What is the recommended workup and treatment for an elderly patient with suspected multiple myeloma, hypercalcemia of malignancy, and potential comorbidities?

Multiple Myeloma Workup

The diagnostic workup for suspected multiple myeloma requires serum and urine protein electrophoresis with immunofixation, bone marrow aspiration/biopsy demonstrating ≥10% clonal plasma cells, complete blood count, comprehensive metabolic panel including calcium and creatinine, serum free light chains, β2-microglobulin, LDH, and full skeletal imaging. 1, 2

Essential Laboratory Testing

Protein Studies

• Serum protein electrophoresis (SPEP) with immunofixation to detect and characterize the monoclonal protein 1, 2
• 24-hour urine collection for protein electrophoresis and immunofixation—random urine samples are insufficient and cannot replace this test 1, 3
• Quantification of IgG, IgA, and IgM immunoglobulins by nephelometry 1
• Serum free light chain assay with kappa/lambda ratio, particularly important when standard SPEP is negative 1, 3

Critical pitfall: Immunofixation must be performed even if there is no measurable protein peak on electrophoresis, as some patients have light chain-only disease 1, 3

Hematologic and Chemistry Panel

• Complete blood count with differential to assess for anemia (hemoglobin <10 g/dL or 2 g/dL below normal) 1, 2
• Comprehensive metabolic panel including serum calcium (hypercalcemia defined as >11.0 mg/dL), creatinine (renal insufficiency defined as >2.0 mg/dL), and albumin 1, 2, 4
• β2-microglobulin and LDH for prognostic staging using the International Staging System 1, 2, 3

Bone Marrow Evaluation

• Unilateral bone marrow aspirate and/or biopsy to confirm ≥10% clonal plasma cells 1, 4
• CD138 immunohistochemistry staining should be used to accurately determine plasma cell percentage 1
• Clonality confirmation by immunoperoxidase or immunofluorescence staining for monoclonal immunoglobulin in plasma cell cytoplasm 1
• Both aspirate and biopsy are recommended during the same procedure—the biopsy provides more reliable assessment if the aspirate is inadequate, and the highest plasma cell count from either procedure is used for diagnosis 1

Cytogenetic Analysis

• Standard metaphase cytogenetics to separate hyperdiploid from nonhyperdiploid patients and capture uncommon abnormalities 1
• Fluorescence in situ hybridization (FISH) after plasma cell sorting with probes for high-risk features: del(17p), t(4;14), and t(14;16) 1, 2

Imaging Studies

Skeletal Assessment

• Full skeletal survey with plain radiographs including spine, pelvis, skull, humeri, and femurs is the standard approach 1, 3
• MRI of spine and pelvis provides greater detail and is mandatory if spinal cord compression is suspected 1, 3
• CT or PET/CT may help distinguish between MGUS, smoldering myeloma, and overt myeloma, and can detect extramedullary disease 1, 3

Diagnostic Criteria (CRAB)

The diagnosis requires ≥10% clonal plasma cells on bone marrow examination AND evidence of end-organ damage: 2, 4

• Calcium: Serum calcium >11.0 mg/dL 2
• Renal insufficiency: Serum creatinine >2.0 mg/dL 2
• Anemia: Hemoglobin <10 g/dL or 2 g/dL below lower limit of normal 2
• Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures 1, 2

Staging and Risk Stratification

International Staging System

The Revised International Staging System combines: 5

• β2-microglobulin levels
• Serum albumin levels
• LDH levels
• High-risk cytogenetic features from FISH

Stage I patients (28% at diagnosis) have a median 5-year survival of 82% 5

Durie-Salmon Classification

Traditional staging system requiring at minimum: 1

• Complete blood count
• Serum and urine protein electrophoresis
• Serum calcium measurement
• Full skeletal survey
• Renal function assessment

Management of Hypercalcemia of Malignancy

For patients presenting with hypercalcemia (>11.0 mg/dL), immediate aggressive IV hydration with normal saline at 150-200 mL/hour is essential to achieve urine output >100 mL/hour. 2, 6

Tumor Lysis Syndrome Prophylaxis

• Aggressive IV hydration with normal saline to prevent uric acid crystallization in renal tubules 2
• Rasburicase 0.2 mg/kg IV as a single dose (or 3-6 mg fixed dose) in high-risk patients with high tumor burden, renal insufficiency, or elevated LDH 2
• Do not delay chemotherapy for extended periods while attempting conservative measures alone—this worsens outcomes, particularly in patients with renal involvement 2

Bisphosphonate Therapy

• Bisphosphonates are the most effective therapy for hypercalcemia in myeloma and potently inhibit bone resorption 6
• Long-term bisphosphonate administration (oral or intravenous) reduces skeletal events and should be initiated for patients with stage III or relapsed disease 1, 3

Critical caveat: Screen for vitamin D deficiency before initiating bisphosphonates, as underlying deficiency can precipitate severe refractory hypocalcemia 7

Treatment Considerations for Elderly Patients

Transplant-Ineligible Patients (>65-70 years or significant comorbidities)

• Oral melphalan (9 mg/m²/day for 4 days) plus prednisone (30 mg/m²/day for 4 days) remains standard treatment, repeated every 4-6 weeks until stable response 1, 3
• Multiagent chemotherapy has not proven superior and may be inferior in elderly patients 1

Transplant-Eligible Patients (<65 years, good performance status)

• Induction with three-drug regimens including bortezomib, lenalidomide, and dexamethasone, associated with median progression-free survival of 41 months 2, 5
• High-dose melphalan 200 mg/m² IV is the preferred preparative regimen prior to autologous stem cell transplantation 1, 2, 3
• Peripheral blood progenitor cells should be used rather than bone marrow 1, 3

Common Diagnostic Pitfalls

• Failing to collect a complete 24-hour urine specimen leads to false-negative results—random samples are inadequate 1, 3
• Omitting immunofixation when electrophoresis shows no peak—some patients have non-secretory or light chain-only disease 1, 3
• Using only bone marrow aspirate without biopsy—biopsy provides more reliable plasma cell assessment if aspirate is inadequate 1
• Missing extramedullary disease by relying solely on skeletal survey without advanced imaging when clinically indicated 3