Assessing the Efficacy and Safety of Reduced Dexamethasone Duration in Newly Diagnosed AL Amyloidosis Versus Standard Therapy

Introduction
AL amyloidosis is characterized by the deposition of misfolded monoclonal immunoglobulin light chains, leading to significant organ damage. Standard treatment involves multi-drug combinations, including prolonged dexamethasone use to suppress light chain production. However, extended use of corticosteroids is associated with severe adverse effects. This retrospective study evaluates whether reduced dexamethasone exposure in newly diagnosed AL amyloidosis patients can maintain treatment efficacy while minimizing adverse events.

Methods
A retrospective chart review was conducted from January 1, 2017, to January 1, 2023, to identify adult patients with newly diagnosed AL amyloidosis at Cleveland Clinic. Baseline data included patient history, demographics, symptoms at diagnosis, markers of organ involvement (NT-proBNP, 24-hour urine protein, alkaline phosphatase), and monoclonal studies, including serum and urine protein electrophoresis and immunofixation. Treatment data included the regimen used, as well as dexamethasone dose and duration. Patients were categorized into quartiles based on their dexamethasone treatment duration: <4.0 months, 4.0-5.4 months, 5.5-13.4 months, and ≥13.5 months. The dexamethasone dosing ranged from 4 to 50 mg per week. Total dexamethasone dose was also recorded and categorized into 34-280 mg, 281-479 mg, 480-1156 mg, and 1157-7634 mg. Hematologic and organ responses were assessed at 6, 12, 18, and 24 months following treatment initiation, according to International Society of Amyloidosis (ISA) criteria. Statistical analyses employed Chi-Square and Fisher’s Exact tests to compare hematologic and organ response rates across the dexamethasone exposure quartiles. Logistic regression was used to determine the impact of dexamethasone duration and total dose on these outcomes. The primary endpoint compared response rates within these quartiles, focusing on early dexamethasone discontinuation (<6 months) versus prolonged exposure (≥6 months). The secondary endpoint involved evaluation of steroid-induced complications.

Results
Patients were divided based on dexamethasone exposure into four quartiles: <4.0 months (n=56), 4.0-5.4 months (n=52), 5.5-13.4 months (n=54), and ≥13.5 months (n=54). The total dexamethasone doses in these quartiles were as follows: <4.0 months (34-280 mg), 4.0-5.4 months (281-479 mg), 5.5-13.4 months (480-1156 mg), and ≥13.5 months (1157-7634 mg). There were no statistically significant differences in hematologic or organ responses across the quartiles at 24 months. Specifically, the complete response (CR) rates at 24 months were 56.0%, 50.0%, 50.0%, and 55.6% across the respective quartiles (p=0.87). Similarly, the rates for combined CR and very good partial response (VGPR) were 78.0%, 83.3%, 83.3%, and 83.3% (p=0.86). Detailed analysis revealed that patients with 4.0-5.4 months of dexamethasone treatment showed optimal outcomes with significantly lower toxicities. This quartile experienced the lowest rates of hospitalizations (48.1%) and heart failure exacerbations (16.7%), significantly fewer than the subsequent quartiles: 5.5-13.4 months (70.4% hospitalizations, 38.9% exacerbations) and ≥13.5 months (75.5% hospitalizations, 44.4% exacerbations) (p=0.005 for hospitalizations, p=0.009 for exacerbations). Early discontinuation of dexamethasone (<6 months) resulted in significantly lower adverse event rates compared to prolonged treatment (≥6 months): hospitalizations at 62.3% vs. 75.5% (p=0.041), heart failure exacerbations at 27.4% vs. 41.4% (p=0.029), and increased diuretic usage at 62.4% vs. 82.8% (p<0.001). Analysis of total dexamethasone doses demonstrated that lower total doses (34-280 mg) were associated with fewer adverse events compared to higher doses (1157-7634 mg), while maintaining similar overall efficacy.

Conclusions
Our analysis supports reduced dexamethasone exposure for newly diagnosed AL amyloidosis, with an optimal duration of 4.0-5.4 months and a total dose of 281-479 mg. This approach achieved favorable response rates while significantly reducing the incidence of severe adverse events. As the data matures, future analyses will focus on survival outcomes, such as progression-free survival (PFS) and relapse rates following initial treatment, to demonstrate improved outcomes with early discontinuation of dexamethasone.