Suspecting Multiple Myeloma: Clinical Presentations and Diagnostic Approach
Multiple myeloma should be suspected in patients presenting with unexplained hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB criteria), particularly when accompanied by symptoms such as bone pain, fatigue, or recurrent infections. 1, 2
Clinical Presentations That Should Raise Suspicion
- Bone pain or pathologic fractures: Multiple myeloma commonly presents with bone pain (especially in the back or chest) or pathologic fractures due to lytic bone lesions 1, 3
- Fatigue or weakness: Anemia (hemoglobin <10 g/dL or 2 g/dL below lower limit of normal) is a common presenting feature 2, 4
- Renal problems: Elevated creatinine (>2 mg/dL) or reduced creatinine clearance (<40 mL/min) may indicate renal involvement 2, 3
- Hypercalcemia: Serum calcium >11.5 mg/dL can cause symptoms like confusion, constipation, and dehydration 2, 4
- Recurrent infections: Due to immune dysfunction from abnormal immunoglobulin production 5, 4
- Neurological symptoms: May indicate spinal cord compression from vertebral involvement 1, 3
Diagnostic Approach
Initial Laboratory Tests
- Serum protein electrophoresis (SPEP) with immunofixation: To detect and characterize monoclonal protein (M-protein) 1, 2
- Urine protein electrophoresis (UPEP): 24-hour urine collection with immunofixation to detect Bence Jones proteins 1, 6
- Serum free light chain (FLC) assay: Essential for detecting light chain myeloma, particularly when standard SPEP is negative 6, 4
- Complete blood count: To evaluate for anemia 1, 2
- Serum creatinine and calcium levels: To assess for renal insufficiency and hypercalcemia 1, 2
- Quantitative immunoglobulins: Measurement of IgG, IgA, and IgM levels 1, 2
Bone Marrow Evaluation
- Bone marrow aspiration and biopsy: Required to confirm ≥10% clonal plasma cells 1, 4
- Immunohistochemistry or flow cytometry: To confirm clonality of plasma cells 6, 3
- Cytogenetic/FISH studies: To identify high-risk features like del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutations 1, 4
Imaging Studies
- Skeletal survey: X-rays of spine, pelvis, skull, humeri, and femurs to detect lytic bone lesions 1, 2
- Advanced imaging: MRI or CT scan for symptomatic bony sites even if skeletal survey is negative 1, 6
- MRI of spine: Recommended when spinal cord compression is suspected 1, 3
Diagnostic Criteria for Multiple Myeloma
Multiple myeloma is diagnosed when the following criteria are met:
- ≥10% clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma 1, 4
- Evidence of end-organ damage (CRAB criteria) attributable to the plasma cell disorder 1, 2
Additionally, multiple myeloma can be diagnosed in the absence of CRAB features if any of the following are present:
- Bone marrow clonal plasmacytosis ≥60% 3, 4
- Serum involved/uninvolved free light chain ratio ≥100 (provided involved FLC is ≥100 mg/L) 3, 4
- More than one focal lesion on MRI 3, 4
Common Pitfalls to Avoid
- Failing to differentiate between MGUS, smoldering myeloma, and symptomatic multiple myeloma: MGUS has <3 g/dL monoclonal protein, <10% bone marrow plasma cells, and no CRAB features 2, 7
- Missing light chain myeloma: Always perform serum free light chain assay when suspecting myeloma, especially with negative SPEP 6, 7
- Overlooking renal involvement: Renal insufficiency can be the first manifestation of myeloma 2, 3
- Attributing bone pain to other causes: Consider myeloma in older patients with unexplained bone pain 5, 4
- Incomplete imaging: Conventional skeletal survey may miss lesions that would be detected by MRI or CT 1, 6
Risk Stratification
Once diagnosed, multiple myeloma should be risk-stratified based on cytogenetic findings:
- High-risk: del(17p), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 3, 4
- Double-hit myeloma: Presence of any two high-risk factors 3, 4
- Triple-hit myeloma: Presence of three or more high-risk factors 3, 4
Risk stratification is crucial for determining appropriate treatment approaches and prognosis 3, 4.