Symptoms and Diagnostic Workup for Multiple Myeloma
The diagnosis of multiple myeloma requires ≥10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma plus evidence of end-organ damage (CRAB criteria: hypercalcemia, renal failure, anemia, or bone lesions) attributable to the plasma cell disorder. 1
Common Presenting Symptoms
- Bone pain, particularly in the spine, ribs, and long bones, due to lytic lesions or pathologic fractures 2
- Fatigue and weakness due to anemia 1
- Recurrent infections due to immune dysfunction 3
- Symptoms of hypercalcemia (confusion, constipation, excessive thirst) 4
- Renal insufficiency symptoms (edema, decreased urine output) 4
- Nonspecific symptoms such as nausea, vomiting, malaise, and weight loss 3
Initial Laboratory Workup
- Complete blood count with differential and peripheral blood smear to assess for anemia and evaluate for rouleaux formation and circulating plasma cells 5, 6
- Chemistry screen including calcium, creatinine, albumin, and electrolytes to detect hypercalcemia and renal dysfunction 5, 6
- Serum protein electrophoresis (SPEP) and immunofixation to detect and characterize monoclonal (M-) protein 5, 7
- Nephelometric quantification of serum immunoglobulins (IgG, IgA, IgM) 5, 6
- Serum free light chain (FLC) assay with kappa/lambda ratio, especially important for detecting light chain myeloma 7, 6
- Serum β2-microglobulin and lactate dehydrogenase (LDH) for prognostic assessment 5, 6
Urine Studies
- 24-hour urine collection for protein electrophoresis and immunofixation 5, 6
- Important caveat: A 24-hour urine collection cannot be replaced by a random urine sample 5, 6
- Routine urinalysis to evaluate for proteinuria 5
Bone Marrow Evaluation
- Bone marrow aspirate and/or biopsy to confirm diagnosis when multiple myeloma is suspected 5, 7
- CD138 staining to accurately determine plasma cell percentage in bone marrow biopsies 5, 7
- Clonality assessment through immunoperoxidase staining or immunofluorescence 5
- Cytogenetics (metaphase karyotype) and fluorescence in situ hybridization (FISH) to detect high-risk features such as del(17p), t(4;14), t(14;16), and t(14;20) 5, 1
Imaging Studies
- Skeletal survey (X-rays) including spine, pelvis, skull, humeri, and femurs to detect lytic bone lesions 5, 7
- MRI of spine and pelvis is mandatory for patients with suspected solitary plasmacytoma 5
- MRI should be considered in patients with smoldering myeloma as it can detect occult lesions 5
- CT scan or PET/CT may be needed to evaluate symptomatic bony sites or distinguish between MGUS, smoldering myeloma, and overt myeloma 7, 6
Diagnostic Criteria
- Clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma 4, 1
- Evidence of end-organ damage (CRAB criteria) attributable to the plasma cell disorder 4, 1:
Common Pitfalls in Diagnosis
- Approximately 3% of patients may have nonsecretory myeloma with neither serum nor urine proteins 6
- Renal impairment can cause decreased clearance of both kappa and lambda free light chains, potentially leading to false elevations 6
- Urine-free light chain assay should not be performed 5, 6
- Immunophenotyping by flow cytometry, while performed by some centers, is not widely standardized and cannot determine plasma cell percentage in bone marrow aspirate 5
Differential Diagnosis Considerations
- Monoclonal gammopathy of undetermined significance (MGUS): serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of end-organ damage 4
- Smoldering multiple myeloma (SMM): serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%, but absence of end-organ damage 5, 4
- Other plasma cell disorders such as amyloidosis, which may require additional testing like renal biopsy 5