There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrőm macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-speci c ow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enrolled into this phase II trial and randomised (2:1) to receive cyclophosphamide and rituximab with either bortezomib (BCR) or udarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BCR (N=41). An ORR of 97.6% (95%CI: 87.1-99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-and 3-year progression-free survival (PFS) rates of 92.7% (95%CI: 79.0-97.6) and 80.5% (95%CI: 64.8-89.7). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02-11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR=0.06, 95%CI:0.01-0.47, p<0.001), and remained independently associated after adjusting for baseline risk strati cation or investigator-assessed response. BCR is a tolerable, highly e cacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes.