Current threshold of measurable disease in AL amyloidosis clinical trials.

Abstract

7547 Background: Eligibility for clinical trials in AL amyloidosis requires measurable disease to ensure that the hematologic response can be adequately assessed, usually set at 5mg/dL. However, there are validated response criteria in low burden disease (dFLC 2-5mg/dL) that correlate with clinical outcomes in the upfront setting (Milani, 2017). Despite validated criteria in low burden disease, most trials maintain a dFLC of 5mg/dL as measurable disease. Shorter survival is seen in patients with high-risk dFLC progression, defined as dFLC >2mg/dL, >20% of baseline value and >50% increase from nadir (Palladini, 2018). Patients with organ progression also have poor outcomes. We examined patients who were excluded from clinical trials to determine if the current measurable disease criteria adequately capture patients who require salvage therapy. Methods: We reviewed patients screened for three clinical trials enrolling patients with relapsed/refractory AL amyloidosis: phase I/II trial of carfilzomib (NCT01789242), phase III trial of ixazomib/dexamethasone versus physician’s choice (NCT01659658) and phase I trial of etentamig (NCT06158854) to identify patients who failed screening. All clinical trials required measurable disease, defined as dFLC at least 5mg/dL. High-risk dFLC progression (Palladini, 2018) and organ progression (Palladini, 2012/2014) were evaluated at the time of screen failure. Results: Among 47 patients screened, 14 (30%) were enrolled: 7 for carfilzomib, 6 on the ixazomib trial, 1 for etentamig (Figure 1). Of 33 excluded patients, 18 (54%) were due to dFLC < 5mg/dL. Among 18 patients excluded due to insufficient dFLC at the time of screening, 6 met criteria for organ progression (cardiac (n=4), renal (n=2)), 6 had high-risk dFLC progression (as defined in background) and 2 had both (Table 1), indicating 10 patients were at high risk of poor outcomes. Four patients were lost to follow-up within 6 months of screening. In the remaining 14 patients, 5 received alternative commercially available therapy within 6 months of screening, 5 enrolled in trials with lower dFLC eligibility, and 1 progressed to dFLC > 5, was rescreened and enrolled on the carfilzomib trial. Among the other 3 patients, none achieved a dFLC of 5mg/dL: 1 died within 12 months, 1 was treated after 12 months and one remains off treatment at 8 months. Conclusions: Two thirds of patients with AL amyloidosis failed screening with >50% due to dFLC<5mg/dL. Among those with dFLC<5mg/dL, the majority met criteria for high-risk dFLC progression or organ progression and were treated within 6 months. The current dFLC threshold for measurable disease excludes AL amyloidosis patients requiring therapy from clinical trials and results in trial patients not being representative of real-world practice. In the era of highly effective T cell redirecting therapies, we advocate a lower dFLC inclusion (>2mg/dL) to enable participation of patients with low-burden disease.