A new validated staging system for AL amyloidosis with Stage IIIC defining ultra-poor risk: AL International Staging System (AL-ISS)

Background Outcomes in systemic AL amyloidosis have improved with modern therapy limiting utility of existing risk stratification models. We validate a new staging system, incorporating longitudinal strain (LS) to the biomarker-based (NT-proBNP and Troponin-T) staging system in the contemporary treatment era (2015-2024). Methods AL International Staging System (AL-ISS) was derived from a cohort of patients with AL amyloidosis from the UK National Amyloidosis Centre (2015-2019). The model was validated in patient cohorts from Europe (Greece, Italy, Netherlands, Switzerland), USA (2015-2024) and UK (2020-2024). Results 2493 patients were included (derivation, n=573; validation n=1920). In a multivariable model for the derivation cohort, LS≥-9% and cardiac biomarkers at previously validated thresholds (NT-proBNP 332 ng/L and 8500 ng/L and hs-TnT>50 ng/L) were independent poor prognostic factors stratifying patients into stages I, II, IIIA, IIIB and IIIC. In the validation cohort, the patient stages were stage I: 317 (17%), II: 782 (41%), IIIA: 551 (29%), IIIB: 174 (9%) and IIIC: 96 (5%), respectively (first-line daratumumab treated: 826; 43%). With a median follow-up of 34 months, median overall survival (OS) was not reached (NR); estimated 1-year, 2-year and 3-year OS was 82%, 74% and 70% respectively. Median survival for stages I-II, IIIA, IIIB and IIIC were NR, 67, 26 and 7 months (1-year OS IIIC 53% v 68% for IIIB in the daratumumab-treated patients), respectively (p<0.001). External validation exhibited good predictive performance: 12-month calibration slope was 1.09, Harrell's C 0.69, Royston’s D 1.19, R 2 D 0.25. Stage IIIC independently discriminated the poorest outcome across all cohorts. Conclusion This defines and validates a new staging system from systemic AL amyloidosis with robust identification of an ultra-poor risk stage (IIIC) in contemporarily treated patients.