Teclistamab in Relapsed or Refractory Multiple Myeloma

Abstract

Background: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma.

Methods: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better).

Results: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2).

Conclusions: Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).

Figure 1.. Response to Teclistamab in Patients with Relapsed or Refractory Multiple Myeloma.

Panel A shows the rates of stringent complete response, complete response (CR), very good partial response (VGPR), and partial response in 165 patients who were treated with teclistamab. A stringent complete response was defined as a complete response with a normal serum free light-chain ratio and an absence of clonal plasma cells on immunohistochemical analysis or negative two-color to four-color flow cytometry. Differences in percentage totals are due to rounding. Responses were assessed by an independent review committee with a cutoff date of March 16, 2022. Panel B shows responses over time in the 104 patients who had an overall response (partial response or better) among the 165 patients treated at the recommended phase 2 dose.

Figure 2.. Kaplan–Meier Analysis of Response Duration and of Progression-free and Overall Survival.

Panel A shows the duration of response to teclistamab therapy in the 104 patients who had an overall response (partial response or better) among the 165 patients who received the recommended phase 2 weekly dose of 1.5 mg per kilogram of body weight. Panel B shows progression-free survival in the overall population. Disease progression was assessed by an independent review committee on the basis of the criteria of the International Myeloma Working Group. Panel C shows overall survival among the 165 patients. Tick marks indicate censored data. NE denotes not estimable.

Figure 3.. Changes in Levels of Soluble B-Cell Maturation Antigen (BCMA) after Teclistamab Therapy, According to Tumor Response.

Serum levels of soluble BCMA were assessed as a potential marker of tumor burden and response. As expected, reductions in soluble BCMA levels were greater in patients with a better response than in those with a poor response. Shown is the percent change from baseline in serum soluble BCMA levels on day 1 of cycle 4 according to the best response in 81 patients with plasma samples that could be evaluated as of August 9, 2021 (data-cutoff date for pharmacokinetic analyses). The median percent change in soluble BCMA levels was a reduction of 82% in 27 patients with a stringent complete response (sCR), a reduction of 87% in the 8 patients with a complete response (CR), a reduction of 90% in 34 patients with a very good partial response (VGPR), an increase of 175% among the 3 patients with a partial response (PR), an increase of 381% in the 1 patient with a minimal response (MR), an increase of 522% in the 6 patients with stable disease (SD), and an increase of 1437% in the 2 patients with progressive disease (PD). The boxes represent interquartile ranges, the horizontal line in each box represents the median, and the whiskers show the minimum and maximum values after the exclusion of outliers (circles) that were more than 1.5 times the values represented at each end of the box.