Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia

Inclusion Criteria: * Subjects must have a diagnosis of WM and meet the requirements for active therapy as defined by the 2nd International Workshop on Waldenstrom's Macroglobulinemia * Age ≥18 years of age * Ibrutinib naïve or previously treated patients currently on ibrutinib with a plateau in disease response are eligible to participate. 1. Ibrutinib naïve subjects may be either treatment naïve or previously treated but ibrutinib naïve to enter cohort A. 2. Subjects entering cohort B must have a plateau response on ibrutinib defined as ≥ 6 months of ibrutinib treatment with 2 IgM measurements at least 2 months apart with ≤ 15% change from the previous measurement. Subjects with IgM level \< 0.7 g/dL will be eligible if their IgM level increases \< 0.15 g/dL over two subsequent IgM measurements as defined above. * Subjects must have measurable disease defined by a serum IgM level ≥0.5g/dL * Eastern Cooperative Oncology Group performance status of 0-2 * Hematology values must be within the following limits: 1. Absolute neutrophil count (ANC) ≥ 1000/mm3 independent of growth factor support for 7 days of study entry if cytopenias are due to marrow involvement. 2. Platelets ≥ 50,000/mm3 independent of transfusion support within 7 days of study entry. TPO mimetics are not allowed to meet eligibility criteria. 3. Hemoglobin ≥ 8g/dL, independent of transfusion support within 7 days of study entry * Biochemical values within the following limits: d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN) e. Total bilirubin ≤ 2 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin f. Creatinine clearance (CLcr) \> 25 ml/min * Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug. * Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin (beta-hCG) or urine beta hCG pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study. * Subjects must be able to sign (or their legally-acceptable representatives must sign) an informed consent indicating that they understand the rational of the study and can participate in all study procedures. Exclusion Criteria: * Subject does not have a recorded IgM level recorded within 3 months prior to ibrutinib initiation. * Subject meeting definition of disease progression while on ibrutinib. Subjects with IgM levels \< 0.7gdL are given special consideration. Please see inclusion criteria for 2b. * Subjects in cohort B experiencing ongoing non hematologic toxicities attributable to ibrutinib \> Grade 1 will be excluded from study entry. * Major surgery or a wound that has not fully healed within 4 weeks of enrollment. * Evidence of disease transformation at time of enrollment. * Waldenstrom's complicated by amyloidosis * Known central nervous system lymphoma. * History of stroke or intracranial hemorrhage within 6 months prior to randomization. * Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon). * Requires chronic treatment with strong CYP3A inhibitors. Subjects that required strong CYP3A inhibitors but completed a course of treatment can be considered for enrollment after a washout period of 14 days prior to study drug administration. * Requires strong CYP3A inducers. Subjects that required strong CYP3A inducers but completed a course of treatment can be considered for enrollment after a washout period of 14 days prior to study drug administration. * Patients with history of Chronic Obstructive Pulmonary Disease or Reactive Airway disease must have PFTs with FEV1 calculated. Patients with a FEV1 ≤ 50% of predicted normal will be excluded. * Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification. * Vaccinated with live, attenuated vaccines within 4 weeks of randomization. * Seropositive for human immunodeficiency virus (HIV). * Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen \[anti-HBc\] and/or antibodies to hepatitis B surface antigen \[anti-HBs\]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. * Seropositive for hepatitis C (except in the setting of a sustained virologic response \[SVR\], defined as aviremia at least 12 weeks after completion of antiviral therapy). * Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk. * Active malignancy not treated with curative intent within 2 years of study entry. Nonmelanotic skin cancers and cervical carcinoma in situ are excluded from this criteria.