What are the diagnostic criteria and tests for multiple myeloma?

Diagnostic Criteria and Tests for Multiple Myeloma

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

Essential Diagnostic Tests

Laboratory Tests

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

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy to quantify plasma cell infiltration (diagnosis requires ≥10% clonal plasma cells) 1, 2
• CD138 staining to accurately determine plasma cell percentage 3
• Cytogenetic/FISH studies on bone marrow sample to assess for high-risk features (del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation) 1, 2
• Immunophenotypic studies to establish clonality of plasma cells 3

Imaging Studies

• Full skeletal survey (X-rays) including spine, pelvis, skull, humeri, and femurs to detect lytic bone lesions 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 1, 3
• CT scan to evaluate symptomatic bony sites when needed 1, 3
• PET scan may help distinguish between MGUS, smoldering myeloma, and overt myeloma 3, 2

Diagnostic Criteria

Multiple Myeloma

All criteria must be met 1:

• Clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma
• Evidence of end-organ damage (CRAB criteria) attributable to the plasma cell disorder:
  • C: Hypercalcemia (serum calcium >11.5 mg/dl)
  • R: Renal insufficiency (serum creatinine >1.73 μmol/l or >2 mg/dl, or estimated creatinine clearance <40 ml/min)
  • A: Anemia (hemoglobin <10 g/dl or ≥2 g/dl below lower limit of normal)
  • B: Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures)

Additional Myeloma Defining Events (MDEs)

Even without CRAB features, multiple myeloma can be diagnosed with 5, 2:

• Bone marrow clonal plasmacytosis ≥60%
• Serum involved/uninvolved FLC ratio ≥100 (provided involved FLC is ≥100 mg/L)

• 1 focal lesion on MRI

Differential Diagnosis

Monoclonal Gammopathy of Undetermined Significance (MGUS)

All three criteria must be met 1:

• Serum monoclonal protein <3 g/dl
• Clonal bone marrow plasma cells <10%
• Absence of end-organ damage (CRAB criteria)

Smoldering Multiple Myeloma (SMM)

Both criteria must be met 1:

• Serum monoclonal protein (IgG or IgA) ≥3 g/dl and/or clonal bone marrow plasma cells ≥10%
• Absence of end-organ damage (CRAB criteria)

Common Pitfalls and Caveats

• Relying solely on serum protein electrophoresis may miss light chain myeloma - always include serum free light chain assay in the diagnostic workup 3, 4
• Random urine samples are insufficient - a 24-hour urine collection is necessary for proper evaluation 3, 4
• Standard X-rays may miss early bone lesions - advanced imaging (MRI, CT, PET) should be considered when clinical suspicion is high despite negative X-rays 1, 3
• Cytogenetic abnormalities significantly impact prognosis - FISH studies should be performed on all newly diagnosed patients 1, 2
• Distinguishing between MGUS, SMM, and MM is critical as treatment approaches differ significantly - immediate treatment is not recommended for MGUS or SMM in most cases 1