Two Decades of Light-Chain Amyloidosis: Real-World Trends in Diagnosis, Treatment, and Survival

Abstract

Background: Systemic light-chain (AL) amyloidosis is a life-threatening disorder with historically poor outcomes. Daratumumab is a newer treatment for AL amyloidosis, but real-world trends in diagnosis, treatment, and survival are not well characterized.

Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, identifying adults with AL amyloidosis from 2006 to 2025. To improve specificity, patients with concurrent multiple myeloma, and other common amyloidosis subtypes were excluded. Survival analyses were stratified by Boston University cardiac stages. Propensity score matching balanced demographics and comorbidities.

Results: We included 43,878 patients. Survival was improved in 2016–2025 vs. 2006–2015 (hazards ratio (HR) = 0.75; 95% confidence interval (CI), 0.68–0.83). Stage II patients showed the most pronounced gains (1-year HR = 0.66, P = 0.020; 10-year HR = 0.77, P = 0.022; median overall survival (OS), 2,009 vs. 1,517 days). Stage IIIa/IIIb showed no decade-level improvement. In the daratumumab era (2021–2025 vs. 2016–2020), stage I demonstrated markedly superior 5-year survival (HR = 0.59; log-rank P = 0.001; median OS, 1,549 vs. 965 days), and stage IIIb showed 51% lower 5-year mortality (odds ratio (OR), 0.49; P = 0.043). Direct comparison of Dara-CyBorD vs. CyBorD (n = 59 matched pairs) confirmed superior survival (3-year HR = 0.33; log-rank P < 0.0001; median OS not reached vs. 694 days). Sensitivity analyses using unstaged patients and AL-specific International Classification of Diseases, 10th Revision (ICD-10) codes yielded consistent results.

Conclusions: Real-world outcomes in AL amyloidosis improved across two decades, with declining mortality and therapeutic shifts following daratumumab adoption. Most improvements occurred post-2021, underscoring CD38-targeted therapy’s transformative impact.