Significance and Management of Elevated Free Light Chains
Elevated serum free light chains (FLC) with an abnormal kappa/lambda ratio (>1.65 for kappa or <0.26 for lambda) strongly suggests a monoclonal gammopathy requiring comprehensive evaluation and possible treatment based on the underlying plasma cell disorder. 1
Diagnostic Significance of Elevated Free Light Chains
Initial Assessment
- First evaluate the kappa/lambda ratio:
- Normal ratio (0.26-1.65): May indicate renal impairment or polyclonal activation
- Abnormal ratio (>1.65 for kappa or <0.26 for lambda): Suggests monoclonal gammopathy 1
- A markedly elevated FLC ratio ≥100 is a predictor of imminent progression in smoldering multiple myeloma (SMM), with 72% risk of progression to multiple myeloma within 2 years 2
Required Laboratory Workup
- Complete diagnostic panel should include:
- Serum protein electrophoresis (SPEP) with immunofixation
- Urine protein electrophoresis (UPEP) with immunofixation
- Quantitative immunoglobulins (IgG, IgA, IgM)
- Complete blood count with differential
- Comprehensive metabolic panel including calcium, creatinine, albumin 1
- 24-hour urine collection for electrophoresis and immunofixation 3
Bone Marrow Examination
- Bone marrow aspirate and/or biopsy is indicated when a plasma cell dyscrasia is suspected
- Diagnosis of multiple myeloma is confirmed when >10% clonal plasma cells are detected
- CD138 stains should be used to accurately determine plasma cell percentage
- Both metaphase cytogenetics and FISH should be performed 3
Clinical Utility in Different Conditions
Multiple Myeloma
- Essential for diagnosis of light chain and nonsecretory myeloma
- Detected elevated FLC in 19 of 28 patients with nonsecretory myeloma 4
- Part of response assessment criteria - stringent complete response requires normal FLC ratio 1
- Helps monitor disease activity and treatment response 1
Smoldering Multiple Myeloma (SMM)
- FLC ratio ≥100 identifies high-risk SMM patients who may benefit from early treatment
- Median time to progression: 15 months with FLC ratio ≥100 vs. 55 months with ratio <100 2
Monoclonal Gammopathy of Undetermined Significance (MGUS)
- Recommended for risk stratification of MGUS progression 1
- Regular monitoring of FLC ratio provides early warning of disease progression 1
Amyloidosis
- Critical for diagnosis and monitoring of light chain amyloidosis 5
- Changes in FLC levels reflect disease activity 4
Management Approach
For Multiple Myeloma with Renal Impairment
- Bortezomib/dexamethasone-based regimens are recommended
- Consider therapeutic plasma exchange for very high FLC levels with renal impairment
- Aim for at least 50-60% reduction in serum FLC concentration 1
Supportive Care Measures
- Aggressive hydration to maintain high urine output
- Urine alkalinization when appropriate
- Treatment of hypercalcemia if present 1
Monitoring Response
- Serial measurement of serum FLC to track disease activity
- Response assessment should follow International Myeloma Working Group criteria 1
Common Pitfalls and Limitations
- Renal impairment can elevate both kappa and lambda chains while maintaining a normal ratio
- In severe renal impairment, the "normal" FLC ratio range may be wider (0.34-3.10) 1
- Different assay systems may not be completely harmonized and can produce discordant FLC ratios 6
- Analytical imprecision (CV) of 6-11% for kappa and lambda FLC measurement and 16% for the calculated ratio 6
- Not all patients with monoclonal gammopathy will have abnormal FLC results despite presence of intact monoclonal immunoglobulin 6
- Three different assays are available (Freelite® being the gold standard) and are not interchangeable during patient follow-up 5