Background: Systemic amyloidosis is a rare, underdiagnosed, often fatal disorder with historically poor prognosis. Over the past two decades, diagnostic tools and therapeutic options have evolved substantially. In particular, anti-CD38 monoclonal antibodies such as daratumumab have demonstrated efficacy in prospective trials. However, real-world longitudinal outcomes and treatment trends across decades remain poorly characterized.

Methods: We conducted a retrospective cohort study using TriNetX. Adults diagnosed with systemic amyloidosis between 2005–2015 and 2015–2025 were included or assessed. Patients were 1:1 propensity score matched based on age, sex, race, and comorbidities. Primary outcomes included all-cause mortality (assessed via odds ratio), overall survival (Kaplan-Meier with log-rank test and hazard ratios), and use of daratumumab. Subgroup analyses were stratified by the Boston University stages.

Results: A total of 104,025 patients with systemic amyloidosis were identified, with a sharp increase in diagnoses in the recent decade (88,646 in 2015–2025 vs. 15,379 in 2005–2015), suggesting enhanced disease recognition. In the matched cohort (n = 3,380), mortality was significantly lower in the recent decade (OR 0.849, 95% CI 0.770–0.936), Kaplan-Meier all-time survival analysis showed greater median survival in the last decade, 2,822 vs. 2,998 days, although did not reach statistical significance (log-rank p = 0.059; hazard ratio 0.930, 95% CI 0.862–1.003).

Use of daratumumab increased more than threefold in the modern cohort (PR 3.063, 95% CI 2.060–4.556, p < 0.0001). Most patients in both cohorts were classified as Stage I (80% in 2005–2015 vs. 76% in 2015–2025), followed by Stage II (10% vs. 16%), Stage IIIa (5% vs. 4%), and Stage IIIb (5% vs. 3%). Among Stage I patients, mortality trended lower in the more recent cohort (OR 0.888, 95% CI 0.789–1.000, p = 0.051), with significantly higher daratumumab use (OR 2.256, 95% CI 1.360–3.743, p = 0.001).

In combined Stage II and III patients, all-time mortality was significantly lower in the 2015–2025 cohort (OR 0.687, 95% CI 0.575–0.820, p < 0.0001). Overall survival was also greater in that group, with median survival of 1,514 vs. 1,193 days (log-rank p = 0.018). Both 1-year (HR 0.776, 95% CI 0.651–0.925, logrank= 0.005) and 3-year (HR 0.832, 95% CI 0.724–0.955, logrank = 0.009) survival were significantly better, although median survival was not reached. Daratumumab use was also higher in this group (OR 2.041, 95% CI 1.133–3.678, p = 0.015), though it was not independently associated with significant improvements in 1- or 3-year overall survival when analyzed alone.

Conclusions: In this large real-world study, systemic amyloidosis diagnoses increased substantially over the past two decades, likely reflecting earlier detection and greater disease recognition. Mortality declined significantly, with the most pronounced improvements observed among patients with advanced-stage disease (Stages II and III). This improvement in prognosis may be attributed in part to the introduction of novel therapies, including daratumumab, which became available in the past decade, as well to earlier diagnosis. While ongoing investigation into emerging therapies remains essential, these findings suggest meaningful progress in the treatment landscape of systemic amyloidosis and offer promise for continued improvement in patient outcomes.

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2025
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