Impact-AL: A phase 2 clinical trial of teclistamab and daratumumab in previously untreated AL amyloidosis

Abstract Background and Significance: Systemic immunoglobulin light chain (AL) amyloidosis remains a challenging disease, with current frontline regimens failing to achieve optimal outcomes in many patients. Despite advances with daratumumab plus bortezomib-cyclophosphamide-dexamethasone (Dara-VCd) initial therapy, nearly half of the patients do not achieve hematologic complete response (heme-CR) by 6 months, highlighting the need for additional effective therapy. Furthermore, bortezomib- and steroid-associated adverse effects, including neuropathy, hypotension, edema, and congestive heart failure, are particularly relevant in AL amyloidosis, further highlighting the urgent need for better tolerated therapies. The TRIMM-2 phase 1b trial in relapsed/refractory multiple myeloma demonstrated that teclistamab weight-based dosing plus daratumumab therapy achieved promising efficacy in a heavily pre-treated population with a manageable safety profile (no dose-limiting toxicity and ~28% grade ≥3 infection risk at latest follow-up). This positions a fixed-duration teclistamab-daratumumab combination as an ideal regimen for newly diagnosed AL amyloidosis-potentially offering the possibility of deep responses while eliminating bortezomib and steroid-associated toxicities. We therefore propose a single-arm open-label multicenter phase 2 trial evaluating teclistamab-daratumumab combination in newly diagnosed AL amyloidosis. Study Design and Methods: The phase 2 trial will enroll patients with previously untreated Mayo 2004 stage I-IIIa AL amyloidosis involving at least one organ. The study will be conducted across 3 sites in the United States-Columbia University Irving Medical Center (NY), Boston Medical Center (MA), and Medical College of Wisconsin (WI). Key inclusion criteria are presence of measurable hematologic disease (defined as difference between involved and uninvolved free light chain dFLC ≥50 mg/L or serum M-protein ≥0. 5 g/dL), ECOG performance status of 0-2, and estimated glomerular filtration rate ≥20 mL/min/1. 73 m2 by CKD-EPI. Principal exclusion criteria are NT-proBNP 8500 pg/mL, New York Heart Association IIIb or IV functional class, planned auto-transplant within 6 months, and concomitant multiple myeloma (except for an isolated involved/uninvolved serum FLC ratio100). Patients will receive subcutaneous teclistamab and daratumumab-hyaluronidase for six 28-day cycles. Teclistamab will follow the approved step-up dosing schedule, followed by treatment dosing. Daratumumab will be administered as per standard dosing. Beginning cycle 2, dexamethasone may be omitted per investigator discretion. The primary endpoint is hematologic complete response (heme-CR) rate at 6 months, with the study powered to detect an improvement from the historical 55% rate with standard therapy to 80% with teclistamab-daratumumab combination. Using Simon's optimal two-stage design with 80% power and two-sided alpha of 0. 1, we will reject the null hypothesis if ≥15 out of 21 patients achieve heme-CR. Accounting for potential 16% attrition due to loss to follow-up, death during screening period, or non-evaluability, 25 patients will be enrolled. Key secondary endpoints include rate of minimal residual (MRD) negativity rate assessed by serum free light chain mass spectrometry and bone marrow multiparametric flow cytometry (sensitivity 10^-5), safety outcomes encompassing all-grade and grade ≥3 cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and incidence of infections. Clinical efficacy will be further evaluated through rate and depth of organ response in heart, liver, and kidneys, major organ deterioration-progression free survival (MOD-PFS), and overall survival. Exploratory analysis will assess patient-reported outcomes using AL-PROfile and SF36v2. 0 instruments, alongside comprehensive immune profiling during treatment and at post-treatment follow-up to elucidate immune reconstitution patterns following fixed-duration teclistamab-daratumumab. The research is supported through the SU2C Catalyst program with funding provided by Johson & Johnson Innovative Medicine.