An international trial with a new standard of care for patients with AL amyloidosis.

We propose to test in a phase III study (oral melphalan and dexamethasone (MDex), the standard therapy for AL patients who are not autologous candidates for stem cell transplant (ASCT), against bortezomib added to MDex (BMDex). The hematologic response rate with MDex is 60% with 30% complete responses. The median overall survival with MDex is 5.1 years and the median progression free survival is 3.8 years. The basis for the combination of BMDex includes the high activity of bortezomib in AL, particularly the high complete response rate and the rapidity of hematologic response to bortezomib and dexamethasone, and the large clinical experience in phase II and phase III studies with bortezomib, melphalan and prednisone in myeloma. Untreated patients diagnosed with AL who are not candidates for stem cell transplant with melphalan 200 mg/m2 are the target population. Patients who are eligible for SCT with melphalan 200 mg/m2 but who decline the procedure can be enrolled in the study as a subgroup with stratified randomization. Because many newly diagnosed AL patients present with limited organ reserve, the eligibility criteria take into consideration the impact of cardiac involvement on overall survival using cardiac biomarker staging. Stage I and II patients will be eligible and stage III patients will be enrolled in an ancillary phase II study.