Abstract
Background: Systemic light chain (AL) Amyloidosis is a rare plasma cell dyscrasia with an estimated global incidence of 10–15 cases per million annually. The true burden is likely underrecognized in low- and middle-income countries (LMICs), where diagnostic delays are common due to nonspecific symptoms, limited access to confirmatory testing (e.g., mass spectrometry), and substantial treatment costs. In India, these challenges contribute to diagnostic inertia and underutilization of effective therapies, resulting in late-stage presentation and poorer outcomes.
Daratumumab, a CD38-directed monoclonal antibody, has demonstrated high efficacy in newly diagnosed AL Amyloidosis when combined with Bortezomib, Cyclophosphamide, and Dexamethasone (Dara-VCD), as shown in the ANDROMEDA trial. However, cost constraints and lack of insurance coverage often preclude its full-dose use in LMICs, prompting dose-modified regimens or continued reliance on VCD alone. Real-world data from such adaptations remain scarce.
Methods: This ambispective, single-center cohort study was conducted at a Multidisciplinary Amyloidosis program in South India between September 2023 and June 2025. Of 92 patients screened, 42 newly diagnosed AL Amyloidosis patients with measurable hematologic disease were included. Measurable disease was defined as a difference between involved and uninvolved serum free light chains (dFLC) ≥50 mg/L, aligning with ANDROMEDA trial criteria.
Patients were categorized based on frontline therapy into:
VCD alone (n=22)
Dara-VCD (n=20), which included:
a) Full-dose Dara-VCD per ANDROMEDA protocol (n=8)
b) Modified-dose Dara-VCD (n=12), with a median daratumumab dose of 650 mg (range 400–1800 mg) over a median 4 weeks (range 1–12 weeks).
Baseline staging used the Mayo 2012 criteria. Hematologic responses (CR, VGPR, PR) were assessed at 2 and 6 months per consensus criteria. Cardiac and renal responses were evaluated at 6 months. Group comparisons were performed using Chi-square tests; survival estimates used Kaplan-Meier curves.
Results: Median age was 60 years in the Dara-VCD group and 65 in the VCD group. Male:female ratio was 60:40 and 77:23, respectively. Over 90% of patients in both groups were Mayo stage III or IV at presentation.
At 2 months, ≥VGPR was observed in 55% of Dara-VCD patients versus 18% in the VCD group (p = 0.01). Within the Dara-VCD group, CR was achieved in 50% (4/8) on full-dose and 25% (3/12) on modified-dose regimens. At 6 months, ≥VGPR was achieved in 60% of Dara-VCD versus 31% in VCD (p < 0.001). Among full-dose patients, CR was achieved in 5 (62.5%), while 8 (66%) in the modified-dose group achieved CR.
Notably, there was no statistically significant difference in hematologic response rates between full-dose and reduced-dose Daratumumab cohorts, suggesting that lower dose regimens may retain substantial efficacy and could be clinically meaningful in constrained settings.
In a subset analysis of the Dara-VCD group, median dFLC declined from 366 mg/L to 11 mg/L in the full-dose group and from 375 mg/L to 70 mg/L in the modified-dose group by week 3, reflecting early hematologic responses in both groups.
Cardiac response at 6 months was higher in the Dara-VCD group (55%) compared to VCD (27%). In the Dara group, PR was seen in 50% of full-dose and 41% of modified-dose recipients, with VGPR seen in 16% of the latter. Renal response rates were comparable between groups. Cardiac progression occurred in 9 (21%) patients—6 in the VCD group and 3 in Dara-VCD.
Nine patients (21%) died during follow-up: 7 from the VCD group and 2 from Dara-VCD. All were Mayo stage IV. Causes included sudden cardiac death (55%) and sepsis with multiorgan dysfunction (45%). Notably, mortality was lower in the Daratumumab cohort despite higher baseline risk.
Conclusion: In this real-world cohort from a resource-limited setting, daratumumab-based regimens significantly improved hematologic and cardiac responses in newly diagnosed AL Amyloidosis. Importantly, modified-dose Daratumumab showed comparable efficacy to full-dose regimens, offering a pragmatic option in cost-constrained environments. These findings support broader access to Daratumumab and underscore the feasibility of dose-adapted strategies in LMICs, especially in advanced-stage disease where outcomes remain suboptimal. Larger prospective studies are warranted to validate these observations and guide policy-level resource allocation.
