Raymond Comenzo, MD – Director, Transfusion Services, Tufts Medical Center; Director, John C. Davis Myeloma and Amyloid Program, Tufts Medical Center; Professor, Tufts University School of Medicine discusses the ASH 2020 abstract – Full results from the pivotal Phase 3 ANDROMEDA study, illustrating the promise of Darzalex Faspro as the first potential treatment for patients with ​pdf icon AL amyloidosis (Abstract #552).
Context:
The deposition of insoluble amyloid fibrils produced by light chains synthesized by clonal CD38+ plasma cells is characterized by systemic AL amyloidosis. In patients with AL amyloidosis, the combination of daratumumab (DARA) with bortezomib, cyclophosphamide, and dexamethasone (VCd) has shown substantially improved outcomes. In this disorder, the classification of hematologic complete response (CR) is developing, and the absolute reduction of the free light chain involved (iFLC) and the gap between iFLC and the free light chain not involved (dFLC) are recognized as very significant endpoints. The findings of the ANDROMEDA study (NCT03201965) are presented here to demonstrate the effect of achieving deep reductions in iFLC and dFLC on the progression-free survival of major organ degradation (MOD-PFS), a recent, primary secondary endpoint in this study.
Methodology:
Newly diagnosed AL amyloidosis with the observable hematologic disease (serum monoclonal protein ⇠0.5 g/dL by protein electrophoresis or serum-free light chain ⇠5.0 mg/dL with an irregular kappa: lambda ratio or dFLC ⇠50 mg/L), ⇠1 involved organ, I-IIIA cardiac level, eGFR ⇠20 mL/min, and absence of multiple symptomatic myeloma were main eligibility requirements. In order to obtain DARA-VCd or VCd alone, patients were randomized (1:1). For six 28-day periods, all patients received bortezomib (1.3 mg/m2 weekly subcutaneous [SC]), cyclophosphamide (300 mg/m2 weekly oral [PO] or intravenous [IV]), and dexamethasone (20-40 mg weekly PO or IV). DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by weekly injection in cycles 1-2, every other week in cycles 3-6, and for up to 24 cycles every four weeks thereafter. Disease tests were conducted every 4 weeks (cycles 1-6) and every 8 weeks (after cycle 7) before significant organ degradation, death, cessation of analysis, or withdrawal occurred. The primary endpoint was overall (i.e. at any time) hematologic CR rate, described here as FLC level and ratio (FLCr) normalization and negative serum and urine immunofixation, verified at subsequent visits; uninvolved FLC level and FLCr normalization were not needed if iFLC