Combination induces durable responses in advanced multiple myeloma
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Key takeaways:
- Researchers observed responses at all dose levels, with the recommended phase 2 regimen linked to durable response.
- Nearly two-thirds of patients developed grade 3 or grade 4 infections.
The combination of a talquetamab and teclistamab induced durable responses among patients with relapsed or refractory multiple myeloma, according to phase 1B/phase 2 study results.
“Combination therapy with teclistamab plus talquetamab showed encouraging antitumor activity in a majority of patients with relapsed or refractory multiple myeloma,” Yael C. Cohen, MD, head of the myeloma unit at Tel Aviv Sourasky Medical Center, and colleagues wrote. “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.”
Talquetamab (Talvey, Janssen) and teclistamab (Tecvayli, Janssen) are bispecific antibodies that activate T cells by targeting CD3. Both agents have been approved for the treatment of triple-class-exposed relapsed or refractory multiple myeloma.
In the phase 1 portion of the study, Cohen and colleagues evaluated five dose levels. Results prompted researchers to identify the recommended phase 2 regimen as talquetamab 0.8 mg/kg plus teclistamab 3 mg/kg every other week.
Adverse events and dose-limiting toxic effects served as the primary outcome measures in the phase 2 portion.
That analysis included 94 patients (median age, 64.5 years; 52% men; 80% white) received treatment, but only 44 patients (median age, 63 years; 52% men; 73% white) received the recommended phase 2 dose regimen.
After median follow-up of 20.3 months, three patients experienced dose-limiting toxic effects.
Researchers reported overall response rates of 78% for all patients in the phase 2 portion, 80% for those who received the recommended phase 2 dose, and 61% for those with extramedullary disease.
Patients who received the recommended phase 2 dose appeared more likely to remain in response at 18 months than those who received other dose regimens (86% vs. 77%).
The most common adverse events in the overall cohort included cytokine release syndrome (79%), neutropenia (73%), taste changes (65%) and non-rash skin events (61%).
Nearly all (96%) patients developed grade 3 or grade 4 hematologic events, with 64% developing grade 3 or grade 4 infections.
“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,” researchers wrote.
Perspective
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Aysa Varshavsky, MD, PhD
Bispecific T-cell engagers have changed the outlook for patients with heavily pretreated relapsed/refractory multiple myeloma. Teclistamab and talquetamab, bispecific T cell engagers targeting BCMA and GPRC5D respectively, both showed excellent efficacy with 60%/70% ORR and durable responses in triple class-exposed relapsed refractory myeloma.The RedirecTT-1 study investigated safety and efficacy of teclistamab and talquetamab in combination, with the rationale of increasing treatment potency and overcoming tumor antigen escape by using dual target. The study was designed as a phase 1/phase 2 dose escalation and dose expansion, and the highest dose level — consisting of teclistamab 3mg/kg and talquetamab 0.8mg/kg every 2 weeks, with the option to transition to every 4 weeks for responders — was selected as the recommended phase 2 regimen.
At the recommended phase 2 dose, the combination demonstrated an impressive response rate of 80%, with 52% complete response or better, in a population of triple class-exposed patients, most of whom were triple class refractory. Responses were durable, with 86% patients maintaining response at 18 months. The most striking result was noted in the subgroup of patients with extramedullary disease (EMD), who achieved overall response rate of 61%, with 82% maintaining response at 18 months. This is unprecedented in this very difficult-to-treat population, and much higher compared with the responses to both teclistamab and talquetamab as monotherapy (ORRs of 36% and 41%, respectively). Patients with relapsed/ refractory myeloma with EMD have very low response rates with conventional therapies, and while CAR-T therapies achieve relatively high response rates, those responses are much less durable compared to general population.
The toxicity profile of the combination therapy was consistent with the individual toxicity profile of each drug, with most patients experiencing low grade CRS early in the treatment course, and very low incidence of ICANS. However, the incidence of significant infection was higher with the combination (64% grade 3/grade 4 infections). Of note, due to the timeline of the study, IVIG prophylaxis and infectious prophylaxis were not universal in the study population.
In conclusion, the combination of teclistamab and talquetamab is a very effective treatment option for triple class-refractory myeloma, with unprecedented efficacy in extramedullary disease, and may become a new standard of care. Aggressive infectious prophylaxis and monitoring is very important for patients treated bispecific T-cell engagers.
Collapse
Cohen YC, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2406536.
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