Prognostic factors and progression biomarkers in AL amyloidosis: mapping current knowledge and critical gaps

ABSTRACT: The therapeutic landscape for systemic immunoglobulin light chain (AL) amyloidosis has been revolutionized by daratumumab-based regimens, achieving 76% 5-year overall survival in the landmark ANDROMEDA trial. However, the current prognostic models were developed using patient populations treated with now-suboptimal therapies, creating a critical gap between risk stratification models and contemporary outcomes. This comprehensive review analyzes prognostic factors and progression biomarkers in AL, categorizing them into disease-specific (clone-related and organ-related) and patient-specific factors. Notably, traditional baseline biomarkers including difference between involved and uninvolved free light chains and bone marrow plasma cell burden are losing prognostic significance with effective clone-directed therapies. Emerging approaches show promise, including dynamic markers such as minimal residual disease by free light chain mass spectrometry, cardiac imaging parameters such as global longitudinal strain, and functional measures. There is an urgent need for validation studies and prognostic model refinement to identify patients at high risk who may benefit from interventions beyond anti-plasma cell therapy.