The combination of talquetamab (Talvey) and teclistamab (Tecvayli) has demonstrated promising results in patients with relapsed or refractory multiple myeloma (RRMM), according to a Phase Ib/II trial. The study, published in The New England Journal of Medicine, found that the combination achieved significant antitumor activity and durable responses, offering a potential new therapeutic avenue for patients with limited treatment options. However, the combination was also associated with a higher incidence of grade 3 or 4 infections compared to either drug as monotherapy, emphasizing the need for careful monitoring and further investigation.
Efficacy and Safety Profile
The open-label, multicenter, nonrandomized trial evaluated five dose levels of the talquetamab and teclistamab combination. The recommended Phase II dosing levels were determined to be talquetamab at 0.8 mg per kilogram of body weight plus teclistamab at 3.0 mg per kilogram every other week. With a median follow-up of 20.3 months, the study reported an 80% response rate in patients administered the recommended Phase II dose, including 61% of patients with extramedullary disease. Across all dose levels, the overall response rate was 78%.
However, the combination therapy also presented safety concerns. While the adverse event profile was generally similar to that of each agent as monotherapy, the incidence of grade 3 or 4 infections was notably higher. Specifically, 64% of patients experienced grade 3 or 4 infections. The most frequently reported adverse events across all dosing levels included cytokine release syndrome (79%), neutropenia (73%), taste changes (65%), and non-rash skin events (61%).
Study Design and Patient Population
The trial enrolled 94 patients with RRMM who had prior exposure to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 therapies. This patient population often has a poor prognosis with standard treatments, highlighting the unmet medical need for new therapeutic options. The primary endpoint of the trial was the occurrence of adverse events and dose-limiting toxic effects. Secondary endpoints included overall response, duration of response, time to response, pharmacokinetics, pharmacodynamics, and immunogenicity, with progression-free survival (PFS) also evaluated.
Implications for Treatment Strategies
The study's findings suggest that dual antigen targeting with talquetamab plus teclistamab may enhance treatment potency, maximize tumor eradication in heterogeneous cell populations, prevent resistance due to tumor antigen escape, and increase durability of response. As the study authors hypothesized, the combination leverages the distinct mechanisms of action of the two bispecific antibodies: teclistamab targets the CD3 receptor on T cells and the B-cell maturation antigen (BCMA) on multiple myeloma cells, while talquetamab targets the novel GPRC5D antigen.
"Responses were observed across dose levels and were particularly deep and durable with the recommended phase 2 regimen," the study authors concluded. "On the basis of these results, this dual-targeting, off-the-shelf combination therapy warrants further investigation in patients with relapsed or refractory multiple myeloma."
