Gammopathy

Gammopathy refers to disorders characterized by abnormal gammaglobulin production, most often a monoclonal immunoglobulin produced by a clonal population of plasma cells or B cells. When a single clone predominates, a monoclonal gammopathy is present; when many clones are involved, immunoglobulins are polyclonal. The term is used for several conditions, including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, Waldenström macroglobulinemia, AL amyloidosis, and cryoglobulinemias. MGUS is the most common asymptomatic gammopathy in older adults and carries a risk of progression to a malignant plasma cell disorder, about 1% per year.

Pathophysiology: A clone of plasma cells or lymphoplasmacytic cells produces a monoclonal protein (M-protein) detectable in serum or urine. M-protein may be an intact immunoglobulin (often IgG or IgA) or a light chain (free kappa or lambda). Abnormal ratios of free light chains and the type and amount of M-protein help classify conditions and guide monitoring.

Diagnosis: Initial testing includes serum protein electrophoresis, immunofixation, and quantitative immunoglobulins; the serum free light chain assay is useful. Bone marrow examination and imaging assess clonal burden and organ damage. Diagnostic criteria distinguish MGUS (M-protein <3 g/dL, bone marrow plasma cells <10%, and no CRAB features—hypercalcemia, renal insufficiency, anemia, or lytic bone lesions) from smoldering myeloma and from active multiple myeloma or Waldenström macroglobulinemia.

Management: MGUS and other gammopathies without symptoms are typically monitored. Treatments for progressive or symptomatic disease aim to control the malignant clone and may include proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, alkylating agents, or BTK inhibitors, often with autologous stem cell transplantation in eligible patients. Supportive care addresses anemia, bone disease, and infection risk.