What is the normal serum free light‑chain κ/λ ratio and what workup is indicated for an abnormal result?

Normal Serum Free Light Chain κ/λ Ratio and Workup for Abnormal Results

Normal Reference Range

The normal serum free light chain κ/λ ratio is 0.26-1.65 in patients with normal renal function. 1, 2, 3 This range indicates polyclonal B-cell activity typical of benign conditions such as chronic infection, inflammation, autoimmune disease, or liver cirrhosis. 3

Critical Adjustment for Renal Impairment

• In severe renal impairment (CKD stage 5 or eGFR <15 mL/min/1.73m²), the normal reference range expands significantly to 0.34-3.10 because free light chains are normally cleared by the kidneys and reduced clearance differentially affects kappa and lambda chains. 2, 3
• Always assess renal function (serum creatinine, eGFR) when interpreting FLC ratios to apply the appropriate reference range. 3

Interpretation of Abnormal Ratios

Ratio >1.65 (Kappa-Dominant)

• Suggests a kappa monoclonal component and warrants hematologic evaluation for plasma cell disorders. 3
• When κ/λ ratio >3.49 with eGFR >60 mL/min/1.73m², the sensitivity and specificity for malignant plasma diseases are 86.1% and 94.0%, respectively. 4
• When κ/λ ratio >2.89 with eGFR <60 mL/min/1.73m², the sensitivity and specificity for malignant plasma diseases are 92.0% and 97.0%, respectively. 4

Ratio <0.26 (Lambda-Dominant)

• Indicates a lambda monoclonal component requiring hematologic workup. 3
• Lambda chain lesions are relatively under-detected compared to kappa lesions, with approximately 25% of lambda chain lesions showing normal κ/λ ratios despite detectable free lambda light chains in urine. 5

Diagnostic Workup for Abnormal FLC Ratio

Initial Laboratory Evaluation

All patients with abnormal FLC ratios require the following confirmatory tests:

• Serum protein electrophoresis (SPEP) to detect M-protein peaks 1, 3
• Serum immunofixation electrophoresis (SIFE) to confirm absence or presence of monoclonal heavy chains—this is more sensitive than SPEP alone 6, 3
• 24-hour urine protein electrophoresis (UPEP) and urine immunofixation (UIFE) to assess for Bence Jones proteinuria, as the serum FLC assay cannot replace urine studies 6, 2, 3
• Complete blood count to evaluate for anemia 1
• Comprehensive metabolic panel including calcium and creatinine to assess for CRAB features (hypercalcemia, renal insufficiency, anemia, bone lesions) 1, 6
• Quantitative immunoglobulins (IgG, IgA, IgM) to detect immunoparesis 1

Bone Marrow Evaluation

Bone marrow aspiration and biopsy are indicated when:

• IgA or IgM M-protein is detected (regardless of level) 1
• IgG M-protein >15 g/L 1
• Light-chain MGUS with FLC ratio >10 or <0.10 1
• Any clinical suspicion of multiple myeloma, AL amyloidosis, or lymphoproliferative disorder 1

Bone marrow evaluation is NOT routinely required for:

• Asymptomatic patients with IgG M-protein ≤15 g/L, normal calcium, creatinine, and CBC, and no clinical features suggesting myeloma or amyloidosis 1
• Patients with limited life expectancy due to advanced age or comorbidities 1

Imaging Studies

Imaging recommendations based on M-protein type:

• For IgG or IgA M-protein: Skeletal survey (or low-dose whole-body CT as alternative) is not routinely needed if IgG ≤15 g/L or IgA ≤10 g/L without bone pain 1
• For IgM M-protein: CT scan of chest, abdomen, and pelvis to detect organomegaly and lymphadenopathy 1
• For light-chain MGUS with high FLC ratios (>10 or <0.10): Consider skeletal imaging 1

Additional Testing When Indicated

• Fat pad, bone marrow, or rectal biopsy with Congo red staining when AL amyloidosis is suspected 1
• Kidney biopsy for significant proteinuria or renal insufficiency to evaluate for light chain deposition disease or cast nephropathy 1
• FISH cytogenetics on bone marrow (if performed) for del(17p13), del(13q), t(4;14), t(11;14), t(14;16) in suspected malignant plasma cell disorders 1

Risk Stratification and Follow-Up

MGUS Risk Categories (Mayo Clinic Model)

Risk is based on three factors: M-protein ≥15 g/L, non-IgG type, and abnormal FLC ratio: 1

• Low-risk (0 factors): 5% progression risk at 20 years—follow at 6 months, then every 2-3 years 1, 3
• Low-intermediate risk (1 factor): 21% progression risk at 20 years—follow at 6 months, then annually 1
• High-intermediate risk (2 factors): 37% progression risk at 20 years—follow at 6 months, then annually 1
• High-risk (3 factors): 58% progression risk at 20 years—follow at 6 months, then annually 1

Light-Chain MGUS Specific Considerations

• Light-chain MGUS has approximately 1% annual progression risk to multiple myeloma or AL amyloidosis 1, 6
• Follow-up at 6 months, then annually with serum FLC measurements 6, 3
• Patients with extreme FLC ratios (<0.01 or >100) in idiopathic Bence Jones proteinuria have higher progression risk 1

Critical Pitfalls to Avoid

• Always use the same FLC assay platform (Freelite or N Latex) for serial monitoring—results are not mathematically convertible between different assays 3
• Do not diagnose progression based on positive immunofixation alone in patients who achieved complete response 1
• Distinguish therapeutic monoclonal antibodies (e.g., daratumumab, elotuzumab) from disease-related M-proteins, as these can appear as IgG kappa bands 1
• Do not rely solely on serum FLC assay—it must be combined with SPEP, SIFE, and 24-hour urine studies for comprehensive evaluation 2, 3
• Recognize that approximately 25% of lambda chain lesions may show normal FLC ratios despite detectable urinary light chains, emphasizing the importance of urine studies 5