Serum protein electrophoresis and serum free light chain (FLC) testing should be performed in this patient with likely multiple myeloma; together, these have a diagnostic sensitivity approaching 100% for multiple myeloma requiring therapy. This patient has several findings suspicious for this disease as the cause of his hypercalcemia, including osteopenia with a thoracic compression fracture, anemia, and kidney dysfunction. However, kidney dysfunction can occur as a direct result of hypercalcemia, regardless of its underlying cause. An important clue in this patient is the discordance between the degree of proteinuria assessed by the urinalysis compared with the urine protein-creatinine ratio. A routine dipstick urinalysis will detect albuminuria but is relatively insensitive at detecting other urine proteins. However, a urine protein-creatinine ratio measures all proteins in the urine, including immunoglobulins, if present. This discrepancy should raise suspicion for monoclonal FLCs in the urine (Bence-Jones proteinuria) and potential cast nephropathy. Similarly, a sulfosalicylic acid test will detect all urine proteins, including light chains, and can be performed for suspected myeloma cast nephropathy. In FLC myeloma, the serum protein electrophoresis may only reveal hypogammaglobulinemia and no monoclonal band or a low-level monoclonal band because of its insensitivity at detecting monoclonal FLCs. However, the serum FLC test, an antibody-based assay that can detect low levels of FLCs, will demonstrate an elevated level of the affected monoclonal FLC and an abnormal serum κ/λ FLC ratio.

Increased 1,25-dihydroxyvitamin D (calcitriol) levels may result from ingestion of calcitriol or increased 25-hydroxyvitamin D (calcidiol) activation to calcitriol as a result of underlying granulomatous disease (for example, sarcoidosis) or lymphoma, thus leading to hypercalcemia. This patient has no history of calcitriol ingestion and no physical examination or radiographic features of granulomatous disease or lymphoma. Increased calcitriol levels do not explain his anemia, osteopenia and thoracic compression fracture, or kidney dysfunction with nonalbumin proteinuria.

Primary hyperparathyroidism can present with hypercalcemia, bone mineral density loss with increased compression fracture risk, and, when hypercalcemia is severe enough or long-standing, kidney dysfunction. However, primary hyperparathyroidism is uncommonly associated with anemia and does not explain the proteinuria, so measuring the intact parathyroid hormone level is not indicated.

Hypercalcemia associated with myeloma results from osteoclast activation, not secretion of parathyroid hormone–related protein (PTHrP). PTHrP is produced more commonly in solid tumors, such as squamous cell (head and neck, lung); renal cell; and bladder, breast, and ovarian carcinomas. Although the patient has an extensive smoking history, no findings on physical examination or chest radiograph suggest the presence of a solid tumor. Additionally, PTHrP-mediated hypercalcemia from an occult solid tumor would not explain this patient's proteinuria.