Sodium Disorders in Multiple Myeloma: Beyond Pseudohyponatremia to Clinical Pitfalls and Mechanistic Insights

Hyponatremia is a relatively frequent finding in multiple myeloma (MM) and may result from either pseudohyponatremia, due to marked hyperproteinemia, or true hyponatremia from genuine sodium-water imbalance. Differentiating between these two entities is essential, as they differ in pathogenesis, clinical relevance, and management. Pseudohyponatremia, observed in approximately 15-20% of MM patients, is a measurement artifact occurring with indirect ion-selective electrode techniques when plasma water fraction is reduced by high M protein levels. Serum osmolality remains normal, and no sodium correction is required. True hyponatremia (<135 mEq/L with hypo-osmolality) is less common but clinically significant, often associated with worse prognosis. Mechanisms include renal impairment (cast nephropathy, Fanconi syndrome, light chain deposition), hypervolemia from advanced renal failure, hypovolemia from gastrointestinal losses or diuretics, drug-induced effects (notably bortezomib, cyclophosphamide), and paraneoplastic SIADH. Alterations in electroneutrality and strong ion difference (SID) from highly cationic M protein may further lower sodium, usually mildly. Pseudohyponatremia is managed by controlling the underlying myeloma and reducing paraproteinemia. True hyponatremia treatment is etiology-specific: isotonic saline for hypovolemia, fluid restriction ± solute supplementation for SIADH, careful diuretic adjustment for hypervolemia, and withdrawal of causative drugs when possible. Optimal control of the plasma cell clone, through modern triplet or quadruplet regimens prevents recurrence. A structured diagnostic approach integrating volume status, laboratory evaluation, and medication review is critical to distinguish pseudo from true hyponatremia, prevent inappropriate interventions, and address the underlying disease.