Rituximab and Ibrutinib (RI) Versus Dexamethasone, Rituximab and Cyclophosphamide (DRC) as Initial Therapy for Waldenström's Macroglobulinaemia

Inclusion Criteria:

1. Patients ≥ 18 years
2. Confirmed diagnosis of WM (according to consensus panel / WHO criteria) withmeasurable IgM paraprotein
3. Previously untreated disease at any stage requiring therapy at the discretion of thetreating physician. Suggested criteria for initiating treatment include:

• haematological suppression to Hb <10g/dl, or neutrophils <1.5x109/l or platelets <150x109/l
• clinical evidence of hyperviscosity
• bulky lymphadenopathy and/or bulky splenomegaly
• presence of B symptoms

4. No previous chemotherapy (prior plasma exchange and steroids are permissible)
5. Eastern Cooperative Oncology Group (ECOG) performance status grade 0 - 2
6. Life expectancy of greater than 6 months
7. Written informed consent
8. Willing to comply with the contraceptive requirements of the trial
9. Negative serum or urine pregnancy test for women of childbearing potential (WOCBP)

Exclusion Criteria:

1. Prior therapy for WM
2. Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein
3. CNS involvement with WM
4. Autoimmune cytopenias
5. Major surgery within 4 weeks prior to randomisation
6. Clinically significant cardiac disease including the following:

• Myocardial infarction within 6 months prior to randomisation
• Unstable angina within 3 months prior to randomisation
• New York Heart Association class III or IV congestive heart failure
• History of clinically significant arrhythmias (e.g. sustained ventriculartachycardia, ventricular fibrillation, torsades de pointes)
• QTcF > 480 msecs based on Fredericia's formula or Bazette's formula
• History of Mobitz II second degree or third degree heart block without apermanent pacemaker in place
• Uncontrolled hypertension as indicated by a minimum of 2 consecutive bloodpressure measurements showing systolic blood pressure > 170 mmHg and diastolicblood pressure > 105 mm Hg
• Cardiac event within 6 months of screening (e.g. coronary artery stent) requiringdual antiplatelet treatment

7. History of stroke or intracranial haemorrhage within 6 months prior to randomisation
8. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (directoral anticoagulants (DOACs) allowed)
9. History of severe bleeding disorders considered not to be disease related (HaemophiliaA, B or von Willebrand's disease)
10. Requires ongoing treatment with a strong CYP3A inhibitor or inducer
11. Known infection with HIV, or serologic status reflecting active hepatitis B or Cinfection as follows:

• Presence of hepatitis B surface antigen (HBsAg). In addition, if negative forHBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will beperformed and if positive the patient will be excluded
• Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCVantibody are eligible if HCV RNA is undetectable

12. Women who are pregnant or breastfeeding or males expecting to conceive or fatherchildren at any point from the start of treatment until the end of the "at riskperiod"
13. Renal failure (creatinine clearance <30 ml/min as estimated by the Cockroft-Gaultequation)
14. Patients with chronic liver disease with hepatic impairment Child-Pugh class B or C
15. Known history of anaphylaxis following exposure to rat or mouse derived CDR-graftedhumanised monoclonal antibodies.
16. Inability to swallow oral medication
17. Disease significantly affecting gastrointestinal function and/or inhibiting smallintestine absorption (e.g. malabsorption syndrome, resection of the small bowel,poorly controlled inflammatory bowel disease)
18. Active systemic infection requiring treatment
19. Concomitant treatment with another investigational agent
20. Any life-threatening illness, medical condition, organ system dysfunction, need forprofound anticoagulation, or bleeding disorder, which, in the investigator's opinion,could compromise the patient's safety, or put the study at risk
21. Unwilling or unable to take PCP prophylaxis (e.g. cotrimoxazole)
22. History of prior malignancy, with the exception of the following:

• Malignancy treated with curative intent and with no evidence of active diseasepresent for more than 3 years prior to screening and felt to be at low risk forrecurrence by treating physician
• Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma,superficial bladder cancer, carcinoma in situ of the cervix or breast orlocalized Gleason score 6 prostate cancer without current evidence of disease.