Which conditions are included in the differential diagnosis of multiple myeloma?

Differential Diagnosis of Multiple Myeloma

The differential diagnosis of multiple myeloma includes monoclonal gammopathy of undetermined significance (MGUS), primary amyloidosis, and metastatic bone disease—options b, c, and e are correct. 1, 2, 3

Key Differential Diagnoses to Consider

MGUS (Monoclonal Gammopathy of Undetermined Significance)

• MGUS is the most critical differential diagnosis because it represents a precursor condition with serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of end-organ damage (CRAB criteria). 1
• Approximately one-fourth of MGUS patients will progress to multiple myeloma or related disorders during long-term follow-up, with intervals ranging from 2 to 29 years (median 10 years). 4
• The distinction is essential because MGUS requires no immediate treatment, only lifelong monitoring, whereas multiple myeloma requires systemic chemotherapy when CRAB criteria are met. 1

Primary Amyloidosis

• Primary amyloidosis must be included in the differential as the fibrils consist of kappa or lambda monoclonal light chains, and 90% of patients have an M-protein in serum or urine. 3
• Systemic amyloidosis can develop 6 to 19 years (median 9 years) after recognition of a monoclonal protein. 4
• Key distinguishing features include nephrotic syndrome, congestive heart failure, orthostatic hypotension, macroglossia (10% of cases), and sensorimotor peripheral neuropathy—symptoms not typically seen in uncomplicated myeloma. 3
• Diagnosis requires demonstration of amyloid in tissues, with subcutaneous fat aspirate positive in 80% and bone marrow positive in 55%. 3

Metastatic Bone Disease

• Metastatic carcinoma to bone is a crucial differential because it can present with similar lytic bone lesions, bone pain, hypercalcemia, and anemia. 5
• The key distinction is that metastatic disease lacks monoclonal protein on serum/urine electrophoresis and shows <10% plasma cells on bone marrow biopsy. 1
• Imaging patterns differ: myeloma shows focal lytic "punched-out" lesions particularly in skull, spine, ribs, and pelvis with asymmetric distribution, while metastatic disease often has different patterns depending on primary tumor. 6

Smoldering Multiple Myeloma (SMM)

• SMM represents an intermediate stage with serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%, but without CRAB criteria or myeloma-defining biomarkers. 1
• This carries higher progression risk (10% per year for first 5 years) compared to MGUS but does not require immediate treatment. 1

Why Hyperthyroidism and Hypoparathyroidism Are NOT in the Differential

Hyperthyroidism (Option a - Incorrect)

• Hyperthyroidism causes diffuse osteoporosis through increased bone turnover but does not produce monoclonal proteins, plasma cell infiltration, or the characteristic lytic lesions of myeloma. 6
• While both conditions can cause hypercalcemia, hyperthyroidism lacks the defining features of myeloma: M-protein, clonal plasma cells, and focal bone destruction. 6

Hypoparathyroidism (Option d - Incorrect)

• Hypoparathyroidism causes hypocalcemia, not hypercalcemia, making it incompatible with the typical myeloma presentation where 73% have anemia and hypercalcemia is a CRAB criterion. 1
• The laboratory algorithm for differentiating bone lesions shows that intact PTH levels are suppressed or normal in multiple myeloma, but this reflects secondary suppression from hypercalcemia, not primary hypoparathyroidism. 6

Diagnostic Algorithm to Differentiate These Conditions

When evaluating suspected multiple myeloma, immediately order:

• Complete blood count, comprehensive metabolic panel (including calcium and creatinine)
• Serum protein electrophoresis with immunofixation
• Serum free light chain assay with kappa/lambda ratio
• Quantitative immunoglobulins (IgG, IgA, IgM)
• 24-hour urine collection for protein electrophoresis 7, 1

If M-protein is detected or abnormal free light chain ratio is present:

• Proceed immediately to bone marrow aspiration and biopsy with CD138 staining
• Obtain cytogenetic/FISH studies for risk stratification
• Perform whole-body low-dose CT or FDG-PET/CT (detects 25.5% more lesions than plain radiographs) 6, 7

Critical diagnostic patterns:

• Multiple myeloma: M-protein present + abnormal FLC ratio + ≥10% clonal plasma cells + CRAB criteria present 1
• MGUS: M-protein <3 g/dL + <10% plasma cells + no CRAB criteria 1
• Primary amyloidosis: M-protein present + tissue biopsy showing amyloid deposits + systemic symptoms (cardiac, renal, neurologic) 3
• Metastatic disease: No M-protein + <10% plasma cells + history of primary malignancy 5