts with NDMM vs RRMM suggests that earlier treatment with novel combinations, such as tec-dara-len and tal-dara-len, may improve pt outcomes. Correlations with efficacy will be presented at the meeting.