Efficacy and safety of bendamustine, rituximab and bortezomib treatment in relapsed/refractory Waldenstrom Macroglobulinaemia: results of phase 2 single‐arm FIL‐BRB trial

Summary This multicentre phase II study Fondazione Italiana Linfomi (FIL)‐bortezomib plus rituximab plus bendamustine (BRB) tested a combination of bendamustine (90 mg/m 2 on days 1–2), rituximab (375 mg/m 2 intravenously on day 1) and bortezomib (1.3 mg/m 2 sc on days 1, 8, 15, 22) every 28 days for six cycles in 38 symptomatic patients with relapsed/refractory Waldenstrom macroglobulinaemia (RR‐WM). Moreover, MYD88 L265P and CXCR4 S338X mutations were tested by droplet digital polymerase chain reaction (ddPCR) both at baseline and at the end of treatment in 21 patients. Overall response rate at the end of therapy was 84.6%, including 4 (11%) complete remission, 15 (39%) very good partial response, 12 (32%) partial responses according to IWWM response criteria. At 18, 24 and 30 months, progression‐free survival was 84.2% (95% CI 68.2%–92.6%), 81.5% (95%CI 65.1–90.7) and 78.8% (95%CI 62.0–88.8) respectively. At 18 months, the Overall survival was 92.1% (95%CI 77.5%–97.4%). Overall, 19 patients (50%) experienced grade 3–4 haematological toxicity, mainly thrombocytopenia, and grade 1–3 neuropathy rate was about 10% and required bortezomib dose reduction but did not result in treatment interruption. Moreover, BRB treatment induced the high rates of undetectable molecular minimal residual disease (MRD) at the end of the therapy. BRB regimen used as second line is an effective and well‐tolerated salvage treatment for relapsed refractory Waldenstrom macroglobulinaemia patients. MRD monitoring showed promising efficacy in clearing the residual disease.