Talquetamab Continues to Elicit High Treatment Responses in a Heavily Pre-treated Multiple Myeloma Population

Updated findings from the phase 1/2 MonumenTAL-1 trials (NCT03399799; NCT04634552), investigating the recommended phase 2 doses of talquetamab, showed that treatment with the agent resulted in an overall response rate (ORR) exceeding 70% in a population of patients with heavily pre-treated relapsed/refractory multiple myeloma.

Data from the study, which were presented at the 2022 American Society of Hematology Annual Meeting, indicated that patients treated with the subcutaneous agent yielded an ORR of 74.1% and 73.1% at the recommended phase 2 doses (RP2D) of 0.4 mg/kg weekly and 0.8 mg/kg every 2 weeks.

This included a stringent complete response rate (sCR) of 23.8%, a CR rate of 9.8%, a very good partial response rate (VGPR) of 25.9%, and PR rate of 14.7% in the 0.4 mg/kg cohort, as well as 20.0%, 12.4%, 24.8%, and 15.9% in the 0.8 mg/kg group, respectively. ORR was notably consistent across all patient subgroups. As of the data cut-off, the median duration of response (DOR) was not reached.

The study comprised a cohort of patients who previously received T-cell redirection therapy who were notably younger and had increased higher-risk cytogenetics and previously received a median of 6 lines of therapy.

Most of the patient population (70.6%) were previously treated with CAR T-cell therapy, 35.3% received a prior bispecific antibody, and 7.8% were refractory to belantamab (Blenrep). Patients who received prior T-cell redirection achieved an ORR of 62.7%, including an sCR rate of 17.6%, a CR rate of 5.9%, a VGPR rate of 29.4%, and a PR rate of 9.8%. Additionally, the median DOR was 12.7 months.

Lead study author Ajai Chari, MD, director of clinical research in the Multiple Myeloma Program at Mount Sinai Health System in New York, noted how important these findings are.

He explained that for novel treatments within the multiple myeloma space to receive an accelerated FDA approval, data must show response rates between 20% to 30%. But now, he said, these findings show response rates around 70%.

“These are incredible responses, and it was maintained in important subgroups including ISS stage III, high-risk disease, and number of prior therapies,” Chari said during the presentation.

Talquetamab is a first-in-class, off-the-shelf T-cell redirecting bispecific antibody against GPRC5D, a novel antigen target in multiple myeloma.

To be eligible for the study, patients needed to have measurable disease. In the phase 1 portion, patients were required to have progressed or be intolerant to all available therapies. Additionally, they needed to have an ECOG performance status of 0 to 2.

In phase 2 of the MonumenTAL-1 trial, patients needed to have received 3 or more prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 agent. This group of patients also had to have an ECOG performance status of 0 to 2.

The study included patients who were treated with either 0.4 mg/kg (n = 143) of talquetamab or 0.8 mg/kg of study drug (n = 145).

Prior treatment with an anti–B-cell maturation antigen antibody drug-conjugate was allowed, although patients needed to be T-cell redirection therapy naïve. A third cohort was included in which patients could receive either dose level and were allowed to have previously received prior T-cell redirection therapy (n = 51).

The primary end point was to determine the safety and efficacy of the 2 recommended phase 2 doses.

The median patient age in the 0.4 mg/kg and 0.8 mg/kg groups were 67 years. A total of 31.1% of patients in the 0.4 mg/kg cohort and 28.9% had high-risk cytogenetics. Notably 93.0% and 92.4% of patients were previously exposed to an anti-CD38 monoclonal antibody agent and 74.1% and 69.0% were triple-class refractory, respectively.

The investigators also reported that the median progression-free survival was 7.5 months (95% CI, 5.7-9.4) and 11.9 months (95% CI, 8.4-not estimable) in the 0.4 mg/kg and 0.8 mg/kg, respectively.

The most common high-grade hematologic adverse effects (AEs) were cytopenias. In both the 0.4 mg/kg cohort and 0.8 mg/kg cohort, common grade 3/4 AEs were anemia (31.5% and 24.8%), neutropenia (30.8% and 22.1%), lymphopenia (25.9% and 25.5%), and thrombocytopenia (20.3% and 16.6%).

Moreover, infections occurred in 57.3% and 50.3%, respectively, 16.8% and 11.7% of which were high-grade. A total of 13 and 16 patients in each respective arm contracted COVID-19, with 2 patients dying.

The investigators also reported a low rate of discontinuation due to AEs. The majority of cytokine release syndrome (CRS) events were grade 1/2. High-grade skin, nail, and rash toxicities were primarily low.

Dysgeusia was managed via supportive care and occasionally dose reduction. Moreover, 10% to 11% of patients developed immune effector cell–associated neurotoxicity syndrome, the majority of which were grade 1/2.

In the 0.4 mg/kg arm, common any-grade toxicities included CRS (79.0%), skin AEs (55.9%), and nail AEs (51.7%), with high-grade AEs including fatigue (3.5%) and pyrexia (2.8%). Additionally, in the 0.8 mg/kg cohort, any-grade AEs included CRS (72.4%), skin AEs (67.6%), and dysgeusia (46.2%), with high-grade toxicities including rash (5.5%) and dysphagia (2.1%).

Chari concluded the presentation noting that an ongoing phase 3 trial is investigating talquetamab vs FDA-approved therapies.

“The ability to give this drug with other agents is very important,” he said. “So it's being studied in combination with standard backbone myeloma drugs with another bispecific, which would be completely chemotherapy sparing and also with novel immune modulating drugs like checkpoint inhibitors.”

Reference

Chari A, Touzeau C, Schinke C, et al. Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): phase 1/2 results from MonumenTAL-1. Presented at 2022 American Society of Hematology (ASH) Meeting and Exposition; December 10-13, 2022; abstract 157.