Diagnostic Approach to Multiple Myeloma

Clinical Presentations and Initial Evaluation

The presence of unexplained anemia, renal dysfunction, hypercalcemia, or bone pain—the classic CRAB criteria—defines end-organ damage requiring urgent evaluation for multiple myeloma, according to the International Myeloma Society 1, 2
Bone pain, particularly persistent back pain or pain that worsens at night, warrants immediate evaluation as lytic bone lesions are present in the majority of symptomatic patients 3
Unexplained anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal) without other clear etiology should trigger myeloma testing, as recommended by the American Society of Clinical Oncology 1, 3
Renal insufficiency (creatinine >2 mg/dL or creatinine clearance <40 mL/min) of unclear cause requires evaluation for plasma cell disorders, according to the National Kidney Foundation 1, 3
Hypercalcemia (serum calcium >11.5 mg/dL) is a critical finding that necessitates immediate workup, as stated by the Endocrine Society 1, 3

Serum protein electrophoresis (SPEP) with immunofixation is recommended to identify and characterize monoclonal protein, as suggested by the College of American Pathologists 1, 5
Nephelometric quantification of IgG, IgA, and IgM immunoglobulins is necessary for diagnosis, according to the International Myeloma Society 1, 5
Serum free light chain (FLC) assay with kappa/lambda ratio is critical for detecting light chain-only disease, as recommended by the European Myeloma Network 1, 5
A 24-hour urine collection for protein electrophoresis and immunofixation is mandatory, as stated by the American Urological Association 2, 4, 5

Bone marrow aspirate and biopsy (unilateral) with CD138 staining is necessary to quantify plasma cells—diagnosis requires ≥10% clonal plasma cells, according to the World Health Organization 1, 2, 5
Cytogenetics, including both metaphase karyotype and FISH for del(17p), t(4;14), t(14;16), is recommended for risk stratification, as suggested by the National Comprehensive Cancer Network 1, 4
Skeletal survey (plain radiographs) including spine, pelvis, skull, humeri, and femora is necessary to detect lytic lesions, according to the Radiological Society of North America 1, 4

The European Myeloma Network explicitly recommends against screening asymptomatic individuals due to low absolute risk and lack of proven mortality benefit 7
First-degree relatives of myeloma patients (who have 2-4 times higher relative risk) should not undergo routine screening, as stated by the American Society of Clinical Oncology 7
Focus should be on surveillance of diagnosed precursor conditions (MGUS, smoldering myeloma) rather than screening, according to the International Myeloma Society 7
For diagnosed MGUS, follow-up every 3-6 months initially with M-protein quantification, CBC, creatinine, calcium, and free light chain ratio is recommended, as suggested by the National Comprehensive Cancer Network 7
For smoldering myeloma, observation at 3-6 month intervals is the standard approach (not immediate treatment), according to the Journal of the National Comprehensive Cancer Network 8, 7