Efficacy of First Line B-RI for Treatment Naive Waldenström's Macroglobulinemia

Inclusion Criteria * Clinicopathological diagnosis of WM as defined by consensus panel one of the Second International Workshop on WM, diagnosed by a reference pathology center. Pathological diagnosis has to occur before study inclusion. In addition, pathological specimens have to be sent to the national pathological reference center at study inclusion. The positivity for Cluster of Differentiation (CD) 20 can be assumed from any previous bone marrow immunohistochemistry or flow cytometry analysis performed up to 6 months prior to enrollment. Inclusion in the study will be based on morphological and immunological criteria. Immunophenotyping will be performed in each center and saved locally. Flow cytometry of bone marrow and blood cells will include at least one double staining and assess the expression of the following antigens: surface immunoglobulin, CD19, CD20, CD5, CD10 and CD23. Patients are eligible if tumor cells express the following antigens: CD19, CD20, and if they are negative for CD5, CD10 and CD23 expression. Patients with tumor cells positive for CD5 and/or CD23 and morphologically similar to WM cells may be included after ruling out other low-grade B-cell malignancies. * Presence of at least one criterion for initiation of therapy, according to the 2nd Workshop on WM: * Recurrent fever, night sweats, weight loss, fatigue (at least one of them) * Hyperviscosity * Lymphadenopathy which is either symptomatic or bulky (≥5 cm in maximum diameter) * Symptomatic hepatomegaly and/or splenomegaly * Symptomatic organomegaly and/or organ or tissue infiltration * Peripheral neuropathy due to WM * Symptomatic cryoglobulinemia * Cold agglutinin anemia * Immunoglobulin M (IgM) related immune hemolytic anemia and/or thrombocytopenia * Nephropathy related to WM * Amyloidosis related to WM * Hemoglobin ≤10g/dL * Platelet count \<100x109/L * Serum monoclonal protein \>5g/dL, even with no overt clinical symptoms * Low or absent IgG serum levels * World Health Organization (WHO)/Eastern Co-operative Oncology Group (ECOG) performance status 0 to 2. * Other criteria: * Age ≥ than 18 years * Life expectancy \>3 months. * Baseline platelet count \>100x10exponential (E)9/L if not due to bone marrow (BM) involvement by the lymphoma, independent of any transfusions * absolute neutrophil count \>1x10E9/L independent of growth factor support. * Meet the following pretreatment laboratory criteria at the Screening visit conducted within 28 days of study enrollment: * aspartate aminotransferase (AST): \<3 times the upper limit of institutional laboratory normal value * alanine aminotransferase (ALAT): \<3 times the upper limit of institutional laboratory normal value * Total Bilirubin: \< 1.5 times the upper limit of institutional laboratory normal value, unless clearly related to the disease (except if due to Gilbert's syndrome) * Serum creatinine: ≤ 2 times the upper limit of institutional laboratory normal value or estimated Glomerular Filtration Rate (cockroft-gault ≥ 40 mL/min/1.73m2) * Premenopausal fertile females must agree to use a highly effective method of birth control for the duration of the therapy up to 6 months after end of therapy. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. * Men must agree not to father a child for the duration of therapy and 12 months after and must agree to advice a female partner to use a highly effective method of birth control. * Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. * Affiliation to a social security scheme (relevant for France only) Exclusion Criteria: * Prior systemic treatment of the WM (plasmapheresis and short - term administration of corticosteroids \< 4 weeks administered at a dose equivalent to \< 20 mg/day prednisone is allowed) * Patient with hypersensitivity to Bortezomib * Patient with hypersensitivity to MabThera * Patient with hypersensitivity to Ibrutinib * Serious medical or psychiatric illness likely to interfere with participation in this clinical study. * Uncontrolled viral infection * Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics. * Congenital or acquired severe immunodeficiency not attributed to lymphoma (clinical appearance: recurrent infections, necessity of immunoglobulin substitution therapy, patients after transplantation) * Known interstitial lung disease * Prior allergic reaction or severe anaphylactic reaction related to humanized or murine monoclonal antibody. * Central Nervous System involvement by lymphoma * Prior history of malignancies unless the subject has been free of the disease for ≥ 5 years. Exceptions include the following: * Basal cell carcinoma of the skin, * Squamous cell carcinoma of the skin, * Carcinoma in situ of the cervix, * Carcinoma in situ of the breast, * Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b). * Uncontrolled illness including, but not limited to: * Uncontrolled diabetes mellitus (as indicated by metabolic derangements and/or severe diabetes mellitus related uncontrolled organ complications) * Chronic symptomatic congestive heart failure (Class New York Heart Association (NYHA) III or IV). * Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months * Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia. * Known pericardial disease * acute diffuse infiltrative pulmonary and pericardial disease * Subjects with ≥ Grade 2 neuropathy. * Recent major surgery (within 4 weeks prior to study inclusion) * History of stroke or intracranial haemorrhage within 6 months prior to study inclusion * Women who are pregnant as well as women who are breast-feeding and do not consent to discontinue breast-feeding. * Participation in another clinical trial within four weeks prior to study inclusion * No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician about study participation * St. John's Wort with Ibrutinib * Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon). * Requires treatment with strong cytochrome P (CYP) 3A inhibitors. * Vaccinated with live, attenuated vaccines within 4 weeks prior to study inclusion. * Person of legal age who is incapable of comprehending the nature, significance and implications of the clinical trial and of determining his/her will in the light of these facts