A Phase II Study of Risk-Adapted Intravenous Melphalan in Patients with AL Amyloidosis,

High-dose IV melphalan is standard autograft (ASCT) conditioning in patients with AL amyloidosis, but careful patient selection is required to avoid high transplant-related mortality rates. In patients ineligible for ASCT, intermediate-dose IV melphalan (IDM) may provide advantages over oral dosing where the already variable intestinal absorption is complicated by gastrointestinal amyloid deposition. We aimed to assess a risk-adapted strategy to IV melphalan dosing in patients with AL amyloidosis.

The MM8 study was a prospective clinical trial conducted by the Australasian Leukaemia and Lymphoma Group. Transplant candidates (minimal cardiac disease including BNP<300ng/L, age <65, ECOG<2, <2 organs involved) received melphalan at 140 or 200mg/m² IV. All other patients received IDM (melphalan 20mg/m² IV d1 and dexamethasone 40mg PO d1-4 every 4 weeks for 3–6 cycles). Treatment was continued until 2 cycles beyond free light chain normalisation or maximal response, or to a maximum of 6 cycles. IDM was discontinued if there was no haematologic response after 3 cycles.

21 patients enrolled with median age 61yrs. Organ involvement was cardiac 48%, renal 81%, liver 14%, neurologic 43%. 6, 10 and 5 were low, intermediate and high cardiac biomarker risk, respectively. 7 underwent ASCT and 14 IDM.

The trial closed early due to excessive myelotoxicity in the IDM arm. In this cohort, grade 3/4 neutropenia and thrombocytopenia during the 1^st cycle occurred in 54% and 23%, with 15% having neutropenic fever. Grade 3/4 neutropenia and thrombocytopenia during any cycle occurred in 85% and 54% of patients, with 38% having neutropenic fever. First cycle severe neutropenia was not predicted by age, cardiac or renal function but was significantly more common with lower body surface area (p=0.01). 8 IDM patients died before the 6 month response assessment, 2 achieved a 50% reduction in baseline involved FLC and 4 failed to respond. All 7 patients receiving ASCT are alive at a median of 33 months.

IV melphalan at 20mg/m² is excessively myelotoxic for patients with AL with no evidence of response benefit to offset this toxicity. BNP<300ng/L may identify patients suitable for ASCT.

This study was supported by the Leukaemia Foundation of Queensland and Amgen Australia.

Mollee:Amgen Australia: Research Funding; Leukaemia Foundation of Queensland: Research Funding. Cannell:Nereus Pharmaceuticals:.