Characteristic Serum Free Light Chain Assay Results in Multiple Myeloma
Primary Characteristic Finding
The hallmark serum free light chain (FLC) assay finding in multiple myeloma is an abnormal kappa/lambda ratio, typically with marked elevation of the involved light chain and suppression of the uninvolved light chain. 1, 2
Defining the Abnormal FLC Ratio
The normal reference range for the kappa/lambda FLC ratio is 0.26-1.65. 2, 3 In multiple myeloma, this ratio becomes significantly distorted:
- For kappa-producing myeloma: The ratio is elevated above 1.65, often substantially higher 2, 3
- For lambda-producing myeloma: The ratio is decreased below 0.26, often substantially lower 2, 3
Severity Stratification of FLC Ratio Abnormalities
The degree of FLC ratio abnormality carries important diagnostic and prognostic implications:
Myeloma-Defining Event Threshold
- An FLC ratio ≥100 (for involved kappa) or ≤0.01 (for involved lambda), with involved FLC ≥100 mg/L, constitutes a myeloma-defining event that allows diagnosis of active multiple myeloma even without CRAB features, provided ≥10% clonal bone marrow plasma cells are present. 2, 4
- This ultra-high FLC ratio identifies patients at imminent risk who require immediate treatment. 2, 4
Prognostic Thresholds
- Severely abnormal ratios (<0.03 or >32) predict significantly worse overall survival (median 30 months) compared to less abnormal ratios between 0.03-32 (median 39 months). 3
- Patients with FLC ratios ≥100 in smoldering myeloma have a 72-79% risk of progression to active disease within 2 years, with median time to progression of only 15 months. 2, 5
Moderate Abnormalities
- FLC ratios between 8-100 suggest possible light chain MGUS or smoldering multiple myeloma, requiring comprehensive evaluation to distinguish between these entities. 2
Quantitative Light Chain Elevation
Beyond the ratio abnormality, the absolute level of the involved light chain is characteristically elevated:
- The involved FLC must be ≥100 mg/L to meet the myeloma-defining event criterion when the ratio is ≥100 or ≤0.01. 4
- Both kappa and lambda may be elevated above normal ranges in the setting of renal impairment, but the ratio remains the key discriminator of clonality. 2
Clinical Context and Interpretation
Diagnostic Utility
- The serum FLC assay combined with serum protein electrophoresis (SPEP) and immunofixation (SIFE) provides high sensitivity for screening multiple myeloma and related plasma cell disorders, making it a standard component of initial diagnostic workup. 1
- The FLC assay is particularly valuable for monitoring the 3% of patients with nonsecretory myeloma who lack measurable serum or urine M-proteins. 1
Monitoring Disease Response
- Normalization of the FLC ratio during treatment, even without achieving complete response, predicts improved progression-free survival (29 vs 16 months) and overall survival (91 vs 58 months). 6
- Serial measurements must use the same assay to ensure accurate relative quantification. 1, 7
Important Caveats
- The FLC assay cannot replace 24-hour urine protein electrophoresis for monitoring patients with measurable urinary M-proteins. 1, 7
- Renal impairment can cause elevation of both light chains through decreased clearance, potentially affecting interpretation. 2, 7
- A normal or mildly abnormal FLC ratio does not exclude multiple myeloma, as most patients with active disease have ratios well below the ≥100 threshold. 4
Bone Marrow Immunohistochemistry Correlation
When assessing plasma cell clonality by immunohistochemistry on bone marrow specimens: