Multicenter, open*label, phase II study in patients with monoclonal
gammopathy of unknown significance (MGUS) and anti Myelin Associated
Gycoproteine (MAG) Neuropathy and Zanubrutinib Treatment * MAGNAZ trial

- Able to provide written informed consent and understand and comply with the
requirements of
the study
- Demyelinating polyneuropathy defined by electrophysiological criteria
according to EFNS/PNS
PDN guideline, 201019
- Some functional impairment; defined as an iRODS * 44 at baseline
- Age * 18 years
- IgM MGUS, defined as the presence of an IgM M protein (detectable but < 30
g/L) AND elevated total IgM level in serum
- Presence of anti MAG antibodies * 10.000 titer units, measured with the
Bühlmann ELISA
- ECOG performance score 0, 1, or 2
- Adequate hematological laboratory values defined as
hemoglobin * 5.0 mmol/L neutrophils > 1.0 × 10^9/L and platelets > 100 × 10^9/L
- Adequate hepatic and renal function laboratory values defined as ASAT/ALAT
< 3 × ULN, bilirubin < 2.0 × ULN and creatinine clearance * 30 ml/min
- No history of severe bleeding disorder such as hemophilia A, hemophilia B,
von Willebrand
disease, or history of spontaneous bleeding requiring blood transfusion or
other medical intervention
- Previous treatment with intravenous immunoglobulins is allowed if > 3
months before inclusion
- Previous treatment for PNP with Anti CD20 MoAb and/or cyclophosphamide is
allowed only if
given > 6 months before inclusion

- Hematological malignancy e.g known Multiple Myeloma or confirmed Waldenstrom*s
Macroglobulinemia based on bone marrow analysis
- Any history of malignancy of any organ system (other than localized basal or
squamous cell
carcinoma of the skin, superficial bladder cancer or carcinoma in situ of the
cervix or breast),
treated or untreated within the last 3 years
- History of ischemic stroke within 180 days before first dose of Zanubrutinib.
- History of CNS hemorrhage.
- History of inherited or acquired hemorrhagic disorder
- Prior treatment with purine analogues (fludarabine or cladribine)
- Prior treatment with a BTK inhibitor
- Major surgery within 4 weeks of study treatment
- Participation in another interventional clinical trial
- Women with child*bearing potential (WOCBP) not able or willing to prevent
pregnancy and
lactating women as well. WOCBP will agree to use highly effective contraception
for the duration of the trial treatment and for 120 days after treatment stop
- Other known concomitant causes of chronic (demyelinating) PNP, including
Charcot Marie Tooth Disease, other hereditary neuropathies, diabetes mellitus,
use of amiodarone, past or current dependence on alcohol, other lymphoma or
malignant blood dyscrasias, previous Guillain*Barré syndrome
- Currently active, clinically significant cardiovascular disease such as
uncontrolled arrhythmia,
congestive heart failure, any Class 3 or 4 cardiac disease (congestive heart
failure) as defined by
the New York Heart Association (NYHA) Functional Classification, or history of
myocardial
infarction within 6 months of screening
- A history of clinically significant ECG abnormalities, or any of the
following ECG abnormalities
at screening:
o QTcF >450 msec (males)
o QTcF >460 msec (females)
o History of familial long QT syndrome or known family history of Torsades de
Pointes
o Use of agents known to prolong the QT interval unless they can be permanently
discontinued for the duration of the study
o second degree atrioventricular (AV) block Type II, or third*degree AV block
* Controlled atrial fibrillation is allowed
- Unable to swallow capsules or disease significantly affecting
gastrointestinal function such as
malabsorption syndrome, resection of the stomach or small bowel, symptomatic
inflammatory
bowel disease, or partial or complete bowel obstruction
- Uncontrolled active systemic infection or recent infection requiring
parenteral anti*microbial
therapy that was completed * 14 days before the first dose of study drug.
Active tuberculosis
- Known infection with human immunodeficiency virus (HIV), or serologic status
reflecting active
hepatitis B or hepatitis C infection as follows: Presence of hepatitis B
surface antigen (HBsAg) or
anti*hepatitis B core antibody (anti*HBc). Patients with anti*HBc, but absence
of HBsAg, are
eligible if hepatitis B virus (HBV) DNA is undetectable and if they are willing
to undergo monthly
monitoring for HBV reactivation
- Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV
antibody are eligible if HCV ribonucleic acid (RNA) is ndetectable
- At time of study entry, taking any medications which are strong cytochrome
P450, family 3,
subfamily A (CYP3A) inhibitors or strong CYP3A inducers
- Intolerance to previous Anti CD20 MoAb or other anti CD20 MoAb treatment
- History of intolerance to the active ingredients or other ingredients of
Zanubrutinib