Efficacy and Safety of Carfilzomib in Combination With Ibrutinib vs Ibrutinib in Waldenström's Macroglobulinemia

Inclusion Criteria: Each patient must meet all of the following inclusion criteria to be enrolled in this study: * Proven clinicopathological diagnosis of WM as defined by consensus panel one of the Second International Workshop on WM. Histopathology has to occur before randomization within the last 4 months. In addition, pathological specimens have to be sent to the pathological reference center prior to randomization for the determination of the mutational status of MYD88 and CYCR4. Immunophenotyping will be performed in each center and saved locally. The positivity for CD20 can be assumed from any previous bone marrow immunohistochemistry or flow cytometry analysis performed up to 4 months prior to enrollment. Flow cytometry of bone marrow and blood cells will include at least one double staining and assess the disease specific expressions. * De novo and relapsed/refractory WM independent of the genotype. * Determination of mutational status of MYD88 and CXCR4. * Patients must have at least one of the following criteria to initiate treatment as partly defined by "Consensus Panel Two" recommendations from the Second International Workshop on Waldenström Macroglobulinemia: * Recurrent fever, night sweats, weight loss, fatigue (at least one of them). * Hyperviscosity. * Lympadenopathy 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. * IgM related immune hemolytic anemia and/or thrombocytopenia. * Nephropathy related to WM. * Amyloidosis related to WM. * Hemoglobin ≤ 10 g/dL (patients should not have received red blood cells transfusions for at least 7 days prior to obtaining the screening haemoglobin). * Platelet count \< 100 x 109/L (caused by BM infiltration of the lymphoma). * Serum monoclonal protein \> 5 g/dL, even with no overt clinical symptoms. * IgM serum concentration ≥ 5g/dl. * and other WM associated relevant symptoms. * World Health Organization (WHO)/ECOG performance status 0 to 2. * Left ventricular ejection fraction ≥ 40% as assessed by transthoracic echocardiogram (TTE). * Other criteria * Age ≥ than 18 years (male and female). * Life expectancy \> 3 months. * Baseline platelet count ≥ 50 x 109/L, absolute neutrophil count ≥ 0.75 x 109/L. (if not due to BM infiltration by the lymphoma). * Meet the following pre-treatment laboratory criteria at the Screening visit conducted within 30 days prior to randomization: * ASAT (SGPOT): \< 3.0 times the ULN. * ALAT (SGPT): \< 3.0 times the ULN. * Total Bilirubin: \< 1.5 times the ULN, unless clearly related to the disease (except if due to Gilbert's syndrome). * Serum creatinine: ≤ 2 mg/dl. * Women of childbearing potential (WOCBP) 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 combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. Contraception and pregnancy testing are required according the CTFG recommendations. * Men must agree not to father a child for the duration of therapy and 6 months after (use of a condom) and must agree to advice a female partner to use a highly effective method of birth control. Males must refrain from sperm donation for at least 6 months after the last dose of treatment. * Voluntary written informed consent in the native language of the patient 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. Exclusion Criteria: The presence of any of the following will exclude a subject from enrolment: * Previous treatments with following substances: * Prior exposure to Ibrutinib or other BTK inhibitors. * Prior exposure to Carfilzomib. Prior exposure to other proteasome inhibitors is allowed if the patients were not refractory, that is, had a remission (at least minor response) duration of ≥ 6 months. Prior plasmapheresis and short-term administration of corticosteroids ≤ 6 weeks administered at a dose equivalent to ≤ 20 mg/day of prednisone is also allowed. * Serious medical or psychiatric illness (especially undergoing treatment) likely to interfere with participation in this clinical study. * Active HIV, HBV or HCV infection. * Central Nervous System involvement by lymphoma. * History of a non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for ≥ 1 year prior to randomization, other Stage 1 or 2 cancer treated with a curative intent and currently in complete remission, for ≥ 3 years. * 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 NYHA III or IV) or LVEF \< 40%. * Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months prior to randomization. * Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia. * Known pericardial disease. * Malabsorption syndrome, 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. * Cardiac amyloidosis. * Recent major surgery within 30 days prior to randomization. * Known cirrhosis (meeting child-pugh stage C). * Approved or investigational anticancer treatment within 21 days prior to randomization. * Glucocorticoid therapy within 14 days prior to randomization that exceeds a cumulative dose of 160 mg of Dexamethasone or equivalent dose of other corticosteroids. * Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to randomization (i.e. prior radiation must have been to less than 30% of the bone marrow). * Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs. * Hypersensitivity to the active substances or to any of the excipients of the investigational medicinal products. * Active infection within 14 days prior to randomization requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents. Such infection must be fully resolved prior to randomization. * Ascites requiring paracentesis within 14 days prior to randomization. * Uncontrolled hypertension, defined as an average systolic blood pressure \> 159 mmHg or diastolic \> 99 mmHg despite optimal treatment (measured according European Society of Hypertension/European Society of Cardiology \[ESH / ESC\] 2013 guidelines\[65\]. * History of stroke or intracranial hemorrhage within 6 months prior to randomization. * Known interstitial lung disease. * Infiltrative pulmonary disease, known pulmonary hypertension. * Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \< 50% of predicted normal. * Known severe persistent asthma within the past 2 years (see also https://www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf), or currently has uncontrolled asthma of any classification or at time of screening has an FEV1 of \< 50% of predicted normal. * Autologous or allogeneic stem cell transplant less than 100 days prior to randomization. * Vaccination with live attenuated vaccines within 30 days prior to randomization. * Patients who require strong or moderate inducers or inhibitors for cytochrome P450, family 3 or subfamily A (CYP3A). * Patients who have an uncontrolled bleeding disorder or require an anticoagulant (e.g. warfarin or other vitamin K antagonists; novel oral anticoagulants (NOACs) are allowed) at time of screening. * History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or sponsor, if consulted, would pose a risk to patient safely or interfere with the study evaluation, procedures or completion. * Patient is a woman who is pregnant or breastfeeding (and do not consent to discontinue breast-feeding) or planning to become pregnant while enrolled in this study or within 6 months after the last study treatment. * Vulnerable patients, e.g. patients who are incapable of giving informed consent (severe dementia or psychosis, patients kept in detention). * Participation in another interventional clinical study within 30 days before randomization in this study.