Evaluating AL-ISS within a BNP-based model for AL amyloidosis in the daratumumab era

Survival in AL (light chain) amyloidosis is strongly influenced by the severity of cardiac involvement. The recently proposed AL International Staging System (AL-ISS) incorporates echocardiographic global longitudinal strain (GLS) to subdivide biomarker-defined stage IIIb disease into stages IIIb and IIIc; however, its prognostic relevance in the daratumumab era remains uncertain. We evaluated the AL-ISS GLS cutoff of 9% in 53 patients with newly diagnosed stage IIIb AL amyloidosis. Patients classified as proposed stage IIIc (GLS, 0%-9%) had higher baseline difference between involved and uninvolved free light chains (dFLC; 300 vs 167 mg/L; P = .08), similar left ventricular wall thickness (14.5 vs 15.0 mm; P = .57), and lower left ventricular ejection fraction (LVEF; 45% vs 55%; P = .02) compared with those with GLS >9%. GLS correlated moderately with LVEF (ρ = 0.47; P< .001). On multivariate analysis, LVEF <50% (hazard ratio [HR], 3.18; P = .006) and dFLC ≥180 mg/L (HR, 3.26; P = .003) independently predicted overall survival, whereas GLS did not. Median overall survival was longer in proposed stage IIIc disease (31 vs 13 months), reflecting greater use of daratumumab-based therapy (82% vs 25%). Among daratumumab-treated patients, survival did not differ by GLS category. These findings suggest limitations of GLS-based substaging in advanced cardiac AL amyloidosis in the daratumumab era.