Teclistamab Triplet Shows Manageable Safety, Early Efficacy in Transplant-Ineligible Myeloma

Teclistamab (Tecvayli) plus daratumumab (Darzalex) and lenalidomide (Revlimid) had a manageable safety profile and showcased early efficacy signals in patients with transplant-ineligible, newly diagnosed multiple myeloma, according to data from the safety run-in cohort 1 of the phase 3 MajesTEC-7 trial (NCT05552222).

The findings, which were presented at the 2024 ASCO Annual Meeting, demonstrated that as of March 18, 2024, 26 patients with newly diagnosed multiple myeloma had received teclistamab plus daratumumab and lenalidomide for a median of 15 cycles (range, 2-17). Also, since this date, 23 patients (88.5%) remained on treatment. Follow-up was conducted for a median of 13.8 months (range, 2-15.4). The median relative dose intensity was 97.0% for teclistamab, 95.8% for daratumumab, and 58.6% for lenalidomide; 17 patients had their dose of lenalidomide reduced.

At baseline, patients had a median age of 72.5 years (range, 66-84), with 80.8% of patients aged 70 years and older. In addition, 15.4% of patients had at least 1 soft-tissue plasmacytoma, and 11.5% of patients had an ECOG performance score of 2. Of note, 84.6% of patients were ineligible for transplant.

All patients in the study experienced treatment-emergent adverse events, of whom 24 patients (92.3%) had grade 3 or 4 adverse events. Infections were reported in all 26 patients, with 8 patients (30.8%) experiencing infections considered grade 3 or 4. Most of the grade 3/4 infections were COVID-19 (n = 3; 11.5%). One patient died from a treatment-emergent adverse event in cycle 3, specifically pneumonia influenza. Most patients—80.8% (n = 21)— had hypogammaglobulinemia, and 19 patients (73.1%) received at least 1 dose of intravenous immunoglobulin.

“Most of these [infection] events occurred during the first 3 cycles, so very early,” Salomon Manier, MD, PhD, associate professor of hematology at Lille University Hospital in France, explained during the presentation. “We can see that the cumulative exposure to [teclistamab plus daratumumab and lenalidomide] over time did not increase the incidence of grade 3/4 infections [much[. So this emphasized the need for [intravenous immunoglobulin] supplementation and infection prophylaxis that should be initiated early to prevent, as much as possible, the early risk of infections. And, of course, it should be maintained throughout the treatments.”

Cytokine release syndrome (CRS) was observed in 16 patients (61.5%), which occurred mostly in cycle 1 and all cases resolved. Grade 1 CRS occurred in 57.7% of patients, and grade 2 was observed in 3.8% of patients. One patient experienced grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) during cycle 1.

Patients treated with teclistamab plus daratumumab and lenalidomide had an overall response rate of 92.3%. Patients with complete responses to treatment or better accounted for 80.8% of patients, and very good partial responses or better occurred in 92.3% of patients. Manier noted that no disease progressions occurred in cohort 1 of this study.

The median time to first response to treatment was 1.0 month (range, 0.9-4.6), and the median time to best response was 6.5 months (range, 1.0-12.1).

During follow-up, 1 progression-free survival event has occurred. The estimated 12-month duration of response and progression-free survival was 100% and 96.2%, respectively.

Methods

Patients included in the MajesTEC-7 trial were aged 18 years and older with newly diagnosed multiple myeloma who were either ineligible or not intended for autologous stem cell transplant as an initial treatment. Also, patients had measurable disease and an ECOG performance status score of 0 to 2.

Patients in the safety run-in of this trial, which was performed to established safety prior to enrolling the randomized study, received teclistamab as a step-up dose in cycle 1; every week for cycle 2; once every 2 weeks for cycles 3 through 6; and every 4 weeks for cycle 7 and beyond. These patients also received standard-of-care daratumumab and lenalidomide. All therapies were given until unacceptable toxicity, progression, or death.

Responses were assessed based on the International Myeloma Working Group criteria. Adverse events were graded by Common Terminology Criteria for Adverse Events v. 5.0, and American Society for Transplantation and Cellular Therapy criteria were used to assess ICANS and CRS. Prophylactic immunoglobulin replacement was higher recommended in this trial.

Other Safety Run-In Cohorts in MajesTEC-7

Manier also noted the 2 other safety run-in cohorts that are included in this part of the trial. In particular, cohort 2 consisted of teclistamab plus darolutamide and lenalidomide, in addition to a daratumumab, lenalidomide, and dexamethasone lead-in. Cohort 3 also included a lead-in with daratumumab, lenalidomide, and dexamethasone, but instead of teclistamab, patients would receive talquetamab (Talvey). These 2 cohorts have a shorter follow-up (3.7 months and 3.5 months, respectively) than the first cohort for which data were presented at the meeting, Manier said.

He added that in cohorts 2 and 3, with the daratumumab, lenalidomide, and dexamethasone lead-in strategy, there was an increased incidence of neutropenia and grade 3 CRS events. There was also an increased risk for serious/fatal infections in cohort 2.

“So the hypothesis is that the administration of lenalidomide prior to and during the bispecific step-up schedule may have increased the T-cell fitness and the T-cell activation and bone marrow suppression,” Manier said. “We didn't observe this in the cohort 1 of the safety run-in with the bispecific step-up schedule prior to the first dose of lenalidomide, so the [daratumumab, lenalidomide, and dexamethasone] lead-in strategy will not be adopted for the randomized phase of the study.”

Manier concluded that MajesTEC-7 randomization is proceeding with lenalidomide initiated in cycle 2, as informed by the safety run-in cohorts.

Reference

Touzeau C, Beksac M, Terpos E, et al. Safety results from the phase 3 MajesTEC-7 study in patients (pts) with transplant ineligible/not intended newly diagnosed multiple myeloma (NDMM). J Clin Oncol. 2024;42(suppl 16):7506. doi:10.1200/JCO.2024.42.16_suppl.7506