Study of Ibrutinib in Patients With Symptomatic, Previously Untreated Waldenstrom's Macroglobulinemia, and Impact on Tumor Genomic Evolution Using Whole Genome Sequencing

Inclusion Criteria: * Clinicopathological diagnosis of Waldenstrom's Macroglobulinemia and meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenstrom's macroglobulinemia (Kyle et al, 2003). * Measurable disease, defined as presence of serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the upper limit of normal is required. * Age ≥ 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (see Appendix A.). * Participants must have normal organ and marrow function as defined below: * Absolute neutrophil count ≥ 1,000/μL * Platelets ≥ 50,000/μL * Hemoglobin ≥ 8 g/dL * Total bilirubin ≤ 2.0. mg/dL or \< 2.5 mg/dL if attributable to hepatic infiltration by neoplastic disease or Gilbert's syndrome. * Aspartate aminotransferase (AST or SGOT) and Alanine aminotransferase (ALT or SGPT) ≤ 2.5 X institutional upper limit of normal * Estimated Creatinine Clearance ≥30ml/min * Not on any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin. * Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or have or will have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 28 days after discontinuation from the study. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. FCBP must be referred to a qualified provider of contraceptive methods if needed. * Able to adhere to the study visit schedule and other protocol requirements. * Ability to understand and the willingness to sign a written informed consent document. * Both men and women of all races and ethnic groups are eligible for this trial. Exclusion Criteria: * Prior systemic therapy for WM * Any serious medical condition, laboratory abnormality, uncontrolled intercurrent illness, or psychiatric illness/social condition that would prevent the participant from signing the informed consent form. * Concurrent use of any other anti-cancer treatments or any other investigational agents. * Concomitant use of warfarin or other Vitamin K antagonists. * Concomitant treatment with strong CYP3A4/5 inhibitor. * Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. * Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion could interfere with the absorption or metabolism of ibrutinib. * Known Central nervous system (CNS) lymphoma. * Concomitant use of medication known to cause QT prolongation. * Currently active, clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction, unstable angina or acute coronary syndrome within 6 months of screening. * Malabsorption, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. * Known history of Human Immunodeficiency Virus (HIV), active infection with Hepatitis B Virus (HBV), and/or Hepatitis C Virus (HCV). Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. * Lactating or pregnant women. * Inability to swallow capsules. * History of non-compliance to medical regimens. * Unwilling or unable to comply with the protocol. * Major surgery within 4 weeks of first dose of study drug. * No active infections requiring systemic therapy. * Known bleeding disorders with the exception of acquired Von Willebrand Disorder suspected on the basis of WM. * History of stroke or intracranial hemorrhage within 6 months prior to enrollment.