Treatment with a subcutaneous formulation of teclistamab, a novel bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3 receptors, was well tolerated and associated with durable responses in patients with relapsed or refractory multiple myeloma (MM), according to findings from a phase I study. These responses continued to deepen over time, the authors, led by Saad Usmani, MD, of the Levine Cancer Institute/Atrium Health in Charlotte, North Carolina, reported.
“The cytokine release syndrome (CRS) and neurotoxicity rates are low with teclistamab, making it feasible to administer as an off-the-shelf option in the community setting if and when this therapy gets a regulatory approval,” Dr. Usmani told ASH Clinical News.
In the study results, published in The Lancet, Dr. Usmani and colleagues wrote that there is an increased need for new treatments for relapsed/refractory MM, with BCMA representing a validated target for this patient population. Teclistamab holds promise, considering the novel agent “binds BCMA and CD3 to redirect T cells to multiple myeloma cells,” the authors wrote.
To further understand teclistamab’s activity in this setting, the researchers examined the safety and efficacy of the therapy in 157 patients with relapsed/refractory MM. Patients had heavily pretreated disease, having received a median of six prior lines of therapy.
Per study protocol, patients received either intravenously administered teclistamab (range = 0.3-19.2 μg/kg once every 2 weeks or 19.2-720 μg/kg once per week; n=84) or subcutaneously administered teclistamab (range = 80-3,000 μg/kg once per week; n=73). Step-up dosing was performed for 38.4 μg/kg or higher treatment doses. “Subcutaneous injection was assessed because it requires shorter administration time, is expected to increase convenience for patients and health-care providers, and might delay CRS due to more gradual absorption,” the authors explained.
In the first part of the study, the investigators sought to establish a recommended phase II dose of teclistamab, while the second part of the study sought to characterize the safety and tolerability of the recommended phase II dose. All patients who received at least one dose of teclistamab were included in the safety analysis. Only response-evaluable patients, or those who received at least one dose and had at least one post-baseline response assessment, were included in the efficacy analysis (n=155).
Two dose-limiting toxicities occurred in the once per week intravenous cohorts (grade 4 delirium at 20.0 μg/kg step-up dose in a patient assigned to the 120 μg/kg cohort and grade 4 thrombocytopenia in the context of CRS and disseminated intravascular coagulation at the 180 μg/kg dose). No dose-limiting toxicities occurred with subcutaneous dosing, the authors reported.
The maximum tolerated dose of teclistamab was not reached, but safety and pharmacokinetic data suggest that the recommended phase II dose of teclistamab was once per week subcutaneously administered at 1,500 μg/kg, following 60 μg/kg and 300 μg/kg step-up doses (median follow-up=6.1 months). A total of 40 study participants received the recommended phase II dose.
No dose-limiting toxicities were observed at the recommended phase II dose in the first part of the study. Among the 40 patients who received the therapy at the phase II dose, the most frequently reported treatment-emergent adverse events were grade 1 or 2 CRS events in 28 patients (70%) and neutropenia in 26 patients (65%). Grade 3 or 4 neutropenia was reported in 16 patients (40%).
In the group of 40 response-evaluable patients treated at the recommended phase II dose, the overall response rate was 65%. Fifty-eight percent of these patients experienced a very good partial response or better and the median duration of response at the phase II dose was not reached during the study.
Of the 26 responding patients, 85% were alive and continuing teclistamab treatment after a median follow-up of 7.1 months. Approximately three-quarters of the 17 responding patients who received the recommended phase II dose who had at least six months of follow-up were also alive and continuing therapy. In pharmacokinetic and pharmacodynamic analysis, teclistamab exposure at the recommended phase II dose was maintained above the target exposure levels. The researchers also reported consistent T-cell activation with the therapy.
According to Dr. Usmani, results from this phase I study provide “evidence that bispecific IgG4 antibodies can redirect T cells to multiple myeloma cells with intermittent subcutaneous dosing and high efficacy.” However, the limitation of the study, according to Dr. Usmani, was the relatively short duration of follow-up, which limited the researchers’ ability to examine long-term safety of the agent. “The other questions to be explored are the optimal combinations and sequencing with other anti-MM therapies in different disease settings, as well as less-frequent scheduling after achieving sustained deep responses,” he said.
The authors reported relationships with Janssen, which funded the study.
Usmani SZ, Garfall AL, van de Donk NWCJ, et al. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet. 2021;398(10301):665-674.