Reduced talquetamab dose intensity maintains efficacy, may lessen toxicities in myeloma
SAN DIEGO — Reduced-intensity dosing of talquetamab may improve tolerability without compromising efficacy among patients with relapsed or refractory multiple myeloma, according to study results.
Most patients in the phase 1/phase 2 MonumenTAL-1 study who responded to the agent and then switched to lower or less frequent doses maintained or deepened responses, findings presented at ASH Annual Meeting showed.
In addition, treatment-emergent adverse events generally improved among those who switched.
“These data support flexibility to adjust dosing of talquetamab [for] responders to potentially improve patient experience while maintaining efficacy,” Ajai Chari, MD, professor of medicine at University of California, San Francisco, said during a presentation.
Background and methods
Talquetamab (Janssen) is a T cell-redirecting bispecific IgG4 antibody that targets G protein-coupled receptor family C group 5 member (GPRC5D) and CD3.
In the phase 1/phase 2 MonumenTAL-1 trial, nearly three-quarters of patients with relapsed or refractory multiple myeloma achieved objective response to subcutaneous talquetamab. However, more than half of patients experienced dysgeusia (77%), non-rash skin toxicities (73%) and nail toxicities (63%).
The potential to reduce dose intensity of bispecifics has been an area of considerable interest, Chari said.
At ASH, he reported efficacy and safety outcomes from MonumenTAL-1 participants who switched to reduced or less frequent talquetamab dosing once they achieved response.
Results
The analysis included two cohorts — one retrospective and one prospective.
The retrospective cohort included 367 eligible patients who started talquetamab at one of three doses. Patients who had not received prior T cell redirection therapy started with doses of 0.4 mg/kg weekly or 0.8 mg/kg every 2 weeks, and those who had received prior T-cell redirection therapy received talquetamab on either schedule.
Patients who achieved partial response or better, or those who experienced adverse events requiring mitigation, could receive lower or less frequent doses.
Fifty patients ultimately had dose-intensity reduction. Median time to dose reduction ranged from 3.2 months to 4.7 months depending on initial dose level. Median follow-up ranged from 20.8 months to 27.6 months.
PFS curves showed “relatively favorable patterns” in outcomes among responders with dose reductions, Chari said. Median response durations ranged from 19.8 months to not estimable, and the percentage of patients who maintained response for 12 months ranged from 78.3% to 100% depending on initial dose level.
Chari and colleagues aimed to validate these findings prospectively in a second cohort that included 19 evaluable patients who had achieved response to talquetamab dosed at 0.8 mg/kg every 2 weeks. Upon achieving response, nine had their doses reduced from 0.8 mg/kg every 2 weeks to 0.4 mg/kg every 2 weeks, and 10 had dose frequency reduced from 0.8 mg/kg every 2 weeks to 0.8 mg/kg every 4 weeks.
Dose-intensity reductions occurred at a median 3.1 months (range, 2.3-4.2) after treatment initiation.
Median follow-up was 13.2 months (range, 4+ to 16.1).
Researchers reported median PFS of 13.2 months (8.8 to not estimable) and a 12-month PFS rate of 50.1% (95% CI, 27.9-68.7). Median duration of response was not estimable (8.3 to not estimable).
Outcomes in the prospective cohort compared favorably with those of the registrational cohort (n = 145) that established the 0.8 mg/kg every-2-weeks dose. In the registrational cohort, researchers reported median PFS of 14.2 months (95% CI, 9.6 to not estimable), with a 12-month PFS rate of 54.4% and a median response duration that was not estimable (95% CI, 13 to not estimable).
Patients in the prospective cohort who received dose-intensity reductions showed a trend toward improved resolution of GPRC5D-related adverse events — including oral, nail and skin toxicity (rash and non-rash) — compared with patients in a matched cohort who did not have dose-intensity reductions. Researchers observed no improvement in weight loss among those who received dose reductions.
No patients discontinued talquetamab due to treatment-emergent adverse events.
“Further analyses on the impact of reduced or less frequent talquetamab dosing on clinical outcomes are warranted,” Chari and colleagues wrote.
Perspective
Back to TopIn the past year, FDA approval of the three bispecific T-cell engagers for heavily pretreated relapsed or refractory multiple myeloma changed the outlook for patients with triple class-refractory disease.
Talquetamab is the first FDA-approved therapy targeting GPRC5D, a novel target expressed on myeloma cells. It has been eagerly anticipated due to its excellent efficacy — including for patients who failed B-cell maturation antigen-directed therapies and prior T cell-redirecting therapies and otherwise have little to no viable therapeutic options.
In addition to BITE class-specific toxicities — including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome and cytopenias — talquetamab has unique toxicities of dysgeusia and skin/nail changes. Although skin and nail toxicities observed in MonumenTAL-1 were low grade and manageable, dysgeusia may significantly affect patients’ quality of life.
The question of impact of decreased dose intensity or frequency of BITEs on efficacy and toxicity is clinically very important and is under active investigation. The rationale for decreasing dose frequency or intensity is to potentially help alleviate toxicities, decrease T-cell exhaustion caused by continuous redirecting therapy, improve convenience for patients — especially given indefinite duration of these therapies — and decrease health care costs.
This analysis from MonumenTAL-1 shows that reducing dose intensity of talquetamab among responders is feasible and promising, resulting in maintained efficacy and some improvement in toxicities. This approach, and possibly other alternative dosing regimens, need to be further investigated in larger cohorts of patients.
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Chari A, et al. Abstract 1010. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
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