Everolimus, Bortezomib and/or Rituximab in Patients With Relapsed/Refractory Waldenstrom's Macroglobulinemia

Study Design This is a phase I/II study. The phase I portion of the study will determine the maximum tolerated dose of everolimus, rituximab, and bortezomib combination, while the phase II portion will evaluate the depth of responses to the everolimus, rituximab, and bortezomib combination. If patients show response, they will continue on therapy for a total of 6 cycles, and then go on maintenance therapy with everolimus alone until progression. Patients on maintenance will be monitored every 3 months for response. Because of the potential of an IgM flare after rituximab, patients who show an increase in IgM after rituximab in the first 3 months will not be deemed as having progressive disease unless they show evidence of clinical progression and not just an increase of IgM levels. If biochemical progression is confirmed by m-spike, but the participant is clinically benefitting from therapy, the participant may continue on treatment for a few additional points of assessment and re-discuss benefit of therapy. Additionally, if the participant progressed because the treatment was held, participant may remain on study at the discretion of the overall Principal Investigator. Relapse from CR is defined by the reappearance of monoclonal IgM protein and/or recurrence of bone marrow involvement, lymphadenopathy/splenomegaly or symptoms attributable to active disease (Owen et al., 2012). Progression from PR is defined by ≥ 25% increase in IgM level from lowest recorded value and confirmed by a repeat assessment. The development of new signs and symptoms of disease, including Bing Neel syndrome and histological transformation, is also considered as evidence of disease progression. An absolute increase of at least 5 g/l is required to define progression when the IgM level is the only applicable criterion (Owen et al., 2012).