Title: Phase II Study of Combination Bortezomib (VELCADE, PS-341), Dexamethasone, and Rituximab (MabThera) (BDR) in Patients with previously untreated Waldenstroms Macroglobulinemia (WM).~Objectives:~The primary objective of this study is:~To determine the response rate [the combined complete response (CR) + partial response (PR) + minimal response (MR)] following treatment with BDR in patients with previously untreated WM.~Secondary objectives are:~To determine time to progression following treatment with BDR.~To assess the safety and tolerability of BDR in patients with WM.~Patient population:~Patients with previously untreated WM who have an indication for treatment are candidates for the study.~Specific inclusion and exclusion criteria are detailed in the protocol.~Number of patients:~Sixty-one patients are to be enrolled in this multicenter study. This study will be conducted within centers participating in the European Myeloma Network.~Study design and methodology This is a Phase II multicenter study designed to evaluate the safety and efficacy of combination BDR. BDR will be administered in one 21-day treatment cycle followed by four 35-day treatment cycles to patients with WM. Bortezomib will be administered as an iv push over 3 to 5 seconds at a dose of 1.3mg/m2/day on days 1,4,8 and 11 of cycle 1. On cycles 2-5 bortezomib will be given at a dose of 1.6mg/m2/day on days 1,8,15 and 22 of each cycle. Only on cycles 2 and 5, following the administration of Bortezomib, dexamethasone 40mg iv and Rituximab 375 mg/m2 iv will be administered. A total of 8 infusions of rituximab will be administered. Subsequently patients rated as CR, PR, MR or SD will be followed without any treatment until there is evidence of progressive disease.~A Screening visit will be conducted within 28 days before baseline (baseline being Day 1, Cycle 1, before study drug administration). At this visit, a medical history will be obtained and a complete physical examination will be performed including vital signs, height, weight, and a 12-lead electrocardiogram. A neurological questionnaire will also be completed. Disease assessments will be performed, including performance status, bone marrow aspirate and biopsy, Beta2-microglobulin, serum protein electrophoresis with quantification of immunoglobulins and immunofixation studies, CT scanning of the chest, abdomen and pelvis. Clinical laboratory tests including a complete blood count plus differential, electrolytes, urea, creatinine, total bilirubin, SGOT (ALT), SGPT (AST), LDH, total protein and albumin. Patients who meet the eligibility requirements as assessed at the Screening visit will be enrolled in the study and start study drug treatment. Patients will be evaluated after each cycle with serum protein electrophoresis to determine their response to therapy. If patients demonstrate a response or have stable disease at the end of each cycle they will continue to receive therapy. If the patient demonstrates evidence of progressive disease at the end of each cycle then the patient will be removed from study. Modified response criteria updated at the Third International Workshop on Waldenstroms macroglobulinemia will be used to assess response, stable disease (SD), and progressive disease (PD) in this study. Changes of serum monoclonal protein concentration will be assessed from serum protein electrophoresis rather than from nephelometric measurement of serum immunoglobulins. Patients will receive five cycles of therapy. Subsequently, it is strongly advised that blood stem cells will be collected from patients <70 years of age for future high-dose therapy.~At the end of each cycle patients will have testing performed to assess for toxicity and efficacy. A directed questionnaire for neurologic toxicities, review of concomitant medications and other support therapies, including growth factors and transfusions will also be performed. Three months after the last dose of study drug, and every three months thereafter for 2 years, patients are to attend follow-up study visits. At these visits, a physical examination will be performed and Karnofsky performance status assessed. Patients will have a neurological questionnaire completed, have tests for disease assessments including serum and protein electrophoresis with quantification of immunoglobulins and immunofixation studies, Beta2-microglobulin, bone marrow aspirate and biopsy (only if the patient is in a complete remission), CT scanning of the chest, abdomen and pelvis (only if patient had evidence of WM disease on baseline scans). Serum and protein electrophoresis with quantification of immunoglobulins and immunofixation studies must be repeated > 6 weeks if a patient attains a complete response. At the follow-up study visits, a complete blood count plus differential, electrolytes, urea, creatinine, total bilirubin, SGOT, will also be obtained.
This is a Phase II multicenter study designed to evaluate the safety and efficacy of combination BDR. BDR will be administered in one 21-day treatment cycle followed by four 35-day treatment cycles to patients with WM.