Primary Therapy of Waldenström's Macroglobulinemia (WM) with Weekly Bortezomib, Low-Dose Dexamethasone and Rituximab (BDR): A Phase II Study of the European Myeloma Network
Authors: Dimopoulos Meletios A. , García-Sanz Ramón , Gavriatopoulou Maria , Morel Pierre , Kyrtsonis Marie-Christine , Katodritou Eirini , Michalis Eurydiki , Kartasis Zafiris , Leleu Xavier , Palladini Giovanni , Tedeschi Alessandra , Gika Dimitra , Terpos Evangelos , Merlini Giampaolo , Kastritis Efstathios , Sonneveld Pieter 
Published: October 2019

Abstract
Abstract 1941
Rituximab and bortezomib are active agents in the treatment of WM. Based on preclinical studies which indicated synergism between bortezomib and rituximab, in 2006 we designed a large phase II multicenter trial to evaluate 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 was conducted by the European Myeloma Network in 10 centers. In order to prevent the “IgM flare effect” seen with rituximab-based regimens, one course of single agent bortezomib was first administered at a standard dose of 1.3 mg/m2 IV on days 1, 4, 8 and 11. Ten days later, the patients received four courses of 35 days duration each. In courses 2 to 5, bortezomib was 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 received dexamethasone 40 mg IV followed by rituximab 375 mg/m2 IV. Patients received a total of 8 infusions of rituximab. Bortezomib was 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). A single dose of dexamethasone was 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. During treatment, valacyclovir prophylaxis for herpes zoster was prescribed. After completion of treatment, patients with CR, PR, MR or SD according to consensus criteria (Kimby et al, CLM 2006;3:380) were followed without further therapy until there was evidence of progressive disease. 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, 61 patients were scheduled to be enrolled and the study completed accrual in June 2010. Patients characteristics included: age >65 years in 60% of patients, hemoglobin <11.5 g/dL in 82%, platelet count <100×109/L in 17%, β2-microglobulin >3 mg/dL in 63%, serum monoclonal protein >7 g/dL in 3.4%, lymphadenopathy in 42%, splenomegaly in 29%, and B-symptoms in 42% of patients. According to IPSS for WM, 18% of patients were rated as low risk, 23% as intermediate risk and 59% as high risk. The main reasons to start treatment included cytopenias in 43% of patients, hyperviscosity in 22%, presence of B-symptoms in 18% and lymphadenopathy in 8%. So far, 54 patients are evaluable for response. On an intent to treat, response rating include CR in 2 (4%), PR in 33 (61%), MR in 8 (15%), SD in 5 (9%) and PD in 6 (11%) patients. In responding patients, at least MR occurred within 2.3 months of treatment and the median time to best response is 4.8 months. Plasmapheresis was not required in any patient before or after treatment with BDR. An “IgM flare phenomenon” was not seen and this was attributed to the initial course of single agent bortezomib. Median follow up for all patients is 12 months, and so far 10 patients have progressed. Eight patients have died, 5 due to causes unrelated to WM or complications of treatment. Toxicities include: neutropenia (grade ≥3) in 13% of patients; thrombocytopenia (grade ≥3) in 5%; peripheral sensory neuropathy, grade 1,2 in 30%, but grade ≥3 in only 5%; neuropathic pain in 17%, but grade ≥3 in only 2%, gastrointestinal toxicity, grade 3 in 7%; and infections in 17% (grade ≥3 in 7%). One patient died of septic shock in absence of neutropenia. Three patients (5%) experienced pulmonary toxicity (grade 3/4) which was attributed to bortezomib and consisted of dyspnea, decrease of O2 saturation and diffuse pulmonary infiltrates on chest CT scan. 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. This is the largest trial that has evaluated the role of a bortezomib-containing regimen in the frontline setting of symptomatic patients with WM, most of whom were rated as high risk according to IPSS. We conclude that the BDR regimen is active. An update on response, toxicity and time to progression will be performed in November 2010.

Disclosures:
Dimopoulos: Ortho-Biotech: Honoraria; Millennium: Honoraria. Off Label Use: Bortezomib for Waldenstrom's Macroglobulinemia. García-Sanz:Ortho-Biotech: Honoraria; Millennium: Honoraria; Celgene: Honoraria. Merlini:Millennium: Honoraria; Ortho-Biotech: Honoraria. Sonneveld:Ortho-Biotech: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.