(4.13) A Reason to Keep a Broad Differential : Hypercalcemia in Non-Secretory Multiple Myeloma

Malignancy accounts for most cases of hypercalcemia diagnosed in hospital, with humoral hypercalcemia of malignancy being the most common etiology.  Osteolytic metastases are the other major mechanism for hypercalcemia of malignancy and may occur in cases of multiple myeloma (MM).  We present a case of symptomatic hypercalcemia with delayed diagnosis of the underlying cause due to non-secretory MM.

Case(s) Description :

A 70-year-old male presented to hospital with a 4-day history of polydipsia, fatigue, and lightheadedness. He was taking a prescribed loop diuretic but had no prescriptions for thiazide diuretics, lithium, teriparatide, abaloparatide, or theophylline. He denied taking supplemental calcium in any form.

Serum calcium level was 17.2 mg/dL (8.6-10.3); a measurement 3 months earlier was 9.6 mg/dL.  Creatinine was 6.4 mg/dL, increased from a baseline of 1.6-2.0 mg/dL.  Parathyroid hormone (PTH) was 16 pg/mL, and serum phosphorus and magnesium levels were within their respective reference ranges.  PTH-related peptide was < 2 pM (0.2-3.0), 25-hydroxyvitamin D 8 ng/mL (30-100), and 1,25-dihydroxyvitamin D 21.2 pg/mL (19.9-79.3).

The patient was modestly anemic (hemoglobin 13.2 g/dL, 14.0-18.0), but PTH-independent hypercalcemia and acute renal failure prompted work up for MM.  Serum and urine protein electrophoresis, serum free light chains, immunoglobulin levels, and lactate dehydrogenase level were all unremarkable.  However, computed tomography demonstrated multiple lytic bone lesions, and bone marrow biopsy revealed hypercellular marrow with areas of up to 80% clonal plasma cells, confirming a diagnosis of non-secretory MM.  Hypercalcemia and renal failure were refractory to hydration but improved significantly after treatment with cyclophosphamide, bortezomib, and dexamethasone.

 

Discussion :

Hypercalcemia defined as serum calcium level ≥ 11 mg/dL complicates 10-15% of MM cases and appears to be caused by secretion of factors that promote osteoclast formation and activation including tumor necrosis factor-a, interleukin (IL)-1, IL-3, and IL-6.  True non-secretory myeloma with defective immunoglobulin synthesis accounts for only 1% of cases.  In a large series comparing secretory to non-secretory MM cases, patients with non-secretory MM were less anemic and more likely to have lytic bone lesions and hypercalcemia than patients with secretory MM as in this patient’s case. A skeletal survey to screen for lytic lesions of MM should be obtained when severe hypercalcemia is PTH-independent, PTH-related peptide is undetectable, hypervitaminosis D and ectopic calcitriol production have been excluded, and serologic workup for MM, including serum free light chains, is nondiagnostic.