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

Summary

AL-ISS integrates longitudinal strain with NT-proBNP and troponin-T to stratify AL amyloidosis across five stages and robustly identifies an ultra-poor risk Stage IIIC with median survival of 7 months, validated across international cohorts in the modern treatment era.

Key Findings

• AL-ISS combines LS with NT-proBNP and hs-TnT to define stages I, II, IIIA, IIIB, and IIIC.
• In 2,493 patients, Stage IIIC had median survival of 7 months; IIIA 67 months; IIIB 26 months; I–II not reached.
• External validation showed good performance (12-month calibration slope 1.09; Harrell’s C 0.69).
• The ultra-poor risk IIIC stage remained prognostically adverse even among first-line daratumumab-treated patients (1-year OS 53% vs 68% for IIIB).

Clinical Implications

Incorporate LS into routine staging; identify Stage IIIC to prioritize aggressive therapy, referral to specialized centers, and consideration for novel/clinical trial regimens even in the daratumumab era.

Limitations

• Observational design; strain measurement variability across centers possible
• Moderate discrimination (Harrell’s C 0.69); treatment heterogeneity may confound outcomes

Future Directions

Prospective validation of AL-ISS-guided treatment algorithms, standardization of LS acquisition, and integration with genomic markers to refine risk and personalize therapy.