Page 38 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE
IgM monoclonal gammopathies of clinical significance: diagnosis and management
Jahanzaib Khwaja,1 Shirley D’Sa,1 Monique C. Minnema,2 Marie José Kersten,3 Ashutosh Wechalekar1 and Josephine M.I. Vos3
1University College London Hospital, London, UK; 2Department of Hematology, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands and 3Department of Hematology, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam and Lymphoma and Myeloma Center Amsterdam, Amsterdam, the Netherlands
Abstract
IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenström macroglobulinemia and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/L with a lymphoplasmacytic bone marrow infiltration of less than 10%. A significant proportion, however, develop unique immunological and biochemical manifestations related to the monoclonal protein itself in the absence of overt malignancy and are termed IgM-related disorders or, more recently, monoclonal gammopathy of clinical significance. The indication for treatment in affected patients is dictated by the pathological characteristics of the circulating IgM rather than the tumor itself. The clinical workup and treatment options vary widely and differ from those for Waldenström macroglobulinemia. The aim of this review is to alert clinicians to IgM monoclonal gammopathy of clinical significance and to provide practical guidance on when to screen for these phenotypes. We discuss clinical characteristics, the underlying clonal profile, diagnostic workup and treatment considerations for five important subtypes: cold agglutinin disease, type I and II cryoglobulinemia, IgM-associated peripheral neuropathy, Schnitzler syndrome and IgM-associated AL amyloidosis. The inhibition of the pathogenic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centered on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and IgM-associated peripheral neuropathy are the least well developed. A multidisciplinary approach is required, particularly for IgM-related neuropathies and Schnitzler syndrome. Future work exploring novel, clone-directed agents and pathogenic IgM-directed therapies is welcomed.
Introduction
IgM monoclonal gammopathy of undetermined signifi- cance (MGUS) is defined by asymptomatic circulating IgM monoclonal (M) protein below 30 g/L with a lymphoplas- macytic bone marrow infiltration of less than 10%.1 IgM MGUS is a pre-malignant condition for non-Hodgkin lym- phomas, mostly Waldenström macroglobulinemia (WM), chronic lymphocytic lymphoma, and plasma cell neo- plasms. Most patients are candidates for observation. However, some develop diverse immunological and bio- chemical manifestations related to the monoclonal pro- tein itself.2 This may lead to organ damage, even in the absence of overt malignancy. These so-called IgM-related disorders are a distinct clinical entity termed monoclonal gammopathy of clinical significance (MGCS).3 The clinical workup and treatment options vary widely and differ from
those for WM, which have been outlined in recent con- sensus guidelines.4
The aim of this review is to alert clinicians to IgM MGCS and to provide practical guidance on when to screen for these phenotypes. We discuss the clinical characteristics, diagnostic workup and treatment considerations for five important subtypes: cold agglutinin disease (CAD), cryo- globulinemia, IgM-associated AL amyloidosis, IgM-related neuropathies and Schnitzler syndrome. A comprehensive list of IgM MGCS is listed below (Table 1).
Clonal characterization
It is important to identify the underlying clone as IgM MGUS may progress to a number of lymphoproliferative disorders or very rarely to myeloma.5 IgM MGUS most
Haematologica | 107 September 2022
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Correspondence: J.M. Vos j.m.i.vos@amsterdamumc.nl
Received: Accepted: Prepublished:
March 9, 2022. June 16, 2022. June 30, 2022.
https://doi.org/10.3324/haematol.2022.280953
©2022 Ferrata Storti Foundation Published under a CC-BY-NC license