{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T19:44:47Z","timestamp":1740167087375,"version":"3.37.3"},"reference-count":54,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2017,12,18]],"date-time":"2017-12-18T00:00:00Z","timestamp":1513555200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>Among monoclonal gammopathies of undetermined significance (MGUSs), the immunoglobulin M (IgM) MGUS subtype stands as a unique entity and plays a pivotal role as a pre-malignant condition for multiple B-cell non-Hodgkin lymphomas, most notably Waldenstr\u00f6m macroglobulinemia (WM). A relationship between IgM MGUS and WM has been proposed for decades. However, insight regarding the pathobiology of these two conditions improved significantly in recent years, strengthening the hypothesis that WM and IgM MGUS are different stages of the same disease. Therefore, the understanding of IgM MGUS and that of WM are interconnected and advances in one will likely impact the other. Furthermore, IgM MGUS has been more commonly recognized as the underlying etiology of IgM-related disorders. In this review, we explore recent advances in the understanding of the pathobiology of IgM MGUS and WM and the treatment of common IgM-related disorders.<\/ns4:p>","DOI":"10.12688\/f1000research.12880.1","type":"journal-article","created":{"date-parts":[[2017,12,18]],"date-time":"2017-12-18T09:20:05Z","timestamp":1513588805000},"page":"2142","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Advances in the understanding of IgM monoclonal gammopathy of undetermined significance"],"prefix":"10.12688","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7350-5531","authenticated-orcid":false,"given":"Jonas","family":"Paludo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen 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Leung","year":"2012","journal-title":"Blood."},{"key":"ref-41","doi-asserted-by":"publisher","first-page":"623-30","DOI":"10.1111\/bjh.14279","article-title":"Renal disease related to Waldenstr\u00f6m macroglobulinaemia: incidence, pathology and clinical outcomes.","volume":"175","author":"J Vos","year":"2016","journal-title":"Br J Haematol."},{"key":"ref-42","doi-asserted-by":"publisher","first-page":"301-19","DOI":"10.1016\/j.blre.2015.03.001","article-title":"Waldenstr\u00f6m macroglobulinemia: What a hematologist needs to know.","volume":"29","author":"P Kapoor","year":"2015","journal-title":"Blood Rev."},{"key":"ref-43","doi-asserted-by":"publisher","first-page":"838-50","DOI":"10.1016\/j.mayocp.2017.02.003","article-title":"Monoclonal Gammopathy-Associated Peripheral Neuropathy: Diagnosis and Management.","volume":"92","author":"H Chaudhry","year":"2017","journal-title":"Mayo Clin Proc."},{"key":"ref-44","doi-asserted-by":"publisher","first-page":"792-5","DOI":"10.1002\/ana.410400516","article-title":"A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy.","volume":"40","author":"M Dalakas","year":"1996","journal-title":"Ann Neurol."},{"key":"ref-45","doi-asserted-by":"publisher","first-page":"1370-7","DOI":"10.1007\/s00415-002-0808-z","article-title":"A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy.","volume":"249","author":"G Comi","year":"2002","journal-title":"J Neurol."},{"key":"ref-46","doi-asserted-by":"publisher","first-page":"1742-4","DOI":"10.1212\/01.wnl.0000335268.70325.33","article-title":"Long-term effect of rituximab in anti-mag polyneuropathy.","volume":"71","author":"L Benedetti","year":"2008","journal-title":"Neurology."},{"key":"ref-47","doi-asserted-by":"publisher","first-page":"286-93","DOI":"10.1002\/ana.21577","article-title":"Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy.","volume":"65","author":"M Dalakas","year":"2009","journal-title":"Ann Neurol."},{"key":"ref-48","doi-asserted-by":"publisher","first-page":"485-9","DOI":"10.1136\/jnnp.74.4.485","article-title":"Treatment of IgM antibody associated polyneuropathies using rituximab.","volume":"74","author":"A Pestronk","year":"2003","journal-title":"J Neurol Neurosurg Psychiatr."},{"key":"ref-49","doi-asserted-by":"publisher","first-page":"728-42","DOI":"10.1111\/bjh.14492","article-title":"Investigation and management of IgM and Waldenstr\u00f6m-associated peripheral neuropathies: recommendations from the IWWM-8 consensus panel.","volume":"176","author":"S D'Sa","year":"2017","journal-title":"Br J Haematol."},{"key":"ref-50","doi-asserted-by":"publisher","first-page":"172-90","DOI":"10.1159\/000443200","article-title":"Immunoglobulin Light-Chain Amyloidosis: From Basics to New Developments in Diagnosis, Prognosis and Therapy.","volume":"135","author":"E Muchtar","year":"2016","journal-title":"Acta Haematol."},{"key":"ref-51","doi-asserted-by":"publisher","first-page":"1035-41","DOI":"10.1016\/j.autrev.2014.08.031","article-title":"Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler's syndrome: a French multicenter study.","volume":"13","author":"A N\u00e9el","year":"2014","journal-title":"Autoimmun Rev."},{"key":"ref-52","doi-asserted-by":"publisher","first-page":"1352-4","DOI":"10.1016\/j.jaci.2011.05.023","article-title":"Successful canakinumab treatment identifies IL-1\u03b2 as a pivotal mediator in Schnitzler syndrome.","volume":"128","author":"H de Koning","year":"2011","journal-title":"J Allergy Clin Immunol."},{"key":"ref-53","doi-asserted-by":"publisher","first-page":"1634-8","DOI":"10.1136\/annrheumdis-2012-202192","article-title":"Sustained efficacy of the monoclonal anti-interleukin-1 beta antibody canakinumab in a 9-month trial in Schnitzler's syndrome.","volume":"72","author":"H de Koning","year":"2013","journal-title":"Ann Rheum Dis."},{"key":"ref-54","doi-asserted-by":"publisher","first-page":"114-22","DOI":"10.4065\/84.2.114","article-title":"Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component.","volume":"84","author":"J Lust","year":"2009","journal-title":"Mayo Clin 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