SOHO State of the Art Updates and Next Questions | Monoclonal Gammopathy of Clinical Significance: A Multisystem...

Monoclonal gammopathy of clinical significance (MGCS) has emerged as a clinically important but underrecognized category of clonal plasma cell or B-cell disorders that manifest with significant organ dysfunction in the absence of malignancy-defining criteria such as those used for multiple myeloma (MM) or Waldenström macroglobulinemia. The pathogenesis of MGCS involves various mechanisms through which monoclonal protein or the clonal cells cause tissue damage. These mechanisms include direct deposition of immunoglobulins in target tissues, activation of immune complexes, complement pathway dysregulation, and in some syndromes, paraneoplastic cytokine-mediated effects. The classification of MGCS is broad and heterogeneous, but organizing it based on the primary organ system involved has proven clinically practical. MGCS includes renal (MGRS), neurologic (MGNS), dermatologic (MGSS), and multisystemic syndromes such as POEMS and TEMPI. Strategy The clinical manifestations of MGCS are diverse and often resemble those of autoimmune, inflammatory, or idiopathic disorders. The diagnostic process requires a high index of suspicion, particularly in patients with known MGUS or low-level M-proteins presenting with unexplained organ dysfunction. The complexity of the diagnosis often necessitates multidisciplinary collaboration, involving nephrologists, hematologists, neurologists, dermatologists, and pathologists. Therapeutic strategies are adapted from those used in MM, AL amyloidosis, or lymphoproliferative diseases, depending on the clonal lineage. There is an urgent requirement for consensus on diagnostic criteria and standardized disease definitions. Multinational collaborative efforts and disease-specific registries are essential to better understand the true epidemiology, natural history, and treatment responses for these conditions.