Deeksha Vishwamitra, Janssen Research & Development, discusses an analysis of the TRIMM-2 clinical trial evaluating combination therapy tal-DP in patients with multiple myeloma.
Multiple myeloma is a bone marrow-based plasma cell neoplasm characterized by a serum monoclonal protein and skeletal destruction with osteolytic lesions, pathological fractures, bone pain, hypercalcemia, and anemia.
An analysis was conducted on immunologic pharmacodynamic profiles, correlatives of response, and associations with outcomes in patients treated with tal-DP from the TRIMM-2 clinical trial to look at the effects of this combination therapy. The TRIMM-2 clinical trial is a phase 1b study evaluating subcutaneous daratumumab regimens in combination with bispecific T-cell redirection antibodies for the treatment of patients with multiple myeloma.
Talquetamab is a bispecific antibody that has shown durable response in relapsed/refractory multiple myeloma. Teclistamab (tec) is the first approved B-cell maturation antigen x CD3 bispecific antibody for the treatment of relapsed/refractory multiple myeloma. Daratumumab (D) is a human monoclonal antibody that targets CD38, a protein overexpressed in multiple myeloma cells. Pomalidomide (P) is a thalidomide analogue that stimulates immune function and kills multiple myeloma cells. This combination is referred to as tal-DP.
Results
Patients received tal 0.4 mg/kg weekly or 0.8 mg/kg biweekly with step-up dosing and approved schedules of D 1800 mg and P 2mg. Data from 77 patients was analyzed. Following treatment with tal-DP combination therapy, complementary pharmacodynamic effects were observed. These included the ability to induce T-cell margination, increase absolute T-cell recovery, expand effector memory T-cells, and decrease naive CD8 T-cells during initial cycles of treatment.
The addition of P further amplified these effects, leading to T-cell restimulation, reinduction of CD38 expression on CD8 T cells, and sustained activation of this subset. Notably, tal-DP reduced immunosuppressive CD38+ regulatory T-cells and rescued NK cells initially reduced by D treatment. Patients with prior bispecific antibody (BsAb) exposure, despite presenting more dysfunctional and exhausted baseline immune profiles, demonstrated enhanced CD8 T-cell expansion, NK-cell recovery, and T-cell activation compared to those without prior exposure.
Deeper responses to Tal-DP were associated with higher baseline CD8 T-cell counts, lower expression of activation and coinhibitory receptors, and improved progression-free survival (PFS) and duration of response (DOR). These patients showed earlier and greater recovery of CD8 T-cells and NK cells after P administration, correlating with longer PFS and DOR. In contrast, non-responders exhibited less sustained immune activation and recovery. Preliminary results from a parallel study on Teclistamab (Tec)-DP demonstrated similar findings.
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