Dose reductions of the GPRC5D/CD3 bispecific antibody talquetamab (Talvey) effectively improved on-target adverse events while sustaining high response rates for patients with relapsed/refractory multiple myeloma (RRMM), according to retrospective and prospective findings from the phase 1/2 MonumenTAL-1 studies presented at the 2023 ASH Annual Meeting.
"After achieving response, dose modification may be a strategy to manage GPRC5D-related AEs, and we see that in the retrospective cohort, dose reductions did not affect response significantly and this led to the evaluation in a prospective cohort," said lead investigator Ajai Chari, MD, director of the Multiple Myeloma Program at the University of California, San Francisco (UCSF) Health. "Overall, these data support flexibility to adjust the dosing of talquetamab in responders to potentially improve patient experience while maintaining efficacy."
FDA Approval and Initial Efficacy Data
The FDA granted accelerated approval to talquetamab for RRMM in August 2023, based on initial findings from the MonumenTAL-1 study. In the pivotal analysis, patients receiving the 0.8 mg/kg biweekly dose achieved an objective response rate (ORR) of 73.6% (95% CI, 63.0%-82.4%), while the ORR was 73% in those receiving the 0.4 mg/kg biweekly dose (95% CI, 63.2%-81.4%). These findings led the FDA to approve both dosing regimens.
GPRC5D represents a new target within multiple myeloma, bringing unique on-target adverse events, specifically dysgeusia, skin, and nail toxicities. Notably, patients who reported an on-target adverse event had a 20% higher chance of responding to treatment with talquetamab.
"Although more than 71% of patients responded to talquetamab, recent landmark analysis showed a very interesting finding that patients who have 1 or more GPRC5D-related AE in the first 90 days actually had a 20% higher likelihood of having a response," Chari explained. "These AEs may be correlated with the immune mechanism of action."
Retrospective Analysis of Dose Modifications
In the MonumenTAL-1 study, 367 patients were treated with talquetamab at varying doses and frequencies. All patients had received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Of those treated, 50 patients required a dose reduction or a change in dose frequency.
The median time to dose reduction was 3.2 months in patients receiving talquetamab at 0.4 mg/kg weekly (n = 24), 4.5 months for those receiving 0.8 mg/kg every 2 weeks (n = 13), and 4.7 months for those receiving the bispecific at either schedule or dose after a T-cell redirection therapy (n = 10).
After dose reduction, the median duration of response (DOR) was 19.8 months for the weekly group, not evaluable for the biweekly arm, and 24.2 months for those receiving a prior T-cell redirection therapy. The 12-month DOR rate was 78.3% in the weekly group, 84.6% in the biweekly group, and 100% in the T-cell redirection therapy group.
Prospective Validation of Dose Reduction Strategy
Given the encouraging duration of response data, researchers enrolled a prospective cohort to validate dose reduction following response. The analysis included 9 patients who received a starting dose of talquetamab at 0.8 mg/kg every 2 weeks, reduced to 0.4 mg/kg every 2 weeks following a partial response or better. Another arm enrolled 10 participants receiving 0.8 mg/kg every 2 weeks, reduced to 0.8 mg/kg every 4 weeks following a partial response or better.
In this prospective cohort, dose reductions occurred at a median of 3.1 months following therapy initiation (range, 2.3-4.2). At a median follow-up of 13.2 months, the ORR was 79.2%, with a very good partial response rate of 75.0%. Median progression-free survival was 13.2 months (95% CI, 8.8–not estimable) and the 12-month progression-free survival rate was 50.1% (95% CI, 27.9%-68.7%). The median duration of response was not yet reached.
Significant Reduction in Treatment-Related Toxicities
Following dose reduction, patients experienced fewer new-onset GPRC5D-related adverse events and showed trends toward improved resolution of existing toxicities. At the starting dose in the prospective cohort, 84.2% of patients had new-onset oral toxicity compared with 22.2% after the dose switch.
Similar improvements were observed for nail toxicity, with rates dropping from 42.1% to 27.8%. For skin toxicity, new-onset non-rash toxicities declined from 73.7% to 5.6%, and rash toxicities declined from 31.6% to 0%. Weight loss remained similar between dosing periods.
"Following the switch there was a trend toward resolution of GPRC5D-related oral, skin, and nail toxicities," Chari noted. "The dose-reduced cohorts also showed a trend towards improved immune fitness compared with those who did not reduce."
The findings demonstrate that talquetamab dose modifications can effectively balance efficacy and tolerability, providing clinicians with a valuable strategy to optimize treatment outcomes while maintaining quality of life for patients with relapsed/refractory multiple myeloma.
