Primary Therapy of Waldnestrom's Macroglobulinemia (WM) with Weekly Bortezomib, Low-Dose Dexamethasone and Rituximab (BDR): A Phase II Study of the European Myeloma Network.

Abstract 2886

Poster Board II-862

Rituximab and bortezomib are active single agents in the treatment of WM. Based on preclinical studies in lymphoproliferative disorders which indicated synergism between bortezomib and rituximab, in 2006 we designed a large phase II multicenter trial to assess the toxicity and activity of the combination of these agents in previously untreated patients with WM requiring therapy based on consensus recommendations (Kyle et al, Sem Oncol 2003;30:116). This trial is being conducted within the European Myeloma Network and has been activated in 6 Centers so far. In order to prevent the “IgM flare effect” seen with rituximab-based regimens, one course of single agent bortezomib is first administered at a standard dose of 1.3 mg/m² IV on days 1, 4, 8 and 11. Ten days later, the patients receive four courses of 35 days duration each. In courses 2 to 5, bortezomib is administered weekly at a dose of 1.6 mg/m² on days 1, 8, 15 and 22. During courses 2 and 5, immediately after the administration of bortezomib, patients receive dexamethasone 40 mg IV followed by rituximab 375 mg/m² IV. Patients receive a total of 8 infusions of rituximab. Bortezomib is being administered weekly in order to reduce the incidence of neurotoxicity which can be significant in WM patients treated with standard schedule bortezomib (Treon et al, Clin Cancer Res 2007;13:3320). During treatment, valacyclovir prophylaxis for herpes zoster is given to all patients. A single dose of dexamethasone is given before each dose or rituximab in order to take advantage of potential synergism with rituximab and to reduce allergic reactions but to avoid steroid-induced complications. After completion of treatment, patients with CR, PR, MR or SD according to consensus criteria (Kimby et al, Clin Lymphoma Myeloma 2006;3:380) are being followed without further therapy until there is evidence of progressive disease. The main endpoint was the best response observed after BDR. Dose modifications for toxicity were allowed and bortezomib could be reduced from 1.6 mg/m² to 1.3 mg/m² to 1.0 mg/m². The trial was initiated in March 2007 and 61 patients are scheduled to be enrolled. As of June 2009, 38 patients have started treatment with BDR. Patients characteristics include: age >65 years in 42% of patients, hemoglobin <11.5 g/dL in 84%, platelet count <100×10⁹/L in 19%, β₂-microglobulin >3 mg/dL in 63%, serum monoclonal protein >7 g/dL in 6%, lymphadenopathy in 37%, splenomegaly in 37%, and B-symptoms in 43% of patients. According to the International Prognostic Index Scoring System (IPSS) for WM, 23% of patients were rated as low-risk, 31% of patients as intermediate risk and 46% as high-risk. The main reasons which prompted initiation of treatment include cytopenia in 43% of patients, hyperviscosity syndrome in 22%, presence of B-symptoms in 16% and lymphadenopathy in 14%. So far, 31 patients are evaluable for response, which include CR in 1 (3%), PR in 16 (52%), MR in 5 (16%), SD in 4 (13%) and PD in 5 (16%) patients. In responding patients, at least MR has occurred within 2 months of treatment. Plasmapheresis was not required in any patient before or after treatment with BDR. An “IgM flaire phenomenon” was not seen in any patient and this was attributed to the initial course of simple agent bortezomib. Toxicities include: neutropenia (grade 3,4) in 26% of patients; thrombocytopenia (grade 3,4) in 11%; peripheral neuropathy, grade 1,2 in 44%, but grade 3,4 in only 7%; gastrointestinal toxicity (grade 3: 11%); and infections (grade 1,2: 19%, grade 3,4: 11%). One patient died of septic shock in absence of neutropenia. Three patients experienced pulmonary toxicity (grade 3,4) which was attributed to bortezomib and consisted of dyspnea, decrease of O₂ saturation and diffuse pulmonary infiltrates on CT scan of the chest. This toxicity resolved completely after administration of steroids and 2 of 3 patients continued treatment as per protocol. Only one patient (who had discontinued valacylovir prophylaxis) developed herpes zoster. The dose of bortezomib was reduced in 30% of patients primarily because of peripheral neuropathy. Our ongoing study indicates that the BDR regimen is active in patients with symptomatic WM most of whom had intermediate or high risk disease. Another update on response, toxicity and time to progression will be performed in November 2009.