MAGa: Monoclonal Autoimmune Gammopathies

There is a growing recognition of bidirectional relationships between immune phenomena in plasma cell disorders, such as multiple myeloma and its precursor malignancies, including autoimmune phenomena that either precede or complicate the development of neoplasms. The development of specific autoimmune disorders is a well-known aspect of B-cell lymphoproliferative diseases. At the same time, the development of plasma cell dyscrasia in patients with autoimmune diseases is well established. This may suggest that some subclones of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance, originate in the setting of persistent autoimmune activation. Interestingly, monoclonal immunoglobulins, which are key biomarkers for characterizing and monitoring monoclonal gammopathies, have long been overlooked in clinical research because they are thought to have no significant antibody function. It is plausible that unusual clinical consequences may occur when monoclonal myeloma paraproteins bind to endogenous self-antigens. Published clinical data illustrate this possibility well. This review synthesizes published evidence demonstrating that many patients with multiple myeloma and related plasma cell dyscrasias exhibit specific clinical manifestations of antigen–antibody interactions between a monoclonal immunoglobulin produced by proliferating B-cell or plasma-cell clones and autologous antigens, including neural antigens, insulin, complement components, and others. We present pilot data showing antinuclear antibody reactivity in 38% of IgM monoclonal gammopathy sera. Numerous experimental and clinical data support the importance of identifying the target of the monoclonal immunoglobulins in monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and multiple myeloma. This approach not only aids in selecting an appropriate treatment strategy and predicting prognosis but may also guide the development of targeted therapies for managing monoclonal gammopathy cases that present with a paraprotein reactive against a known self-antigen. We propose the term monoclonal autoimmune gammopathies (MAGa) to describe this clinically distinct subset of plasma cell disorders characterized by pathogenic autoantibody activity of the monoclonal immunoglobulin.