Talvey Plus Tecvayli Shows Promising Results in Multiple Myeloma but Raises Infection Concerns

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The results of a Phase Ib/II dose escalation and expansion trial (NCT04586426) found that the combination of Talvey (talquetamab) plus Tecvayli (teclistamab) achieved promising antitumor activity and durable responses in patients with relapsed or refractory multiple myeloma (RRMM). However, the combination was also associated with a greater incidence of grade 3 or 4 infections compared to either individual drug as monotherapy, which emphasizes the need to further investigate the combination, according to the authors of the study, published by The New England Journal of Medicine.^1,2

The investigators noted the importance of finding new therapeutic options for patients with high-risk disease, who have limited treatment options and poor outcomes.

“Patients with relapsed or refractory multiple myeloma who have had exposure to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 therapies (i.e., triple-class exposure) have a poor prognosis with standard treatments,” the study authors wrote. “Despite the approval of chimeric antigen receptor (CAR) T-cell and bispecific antibody therapies, multiple myeloma remains incurable.”¹

Tecvayli is an off-the-shelf bispecific T cell–engaging antibody that attaches to the CD3 receptor on T cells and the B-cell maturation antigen expressed on multiple myeloma cells and some healthy B-lineage cells. Tecvayli activates T cells, which leads to the release of proinflammatory cytokines and in the lysis of multiple myeloma cells.³

Talvey is a T-cell–redirecting bispecific antibody that targets the novel GPRC5D antigen. In the Phase I/II MonumenTAL-1 trial (NCT03399799; NCT04634552), Talvey achieved a 71% objective response rate and a median progression-free survival (PFS) of 11.2 months, but was linked to unique toxicities, such as skin, nail, and oral adverse events (AEs) because of GPRC5D expression, according to the trial investigators.

“Dual antigen targeting with talquetamab plus teclistamab may further enhance treatment potency, maximize tumor eradication in heterogeneous cell populations, prevent resistance due to tumor antigen escape, and increase durability of response,” the authors of the current study hypothesized.¹

Trial Design

The ongoing, multicenter, nonrandomized, open-label trial was comprised of a Phase I dose-escalation portion, in which the study authors evaluated five dose levels. The results of Phase I led to the recommended Phase II dosing levels of Talvey administered at 0.8 mg per kilogram of body weight plus Tecvayli at a dose of 3.0 mg per kilogram every other week.

The trial’s primary endpoint was to analyze occurrence of AEs and dose-limiting toxic effects. Secondary endpoints included overall response, duration of response, time to response, pharmacokinetics, pharmacodynamics, and immunogenicity, with PFS evaluated as well. The investigators evaluated responses every four weeks and up to 16 weeks following the completion of the therapeutic regimen.

Trial Results

In total, 94 patients were administered treatment, while 44 were administered the recommended Phase II dosing regimen with a median follow-up of 20.3 months. Investigators found that three patients experienced dose-limiting toxic AEs, which included grade 4 thrombocytopenia in one patient at the recommended Phase II dose level.

For all of the dosing levels, the most frequently reported AEs included cytokine release syndrome, neutropenia, changes in the ability to taste, and nonrash skin AEs. A total of 96% of patients reported grade 3 or 4 AEs, the most common of which were hematologic. Grade 3 or 4 infections were observed in 64% of patients.

A response was observed in 80% of patients administered the recommended Phase II dose, which included 61% of patients with extramedullary disease. In total, a response was observed in 78% of patients across all dose levels.

“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,” the study authors 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.”¹

References

1. Cohen, Y., et al. Talquetamab plus Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med 2025;392:138-149. Vol. 392 No. 2.

2. A Study of the Combination of Talquetamab and Teclistamab in Participants With Relapsed or Refractory Multiple Myeloma (RedirecTT-1). ClinicalTrials.gov. Updated January 9, 2025. Accessed January 9, 2025. https://clinicaltrials.gov/study/NCT04586426

3. Kumar SK, Callander NS, Adekola K, et al. Multiple myeloma, version 3.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020;18(12):1685-1717. doi:10.6004/jnccn.2020.0057. Accessed January 9, 2025.