In a phase Ib/II, RedirecTT-1 study of talquetamab plus teclistamab, conducted in patients with relapsed or refractory multiple myeloma, talquetamab plus teclistamab had a similar safety profile to each agent as monotherapy, although the observed incidence of grade 3 or 4 infections was higher with the combination than with talquetamab or teclistamab as monotherapies. Responses were observed across dose levels and were particularly deep and durable with the recommended phase II regimen.
This dual-targeting, off-the-shelf combination therapy warrants further investigation in patients with relapsed or refractory multiple myeloma according to Dr. Yael C. Cohen of the Tel Aviv Sourasky Medical Center in Tel Aviv, Israel and colleagues, who published the findings on 8 January 2025 in The New England Journal of Medicine.
Patients with relapsed or refractory multiple myeloma who have had triple-class exposure to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 therapies have a poor prognosis with standard treatments. Despite the approval of CAR T-cell and bispecific antibody therapies, multiple myeloma remains incurable. Outcomes are worse in patients with high-risk features, such as extramedullary disease.
Teclistamab is a T-cell–redirecting bispecific antibody that targets BCMA and talquetamab is a T-cell–redirecting bispecific antibody targeting GPRC5D. These bispecific antibodies that activate T cells by targeting CD3 have been approved for the treatment of triple-class–exposed relapsed or refractory multiple myeloma.
Based on the results from the MajesTEC-1 study with teclistamab and MonumenTAL-1 study with talquetamab, the RedirecTT-1 study investigators speculated that dual antigen targeting with talquetamab plus teclistamab may further enhance treatment potency, maximise tumour eradication in heterogeneous cell populations, prevent resistance due to tumour antigen escape, and increase durability of response.
In the latest article, the RedirecTT-1 study team reported the early safety and efficacy results from the phase I dose-escalation portion of the phase Ib/II RedirecTT-1 study of talquetamab plus teclistamab in patients with relapsed or refractory multiple myeloma.
In phase I, the researchers investigated five dose levels in a dose-escalation study. Talquetamab at a dose of 0.8 mg per kilogram of body weight plus teclistamab at a dose of 3.0 mg per kilogram every other week was selected as the recommended phase II regimen. The primary objective was to evaluate adverse events and dose-limiting toxic effects.
A total of 94 patients received treatment, with the recommended phase II regimen used in 44. The median follow-up was 20.3 months. Three patients had dose-limiting toxic effects, including grade 4 thrombocytopenia in 1 patient with the recommended phase II regimen. Across all dose levels, the most common adverse events were cytokine release syndrome, neutropenia, taste changes, and non-rash skin events. Grade 3 or 4 adverse events, most commonly haematologic events, occurred in 96% of the patients. Grade 3 or 4 infections occurred in 64% of the patients.
Previously, the study team reported response in the RedirecTT-1 among patients who could be evaluated for response. In the latest article, they reported response in all patients who had their best response confirmed by at least two consecutive assessments. With the recommended phase II regimen, a response occurred in 80% of the patients, including in 61% of those with extramedullary disease; across all dose levels, a response occurred in 78%. The likelihood of patients continuing in response at 18 months was 86% with the recommended phase II regimen (82% among those with extramedullary disease) and 77% across all dose levels.
Limitations of the study include the relatively short follow-up, a small overall sample size, the low representation of African American patients (1 patient), a lack of formal hypothesis testing, the use of investigator-assessed responses, and the open-label, non-randomised nature of the study.
The authors concluded that the incidence of grade 3 or 4 infections with talquetamab plus teclistamab was higher than has been observed with either therapy alone. A response was observed in a high percentage of patients across all dose levels, with durable responses with the recommended phase II regimen.
The study was supported by Janssen Research and Development.
Reference
Cohen YC, Magen H, Gatt M, et al. for the RedirecTT-1 Investigators and Study Group. Talquetamab plus Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med 2025;392:138-149.