Talquetamab and teclistamab combination improved response in relapsed multiple myeloma

1. In this randomized controlled trial, in patients with relapsed or refractory multiple myeloma (MM), combination therapy of talquetamab and teclistamab resulted in a durable response.

2. Although the safety profile of this regimen was comparable to that of monotherapies, grade three and four infections occurred at a higher rate in combination therapy.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Patients with relapsed or refractory MM previously treated with immunotherapy, protease inhibitors, and anti-CD38 therapies (triple-class exposure) have poor prognosis. Talquetamab (anti-G protein-coupled receptor family C group 5 member D) and teclistamab (anti-B-cell maturation antigen) are bispecific antibodies that activate T cells and have demonstrated response in refractory MM with established safety profiles. Dual therapy may be beneficial in increasing response rate and preventing resistance. In this phase 1b-2 trial investigating talquetamab plus teclistamab in patients with relapsed or refractory MM, dose-limiting toxicity was observed in three patients. The most common adverse events included cytokine release syndrome, neutropenia, and non-rash skin events. Grade three or four events occurred in almost all patients, with the most common being hematologic events. The adverse event profiles were similar to those reported in monotherapies, except for grade three or four infections. At the recommended phase two dosing, the disease response rate was 80% by 20.3 months. Overall, talquetamab plus teclistamab resulted in durable responses in patients with relapsed or refractory MM, at a higher risk of serious infections when compared to either therapy alone.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This was an ongoing, international, open-label, phase 1b-2 study investigating the combination of talquetamab and teclistamab, consisting of the phase 1 dose-escalation study followed by the phase 2 study with the recommended regimen. Adult patients with relapsed or refractory MM with at least triple-class exposure and an Eastern Cooperative Oncology Group score of 0 or 1 were eligible for inclusion, including those with extramedullary disease. In total, 94 patients were enrolled in phase one, with 5 dose levels ranging from 0.2mg/kg talquetamab plus 0.75mg/kg weekly teclistamab (dose level 1) to 0.8mg/kg talquetamab plus 3.0mg/kg teclistamab biweekly (dose level 5) in 28-day cycles. The primary outcomes were dose-limiting toxicity and adverse events. Secondary outcomes included overall response, duration of response, and progression-free survival. The median follow-up was 20.3 months. Three patients experienced dose-limiting toxic effects, including oral herpes, elevated alanine aminotransferase and aspartate aminotransferase levels, and thrombocytopenia. A total of 90 patients (96%) had grade 3 or 4 adverse events, most commonly grade three or four hematologic events (in 80% of patients). With the phase two regimen, a disease response occurred in 34 of 44 patients (80%), including 61% of those with extramedullary disease. Complete response occurred in 52% of these patients. The durability of response at 12 months and 18 months was 91% (95% confidence interval [CI] 75-97) and 86% (95% CI 66-95) with the phase 2 regimen; whereas in patients with extramedullary disease, the durability of response was 86% (95% CI 45-95) at both 12 and 18 months. The estimated progression-free survival was 74% (95% CI 57-84) at 12 months and 70% (95% CI 52-82) at 18 months. Although the response rates were higher in the studied dual therapy than in monotherapies with comparable adverse event profiles to those previously observed, the rate of grade 3 or 4 infections was also higher.

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