To improve the efficacy of risk-adapted melphalan (MEL) in patients with amyloidosis (AL), we conducted a phase II trial using bortezomib and dexamethasone (BD) as consolidation. Forty untreated patients with renal (70%), cardiac (65%), liver/gastrointestinal (15%) or nervous system (13%) AL were assigned MEL 100, 140 or 200 mg/m(2) based on age, renal function and cardiac involvement. Hematological response was assessed at 3 months post stem cell transplant (SCT); patients with less than complete hematological response (CR) received BD consolidation. Four patients with advanced cardiac AL died within 100 days of SCT (10% treatment-related mortality). Survival at 12 and 24 months post treatment start was 88 and 82% overall and was 81 and 72% in patients with cardiac AL. At 3 months post SCT, 45% had ≥ partial response (PR) including 27% CR. Twenty-three patients received consolidation and in 86% response improved; all patients responded in one cycle. At 12 and 24 months, 79 and 60% had ≥ PR, 58 and 40% CR. Organ responses occurred in 55 and 70% at 12 and 24 months. Eight patients relapsed/progressed. One patient with serologic progression had organ impairment at time of progression. In newly diagnosed AL, BD following SCT rapidly and effectively improves responses resulting in high CR rates and maintained organ improvement.