National trends and disparities in AL amyloidosis-related mortality among multiple myeloma patients in the United States: A population-based study (1999–2023)

Abstract Background: Immunoglobulin light chain (AL) amyloidosis is a multisystem disorder resulting from the deposition of misfolded monoclonal light chains produced by clonal plasma cells. Around 10–15% of patients with multiple myeloma (MM) develop coexisting AL amyloidosis, a combination that markedly worsens prognosis due to its impact on vital organs, particularly the heart and kidneys. When MM and AL amyloidosis occur together, overall survival is significantly reduced, often to less than three years in patients with cardiac involvement. Timely diagnosis and coordinated, risk-adapted treatment approaches are essential to improving outcomes in this high-risk population.Methods: Mortality data from CDC WONDER (1999–2023) were analyzed. Deaths describing both MM (ICD-10 C90.0–C90.2) and AL amyloidosis (D76.1–D76.2) were included. Age-adjusted mortality rates (AAMRs; per 100,000) were calculated using the 2000 U.S. standard population. Trends were assessed with Joinpoint regression to calculate the Average Annual Percent Change (AAPC) and 95% confidence intervals (CI). For future projections, ARIMA models with Box-Cox transformation were applied after testing for stationarity using ADF/KPSS tests. Models were validated using residual diagnostics and cross-validation. Subgroup analyses were conducted on the basis of sex, race/ethnicity, U.S. census region, and urbanicity.Results: Between 1999 and 2023, there were 3,519 sepsis-related deaths among individuals with AL amyloidosis and multiple myeloma in the United States. AAMR increased from 3.0 to 3.9 per million, reflecting a 30% rise over the study period (AAPC: +0.85%, 95% CI: +0.50% to +1.20%, p < 0.001). Gender-specific trends revealed a modest AAMR decline in males (25.2 to 24.6 per million; −2.4%), while females experienced a more substantial decline (15.1 to 12.0 per million; −20.5%), with a peak in 2004 followed by a steady downward trajectory. Nevertheless, male mortality remained approximately double that of females in 2023. Racial and ethnic analyses showed that White individuals accounted for the majority of deaths (n=2,874), with AAMR rising from 2.8 to 3.6 per million. Black or African American individuals (n=341) demonstrated a persistently elevated mortality burden, with AAMR increasing from 6.2 in 2013 to 7.2 in 2023. Not Hispanic individuals had 3,349 deaths, with a modest increase in AAMR from 3.1 to 4.0 over the same period. Geographically, the Northeast and Midwest consistently exhibited higher AAMRs, peaking at approximately 4.5 per million in the early 2010s and stabilizing at 3.9 and 3.7 per million, respectively, by 2023. In comparison, the South and West maintained lower rates, ending at 3.3 and 3.1 per million. Urbanization patterns revealed the highest mortality burden in small metro (4.1 per million) and micropolitan areas (3.8 per million), while large central metros had the lowest (3.1 per million). Non-core rural areas maintained elevated mortality (3.9 per million), highlighting disparities in healthcare infrastructure and access. ARIMA forecasting projects a stable trend in sepsis-related mortality among AL amyloidosis patients, with AAMR plateauing at ~3.019 per million in 2026, 2028 and ~3.02 per million in 2030 (95% CI: 2.50–3.46), indicating a persistent but non-worsening burden in the years ahead. Conclusions: Sepsis-related mortality in AL amyloidosis patients has gradually increased over the past two decades, with persistent disparities by gender, race, and geography. Despite improvements in certain subgroups, overall mortality remains elevated, particularly in rural and underserved regions. Projections suggest a stable but ongoing burden, signifying the need for targeted interventions in high-risk populations.