Predicting Early Mortality in Newly Diagnosed <scp>AL</scp> Amyloidosis: Development and Validation of the <scp>PACE</scp> Score for Daratumumab‐Treated Patients

Systemic AL amyloidosis is a clonal plasma cell dyscrasia, where toxic free light chains (FLCs) lead to vital organ damage, with risk of early mortality despite effective therapies. Notably, there is a paucity of data on the incidence and predictors of early mortality in the daratumumab (Dara) era. We conducted a multi-center retrospective cohort study to develop and validate a risk-prediction model for early mortality (all-cause death within 6 months) in patients treated with Dara-based frontline regimens. We used univariate analysis to identify covariates for a logistic regression model predictive of 6-month mortality and generated a clinical risk score. Among 339 patients across eight centers, 36 (10.6%) experienced early mortality. Multivariate analysis identified four independent predictors: NT-proBNP > 5300 pg/mL (odds ratio [OR] 3.83, p = 0.006), Age > 75 years (OR 2.96, p = 0.073), absence of t(11;14) on Cytogenetics (OR 3.0, p = 0.022), and ECOG performance status (OR 1.72 per unit increase, p = 0.044). The resulting PACE score stratified patients into three risk groups with a 6-month mortality of 1.2% (low-risk), 11.7% (intermediate-risk), and 50.0% (high-risk). The PACE score demonstrated superior discrimination (C-index 0.78) for early mortality compared to Mayo 2004 (0.69) and Mayo 2012 (0.55) staging systems. External validation confirmed robust discrimination (C-index 0.73) with corresponding 6-month mortality rates of 4.2%, 15.25%, and 37.04% across respective risk groups. The PACE score provides a clinically applicable tool for early mortality risk stratification in AL amyloidosis patients receiving Dara-based therapy, and will enable improved patient counseling, clinical trial design, and identification of ultra-high-risk patients requiring intensive monitoring and novel therapies.