P-034: MAGNAZ trial - A prospective phase II study in patients with monoclonal gammopathy of unknown significance (MGUS) and anti-Myelin Associated Glycoprotein (MAG) Neuropathy and Zanubrutinib Treatment

Introduciton Polyneuropathy (PNP) associated with IgM monoclonal gammopathy (MGUS), also called IgM-related PNP, is mediated by the anti-neural effect of the M-protein component and is classified as one of the MGUS-related diseases. In around 70% of patients with IgM-related PNP anti-myelin associated glycoprotein (MAG) antibodies are detected. There is no established treatment for IgM-related PNP except anti-CD20 monoclonal antibody treatment with 30% or less clinical responses. There is increasing interest to use Bruton’s tyrosine kinase (BTK) inhibitors, approved for the treatment of Waldenstrom Macroglobulinemia, for IgM-related PNP treatment but a formal study is currently lacking. We therefore designed a phase 2 clinical trial to investigate the effect of zanubrutinib, a next generation BTK inhibitor, combined with anti-CD20 monoclonal antibody treatment, in IgM-related PNP with anti MAG antibodies. The primary study endpoint is change from baseline in the Rasch-built Overall Disability Scale (RODS) for inflammatory neuropathies (iRODS) at the end of Cycle 12. The main secondary endpoint is to assess the safety of zanubrutinib treatment in IgM-related PNP as measured by CTCAE, version 5.0. Methods Patients will be treated for a minimum of 6 cycles; patients experiencing hematological response continue until 12 cycles of treatment. All patients will be followed for the duration of 12 cycles for the primary endpoint analysis. Patients who have an anti MAG titer > 10.000 BTU, adequate hematological, renal and hepatic function tests, no hemorrhagic disorder and no New York Heart Association (NYHA) grade 3 or 4 cardiac disease can be included after signing informed consent. Explorative analysis will consist of Next Generation Sequencing of MYD88 and CXCR4 mutations after CD19 selection of the bone marrow aspirate at start. During study participation extensive neurological testing and serum IgM and anti MAG testing will be performed. In total 40 patients will be included and the MAGNAZ study expects to start in Q4 2021.