How do you interpret Free Light Chain (FLC) results in an adult patient with a potential diagnosis of multiple myeloma or another plasma cell disorder?

Free Light Chain (FLC) Interpretation in Plasma Cell Disorders

Direct Answer

The FLC ratio is the critical discriminator for clonality: an abnormal ratio (<0.26 or >1.65) indicates a monoclonal plasma cell disorder, while a normal ratio with elevated absolute levels typically reflects renal impairment rather than malignancy. 1

Understanding the FLC Ratio

Normal vs. Abnormal Ratios

• Normal FLC ratio: 0.26-1.65 in patients with normal renal function 2, 1
• Abnormal ratios indicating clonality:
  • Kappa-dominant: ratio >1.65 (highly suspicious if >8, definitive if >100) 2, 1
  • Lambda-dominant: ratio <0.26 (highly suspicious if <0.125, definitive if <0.01) 2, 1

Renal Impairment Adjustment

• Adjusted reference range for severe renal impairment (eGFR <60 mL/min): 0.31-3.7 1
• Both kappa and lambda chains are elevated proportionally in kidney disease, preserving the ratio 1
• One study found 42.5% of CKD patients without myeloma had abnormal ratios using standard cutoffs 1

Diagnostic Thresholds by Disease State

MGUS (Monoclonal Gammopathy of Undetermined Significance)

• Low-risk MGUS: M-protein <15 g/L, IgG type, and normal FLC ratio 2
• Intermediate/high-risk MGUS: Abnormal FLC ratio (outside 0.26-1.65) increases progression risk 2
• Follow low-risk patients every 2-3 years; intermediate/high-risk annually 2

Smoldering Multiple Myeloma (SMM)

Risk stratification using FLC ratio 2:

• Assign 1 point each for: bone marrow plasma cells ≥10%, M-protein ≥3 g/dL, and FLC ratio <0.125 or >8
• 1 risk factor: median time to progression 10 years
• 2 risk factors: median time to progression 5.1 years
• 3 risk factors: median time to progression 1.9 years 2

Active Multiple Myeloma

Measurable disease criteria 3:

• Involved FLC ≥10 mg/dL (100 mg/L) AND abnormal FLC ratio 3
• This defines light chain myeloma as measurable for treatment monitoring 3

Myeloma-defining events (immediate treatment required) 1:

• FLC ratio ≥100 (kappa-dominant) or ≤0.01 (lambda-dominant) 1
• Bone marrow plasma cells ≥60% 1
• More than one focal lesion on MRI ≥5mm 1

Clinical Interpretation Algorithm

Step 1: Assess the FLC Ratio First

If ratio is normal (0.26-1.65):

• Check serum creatinine and eGFR immediately 1
• If renal impairment present, elevated absolute levels are expected 1
• Normal ratio virtually excludes light chain myeloma and AL amyloidosis 4
• Does NOT exclude intact immunoglobulin myeloma or non-secretory myeloma 4

If ratio is mildly abnormal (1.66-5.0 or 0.05-0.25):

• Inconclusive for malignancy (likelihood ratio ~1) 4
• Obtain SPEP, SIFE, UPEP, UIFE, and quantitative immunoglobulins 1
• Repeat FLC in 6 months to assess stability 1

If ratio is moderately abnormal (>5.0-10 or 0.05-0.25):

• Possible malignant plasma cell disorder (likelihood ratio ~10) 4
• Proceed to bone marrow biopsy and skeletal imaging 1

If ratio is severely abnormal (<0.05 or >10):

• Highly suggestive of malignant plasma cell disorder (likelihood ratio ~50) 4
• Immediate hematology referral and comprehensive workup 1

Step 2: Calculate the Difference Between Involved and Uninvolved FLC

For monitoring disease (not diagnosis):

• The absolute difference (dFLC) between involved and uninvolved FLC is superior to the ratio for serial measurements 5
• Example: If kappa = 150 mg/L and lambda = 20 mg/L, dFLC = 130 mg/L
• This metric is used for response assessment in light chain myeloma 3

Step 3: Integrate with Other Diagnostic Tests

Essential complementary tests 2, 1:

• SPEP and SIFE (serum protein electrophoresis and immunofixation)
• 24-hour urine collection with UPEP and UIFE
• Complete blood count, calcium, creatinine, albumin
• Beta-2 microglobulin and LDH
• Bone marrow aspiration and biopsy with cytogenetics and FISH
• Skeletal survey or low-dose whole-body CT

Critical pitfall: The FLC assay cannot replace 24-hour urine protein electrophoresis for monitoring patients with measurable urinary M-proteins 2, 6

Response Assessment Using FLC

For Light Chain Myeloma (FLC as sole measurable disease)

Stringent Complete Response (sCR) 3:

• Normal FLC ratio (0.26-1.65) on two consecutive assessments
• Negative serum and urine immunofixation
• <5% plasma cells in bone marrow by immunohistochemistry or flow cytometry

Very Good Partial Response (VGPR) 3:

• >90% decrease in dFLC on two consecutive assessments

Partial Response (PR) 3:

• ≥50% decrease in dFLC

Progressive Disease (PD) 3:

• ≥25% increase in dFLC from lowest response value (absolute increase must be >10 mg/dL) 3

Monitoring Frequency

• After one cycle of therapy, then every other cycle once response trend observed 3
• All responses require confirmation with second measurement 3
• Less frequent monitoring once plateau phase reached 3

Special Clinical Scenarios

Light Chain Myeloma

• All patients with light chain myeloma show increased FLC concentrations 7
• Classical SPEP fails to demonstrate M-protein; diagnosis requires IFE and FLC assay 7, 8
• FLC is the primary monitoring tool due to short serum half-life (2-6 hours) 9

Non-Secretory Myeloma

• Approximately 3% of myeloma patients have neither serum nor urine M-proteins 2
• FLC assay is useful for monitoring a proportion of these patients 2
• All non-secretory myeloma patients show increased FLC concentrations 7

Intact Immunoglobulin Myeloma

• 96% have abnormal FLC concentrations at presentation 9
• FLC falls more rapidly than intact IgG in response to treatment 9
• FLC response after 2 months of therapy predicts overall response better than M-protein measurement 5
• Ideal cut-point for FLC change: 40-50% reduction 5

Renal Impairment in Myeloma

• FLC-induced cast nephropathy is the most frequent (90%) form of renal damage 2
• High FLC concentrations cause direct proximal tubular cell injury through inflammatory cytokine production 2
• FLC binds Tamm-Horsfall protein in distal tubules, forming obstructive casts 2
• Myeloma patients with renal impairment at presentation are a medical emergency requiring immediate treatment 2

Critical Pitfalls to Avoid

1. Never assume malignancy based solely on elevated absolute FLC levels - the ratio is the critical discriminator 1

2. Always use the same FLC assay for serial measurements - different assays have different reference ranges and are not interchangeable 1

3. Do not use FLC ratio for serial monitoring in intact immunoglobulin myeloma - use absolute difference (dFLC) or involved FLC level instead 5

4. Cannot replace 24-hour urine collection - FLC assay does not substitute for UPEP in patients with measurable urinary M-proteins 2, 6

5. Interpret in context of renal function - use adjusted reference ranges (0.31-3.7) for severe renal impairment 1

6. At least 100 plasma cells must be analyzed for accurate kappa/lambda ratio determination by immunohistochemistry if bone marrow performed 1

When to Refer Urgently

Immediate hematology referral required if ANY of the following present 1:

• CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions)
• Bone marrow plasma cells ≥60%
• FLC ratio ≥100 (kappa) or ≤0.01 (lambda)
• More than one focal lesion on MRI ≥5mm
• Acute kidney injury with suspected cast nephropathy