TeclistAMY (EMN40): A Phase 2 trial of teclistamab in patients with previously treated light-chain (AL) amyloidosis

Abstract

Abstract Background: Systemic AL amyloidosis is a rare disorder characterized by the deposition of misfolded monoclonal immunoglobulin light chains as insoluble amyloid fibrils in various tissues and organs, leading to serious and life-threatening organ dysfunction. Treatment is mostly directed against plasma cells (PCs) and focuses on stopping the production of the amyloid-forming light chains, with a goal of achieving fast and deep hematologic responses and thus preventing further organ damage. Daratumumab, a human IgGk monoclonal antibody targeting CD38, in combination with bortezomib, cyclophosphamide, and dexamethasone, is the first and only regimen indicated both in the United States and Europe for the treatment of newly diagnosed AL amyloidosis and has demonstrated high rates of hematologic and organ responses. However, some patients become refractory to initial therapy and most patients will ultimately relapse. Unfortunately, there is no currently approved treatment regimen for patients with relapsed or refractory disease. Teclistamab (Tec) is a first-in-class B-cell maturation antigen (BCMA) x CD3 bispecific antibody that has demonstrated deep and durable responses in multiple myeloma (MM), leading to its approval for triple-class exposed relapsed/refractory MM. BCMA is widely expressed on both MM and amyloid PCs; in vivo data confirm that soluble BCMA levels positively correlate with involved free light chain levels in patients with AL amyloidosis [Godara A, et al. Blood. 2019;134(Suppl 1):4409]. Moreover, the results from 2 recent retrospective case series suggest that Tec may induce rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis with no unexpected adverse events [Forgeard N, et al. Blood. 2024;143(8):734-737; Stalker M, et al. Blood. 2023;142(Suppl 1):2035], justifying prospective clinical trials with Tec in AL amyloidosis. The ongoing phase 2 TeclistAMY (EMN40) trial is evaluating the efficacy and safety of Tec monotherapy in patients with previously treated AL amyloidosis. Study Design and Methods: This ongoing international, multicenter, open-label, single-arm phase 2 study will enroll approximately 30 patients aged ≥18 years with histologic diagnosis of systemic AL amyloidosis (affecting ≥1 organ), an Eastern Cooperative Oncology Group performance status of 0-2, Mayo stage I-IIIA cardiac disease at screening, measurable hematologic disease, a creatinine clearance of ≥20 mL/min, and absence of symptomatic MM. Patients must have received ≥1 line of treatment (including daratumumab and bortezomib), and have a wash-out period of ≥14 days from date of last administration of any previous antitumor therapy or investigational treatment for AL amyloidosis. Following initial step-up dosing in Cycle 1, Tec will be administered at a dose of 1.5 mg/kg on Days 8 and 15 of Cycle 1; from Cycle 2 onwards, Tec will be administered every 4 weeks at a dose of 3 mg/kg. All patients will undergo six 28-day cycles of treatment. Patients may continue to receive treatment for a maximum of 12 cycles if clinically indicated and upon discussion between the investigator and the sponsor. A safety analysis will be performed by an Independent Data Monitoring Committee after 6 patients have completed ≥1 cycle of treatment; if no safety signals are observed, the trial will continue as planned. The primary endpoint is hematologic complete response rate after 3 cycles. Secondary endpoints include hematologic overall response rate, very good partial response or better, duration and time to hematologic response, rate and depth of organ response, hematologic progression-free survival, major organ deterioration–progression-free survival, major organ deterioration–event-free survival, time to subsequent therapy, overall survival, safety/tolerability, minimal residual disease after 3 cycles of therapy, and quality of life. Continuous and categorical variables will be summarized using descriptive statistics; time-to-event variables will be evaluated using the Kaplan–Meier method. The study is being conducted at 10 sites across 6 countries, and the first patient was enrolled in July, 2025. The ClinicalTrials.gov identifier is NCT06649695.