Research Summary

Talquetamab Plus Teclistamab Shows Durable Responses in Relapsed or Refractory Multiple Myeloma

Edited by:
Anthony Calabro, MA

Key Highlights:

  • The combination of two bispecific antibodies produced an 80% overall response rate.
  • Grade 3 or 4 infections occurred in 64% of patients, higher than with either monotherapy.
  • The results support continued evaluation of dual-targeting strategies for refractory myeloma, according to the study authors.

Combination treatment with talquetamab, a T-cell redirecting antibody targeting the protein GPRC5D, and teclistamab, a T-cell redirecting antibody targeting the protein BCMA, demonstrated high and durable response rates in patients with relapsed or refractory multiple myeloma, according to findings published in The New England Journal of Medicine.

In their study Cohen and colleagues conducted the ongoing, multicenter, nonrandomized, open-label RedirecTT-1 phase 1B–2 trial across sites in Canada, Israel, South Korea, and Spain. A total of 94 patients with measurable relapsed or refractory multiple myeloma received escalating doses of subcutaneous talquetamab and teclistamab in 28-day cycles. The phase 1 dose-escalation portion used a Bayesian optimal interval design to determine the recommended phase 2 regimen, defined as talquetamab 0.8 mg/kg plus teclistamab 3.0 mg/kg every other week.

The primary endpoint was safety, including adverse events and dose-limiting toxic effects. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. Data were analyzed using the Kaplan–Meier method to estimate response durability and progression-free survival.

Study Findings

The dual bispecific antibody approach achieved responses in 80% of participants who had previously been exposed to immunomodulatory medications, proteasome inhibitors, and anti-CD38 therapy. Digging deeper, at a median follow-up of 20.3 months, 80% of patients treated with the recommended phase 2 regimen achieved an overall response, including 61% of those with extramedullary disease. Across all dose levels, 78% of patients responded. Grade 3 or 4 hematologic adverse events occurred in 96% of patients, and grade 3 or 4 infections were reported in 64%. Cytokine release syndrome, neutropenia, and taste alterations were among the most common adverse events, while immune effector cell–associated neurotoxicity was rare and reversible. Responses were durable, with an 86% probability of being maintained at 18 months.

Clinical Implications

According to the study authors, the combination of talquetamab and teclistamab resulted in deep and sustained responses in patients who were heavily pretreated, including those with high-risk cytogenetic features and extramedullary disease. Although the combination was associated with a higher rate of severe infections than observed with either agent alone, the investigators emphasized the importance of infection prophylaxis, immunoglobulin replacement, and close monitoring. The findings suggest that targeting two antigens—BCMA and GPRC5D—may enhance efficacy and reduce the likelihood of relapse compared with single-antigen therapies.

The authors noted several limitations of their study, including a relatively short follow-up period, a small overall sample size, the low representation of Black patients (one participant), the absence of formal hypothesis testing, reliance on investigator-assessed responses, and the open-label, nonrandomized design.

Expert Commentary

“In this study, 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,” Cohen and colleagues concluded. “Responses were observed across dose levels and were particularly deep and durable with the recommended phase 2 regimen. 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.”

Reference:
Cohen YC, Magen H, Gatt M, et al; RedirecTT-1 Investigators and Study Group. Talquetamab plus teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2025;392(2):138-149. doi:10.1056/NEJMoa2406536