What are the steps to diagnose multiple myeloma?

Diagnostic Approach to Multiple Myeloma

The diagnosis of multiple myeloma requires ≥10% clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma, plus evidence of end-organ damage (CRAB criteria: hypercalcemia, renal insufficiency, anemia, or bone lesions) attributable to the plasma cell disorder. 1, 2

Essential Diagnostic Tests

Laboratory Evaluation

• Serum protein electrophoresis and immunofixation to detect and characterize monoclonal (M-) protein 3, 1
• 24-hour urine collection for protein electrophoresis and immunofixation (random samples are insufficient) 3, 1, 4
• Quantification of immunoglobulins (IgG, IgA, and IgM) by nephelometry 3, 1
• Serum free light chain (FLC) assay with kappa/lambda ratio, especially important for detecting light chain myeloma 1, 4
• Complete blood count to assess for anemia 3, 2
• Serum creatinine and calcium levels to evaluate for renal insufficiency and hypercalcemia 3, 2

Bone Marrow Assessment

• Bone marrow aspiration and biopsy to quantify plasma cell infiltration (diagnosis requires ≥10% clonal plasma cells) 3, 1
• CD138 staining to accurately determine plasma cell percentage 1, 2
• Immunohistochemistry or immunofluorescence to establish clonality of plasma cells 1
• Cytogenetic/FISH studies for risk stratification, particularly to identify high-risk abnormalities such as del(13), t(4;14), and del(17p) 3, 1

Imaging Studies

• Full skeletal survey (X-rays) including spine, pelvis, skull, humeri, and femurs to detect lytic bone lesions 3, 1
• MRI of spine and pelvis if there are symptoms suggesting bone lesions even with negative X-rays, or if spinal cord compression is suspected 3, 1
• CT scan may be needed to evaluate symptomatic bony sites 3, 1
• PET scan may help distinguish between MGUS, smoldering myeloma, and overt myeloma 3, 1

Diagnostic Criteria and Differential Diagnosis

CRAB Criteria for End-Organ Damage

• C: Hypercalcemia (serum calcium >11.5 mg/dL) 2
• R: Renal insufficiency (serum creatinine >2 mg/dL or creatinine clearance <40 mL/min) 2
• A: Anemia (hemoglobin <10 g/dL or 2 g/dL below lower limit of normal) 2
• B: Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures) 2

Differential Diagnosis Between Plasma Cell Disorders

• Multiple Myeloma: ≥10% clonal plasma cells in bone marrow or biopsy-proven plasmacytoma, plus CRAB criteria 3, 2
• Smoldering Multiple Myeloma (SMM): Serum monoclonal protein (IgG or IgA) ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%, but absence of CRAB criteria 3, 2
• Monoclonal Gammopathy of Undetermined Significance (MGUS): Serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of CRAB criteria 3, 2

Risk Stratification

• The Revised International Staging System combines serum biomarkers (β2-microglobulin, albumin, and lactate dehydrogenase) with cytogenetic abnormalities to assess prognosis 5
• Cytogenetic abnormalities such as del(13), t(4;14), and del(17p) are associated with poorer outcomes 3
• Progression rates differ significantly: MGUS progresses at 1% per year, while SMM progresses at 10% per year for the first 5 years 3, 2

Common Pitfalls and Caveats

• Bone marrow examination is not routinely recommended for IgG MGUS if serum M-protein ≤15 g/L without end-organ damage 2
• Bone marrow examination is recommended for all IgA and IgM M-proteins 2
• Serum FLC measurements can be affected by renal function, potentially leading to false elevations 4
• The same test should be used for serial measurements to ensure accurate relative quantification 4
• Unnecessary bone marrow biopsies and imaging in low-risk MGUS patients should be avoided 2
• Serum FLC assay cannot completely replace 24-hour urine protein electrophoresis for monitoring patients with measurable urinary M-protein 4

By following this systematic diagnostic approach, clinicians can accurately diagnose multiple myeloma and differentiate it from related plasma cell disorders, allowing for appropriate treatment decisions and improved patient outcomes.