Novel Aspects Pertaining to the Relationship of Waldenström's Macroglobulinemia, IgM Monoclonal Gammopathy of Undetermined Significance, Polyclonal Gammopathy, and Hypoglobulinemia

Abstract

Waldenstrom macroglobulinemia (WM) is associated with a precursor condition, monoclonal gammopathy of undetermined significance (MGUS) of immunoglobulin-M (IgM) type. The etiology of these conditions is unknown. Recent studies at the population level have provided new data regarding familial aggregation of these disorders and other B-cell malignancies. Studies of familial clusters of WM have demonstrated an increased frequency of IgM MGUS compared to the general population and have provided new data suggesting that the phenotypic spectrum may also include polyclonal gammopathy and hypoglobulinemia. While the preponderance of immunoglobulin abnormalities in relatives of WM cases involves IgM, other immunoglobulin types (IgG and IgA) may also be affected. Large collaborative studies are needed to confirm these findings, which present an opportunity to define the earliest lesion(s) in the WM oncogenic pathway.

Pathophysiology of Waldenstrom's macroglobulinemia

“…The association of RBC transfusion dependency with an increased risk of death or progression to acute leukemia suggests that more aggressive MDS biology may be a factor. 6 However, in this analysis, increasing iron overload (defined as a serum ferritin level >1000 ng/mL) was independently associated with worse survival even after discounting the known negative impact of RBC transfusion dependency, suggesting that iron overload may be an independent negative prognostic factor. Interestingly, the adverse impact of elevated ferritin levels was documented only in low-risk subtypes of MDS, such as refractory anemia, with or without ring sideroblasts, rather than in higher risk subtypes such as refractory anemia with multilineage dysplasia or refractory anemia with excess blasts.…”

“…6,19,27 For example, a patient with Waldenström's macroglobulinemia for 37 years 17 had three children with IgM M-spikes and/or hypogammaglobulinemia. As many as 20% of WM patients have a family member with such immunoglobulin abnormalities.…”

“…Malcovati et al reported that RBC transfusion dependency was an independent negative prognostic factor for overall survival in MDS, and that increasing RBC transfusion load (total transfusions; transfusions per month) was associated with worse survival. 6 RBC transfusion dependency is now incorporated into a WHObased prognostic staging system (WPSS) for MDS. 7 However, it remains uncertain whether impaired outcomes in MDS patients dependent on RBC transfusions are directly related to iron overload, or to worse MDS biology (e.g., increasing dyserythropoiesis).…”

“…[3][4][5] The development of WM is preceded by an IgM monoclonal gammopathy of undetermined significance (MGUS) in most, perhaps all, patients. 6 The incidence of MGUS rises with increasing age. Transformation to overt WM or other malignant lymphoproliferative disorder occurs at a rate of 1.5% per year.…”

Curcumin for the prevention of progression in monoclonal gammopathy of undetermined significance: A word of caution

“…Whether curcumin inhibits iL-12 production from DCs in MGUS is a critical issue in view of the fact that immunosuppression is a known risk factor for the development of MGUS (11). Studies of familial clusters of Waldenstrom's macroglubulinemia, another lymphoproliferative disease often preceded by MGUS, have found an increased frequency of igM MGUS compared to the general population, and have provided data suggesting that the phenotypic spectrum may also include hypoglobulinemia (29).…”