Carfilzomib, a novel proteasome inhibitor, with dexamethasone and rituximab showed responses in 87% of symptomatic WM patients, most of whom were previously untreated. Responses to CARD were not impacted by the presence of MYD88 L265P or CXCR4 mutations. Importantly, no significant treatment related neuropathy was observed in contrast to previous studies in Wm patients with the proteasome inhibitor bortezomib.