In a post-hoc analysis with longer follow-up of a multicentre, open-label, phase I/II MonumenTAL-1 study, talquetamab continued to show deep and durable responses in T-cell redirection (TCR) therapy naive, heavily pretreated patients with relapsed or refractory multiple myeloma. Activity results were promising in patients with previous TCR exposure, which is a population of patients with an emerging unmet need; most of these therapies were BCMA targeting.
Rates of high-grade neutropenia and high-grade and fatal infections remained low with longer follow-up compared with BCMA-directed bispecific antibodies, and although on-target, off-tumour adverse events were frequent, there were few treatment discontinuations due to these adverse events according to Prof. Ajai Chari of the University of California San Francisco, School of Medicine in San Francisco, CA, US and colleagues, who published the findings on 13 March 2025 in The Lancet Haematology.
The authors explained in the background that patients with multiple myeloma have cycles of remission and relapse on standard therapies, with a poorer prognosis with each successive relapse. Although anti-BCMA therapies are approved and have shown clinical benefit for patients with relapsed or refractory multiple myeloma, relapses continue. Therefore, there is a need for novel therapies.
Talquetamab is a first-in-class, off-the-shelf, TCR bispecific antibody targeting GPRC5D on myeloma cells and the CD3 receptor on T cells approved for triple-class exposed relapsed or refractory multiple myeloma. In phase I of the MonumenTAL-1 study, two recommended doses of subcutaneous talquetamab were identified: 0.4 mg/kg once a week and 0.8 mg/kg every 2 weeks. With a median follow-up of 11.7 and 4.2 months in patients treated with these two recommended doses, overall response rate (ORR) was 70% and 64%, and median duration of response (DoR) was 10.2 and 7.8 months, respectively.
In the latest article published in The Lancet Haematology, the study team describes updated safety and activity results with longer follow-up from MonumenTAL-1 in patients treated with subcutaneous talquetamab 0.4 mg/kg once a week or 0.8 mg/kg every 2 weeks with median follow-up of 25.6 and 19.4 months, including analyses in patients who had received previous TCR, CAR-T therapies or bispecific antibodies (median follow-up 16.8 months). Crucially, this post-hoc analysis was conducted with more mature median follow-up to evaluate DoR in patients treated with talquetamab 0.8 mg/kg every 2 weeks.
The 0.4 mg/kg once a week and 0.8 mg/kg every 2 weeks recommended subcutaneous doses identified in phase I were evaluated in phase II in patients who were 18 years of age or older, had at least three previous lines of therapy, had an Eastern Cooperative Oncology Group performance status of 0 to 2, and were naive or exposed to previous TCR. The primary endpoint was ORR assessed by independent review committee in all patients who received at least one dose of talquetamab. Safety was assessed in all patients who received at least one dose of talquetamab.
Between 3 January 2018 and 20 February 2023, 735 patients were screened across all phase I/II cohorts. Of these, 537 patients screened for inclusion were treated across phase I and II cohorts, of whom 1983 patients (27%) were excluded from the study, most commonly due to not meeting eligibility criteria or not having measurable disease. As of 11 October 2023, 375 patients had received recommended talquetamab doses across three groups: 143 (0.4 mg/kg once a week group) and 154 (0.8 mg/kg every 2 weeks group) TCR-naive patients and 78 with previous TCR who received either recommended dose (previous TCR group). A total, 217 of 375 patients (58%) were male and 158 (42%) were female; 325 of 375 patients (87%) were White and 32 patients (9%) were Black.
Median follow-up was 25.6 months (interquartile range [IQR] 8.5-25.9) in the 0.4 mg/kg once a week group, 19.4 months (IQR 9.2-20.7) in the 0.8 mg/kg every 2 weeks group, and 16.8 months (IQR 7.6-18.7) in the previous TCR group. ORR was 74% (106 of 143 patients, 95% confidence interval [CI] 66-81) in the 0.4 mg/kg once a week group, 69% (107 of 154 patients, 95% CI 62-77) in the 0.8 mg/kg every 2 weeks group, and 67% (52 of 78 patients, 95% CI 55-77) in the previous TCR group.
Most common adverse events in the 0.4 mg/kg once a week, 0.8 mg/kg every 2 weeks, and previous TCR groups were cytokine release syndrome (79%, 75%, and 73% of patients), taste changes (72%, 71%, and 76%), and infections (59%, 68%, and 76%). Most common grade 3-4 adverse events were neutropenia (31%, 21%, and 47%), anaemia (31%, 26%, and 27%), and lymphopenia (26%, 26%, and 17%). Fatal adverse events occurred in five patients in the 0.4 mg/kg once a week group, seven patients in the 0.8 mg/kg every 2 weeks group, and no patients in the previous TCR group; none were related to treatment.
The authors concluded that in this post-hoc analysis with longer follow-up, talquetamab continued to show promising activity in TCR-naive patients with heavily pretreated relapsed or refractory multiple myeloma. Promising activity was also observed in the previous TCR group (majority BCMA-targeting), which is an emerging class of patients with a high unmet medical need.
Responses were similar at both recommended doses and were rapid and deep, although median DoR and progression-free survival (PFS) were longer in the 0.8 mg/kg every 2 weeks group than the 0.4 mg/kg once a week group. Median PFS was promising with the 0.8 mg/kg every 2 weeks dose in older patients aged 75 years and older. Importantly, and uncommon in multiple myeloma, similar PFS was observed irrespective of cytogenetic risk profile. In patients who switched to a reduced dose after response, responses were maintained, supporting flexibility to adjust talquetamab dosing in responders to potentially improve patient experience while maintaining activity.
In an accompanied comment, Dr. Susan Bal of the Division of Hematology/Oncology and O'Neal Comprehensive Cancer Center, both at University of Alabama at Birmingham in Birmingham, AL, US wrote that the timeline of development of GPRC5D strategies have predominantly poised these agents in the post-BCMA setting. However, the ongoing development of GPRC5D directed therapies in earlier lines of disease and in combination with anti-BCMA immunotherapies and other novel agents particularly with immunomodulatory approaches will provide key insights to pertaining to sequencing of available immunotherapies.
The study was funded by Janssen Research and Development.
References
- Chari A, Touzeau C, Schinke C, et al. Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): a multicentre, open-label, phase 1–2 study. The Lancet Haematology; Published online 13 March 2025. DOI: https://doi.org/10.1016/S2352-3026(24)00385-5
- Bal S. Monumen-TAL progress in the treatment of relapsed multiple myeloma. The Lancet Haematology; Published online 13 March 2025. DOI: https://doi.org/10.1016/S2352-3026(25)00009-2