Free Light Chain Ratio <100 Does NOT Rule Out Multiple Myeloma
A free light chain (FLC) ratio less than 100 does not exclude the diagnosis of multiple myeloma, as an FLC ratio ≥100 is only one of several myeloma-defining events, and most patients with active myeloma have FLC ratios well below this threshold. 1
Understanding the FLC Ratio ≥100 Criterion
The FLC ratio ≥100 (with involved FLC ≥100 mg/L) represents a specific biomarker for ultra-high-risk disease that was added to diagnostic criteria in 2014, but it is not a screening test for myeloma. 1
- This criterion identifies patients with smoldering myeloma at imminent risk of progression who should be treated before developing end-organ damage 2
- Only approximately 15% of smoldering myeloma patients have an FLC ratio ≥100, yet 56% of all smoldering patients eventually progress 2
- The 2-year progression risk for FLC ratio ≥100 is 72-79%, but patients with lower ratios still progress—just more slowly (median 55 months vs 15 months) 2
Multiple Pathways to Myeloma Diagnosis
Active myeloma requires ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) PLUS any one or more of the following myeloma-defining events: 1, 3
CRAB Features (Traditional End-Organ Damage):
- Calcium >11.5 mg/dL 1
- Renal insufficiency: creatinine >2 mg/dL or creatinine clearance <40 mL/min 1
- Anemia: hemoglobin <10 g/dL or >2 g/dL below normal 1
- Bone lesions: one or more osteolytic lesions on skeletal imaging, CT, PET/CT, or MRI 1
SLiM Biomarkers (High-Risk Features):
- Sixty percent: ≥60% clonal bone marrow plasma cells 1
- Light chain ratio: involved/uninvolved FLC ratio ≥100 (with involved FLC ≥100 mg/L) 1
- MRI: >1 focal lesion ≥5 mm on MRI 1
Most patients are diagnosed based on CRAB features or other SLiM criteria, not the FLC ratio ≥100. 1
Clinical Implications of Different FLC Ratio Ranges
FLC Ratio 0.01-100:
- This range includes the vast majority of myeloma patients 2, 4
- An abnormal ratio (outside 0.26-1.65) with elevated involved FLC still indicates clonal disease requiring full diagnostic workup 5
- Patients can have active myeloma with CRAB features despite FLC ratios <100 1, 6
FLC Ratio <0.01 or ≥100:
- Defines ultra-high-risk disease with worse prognosis 6
- Associated with higher tumor burden, more aggressive disease, and lower treatment response rates 6
- The 40-month overall survival is 87% for high FLC ratio group versus 61% for low FLC ratio group 6
Diagnostic Workup When FLC Ratio is Abnormal but <100
When an abnormal FLC ratio is detected (but <100), complete evaluation must include: 1, 5
- Serum protein electrophoresis (SPEP) and immunofixation to identify M-protein 5
- 24-hour urine collection for protein electrophoresis and immunofixation (not spot urine FLC) 5
- Bone marrow aspiration and biopsy to assess plasma cell percentage and perform FISH for high-risk cytogenetics 5
- Skeletal imaging (skeletal survey, whole-body MRI, or PET/CT) to assess for bone lesions 1, 5
- Laboratory assessment for CRAB features: calcium, creatinine, hemoglobin, albumin, beta-2 microglobulin, LDH 1
Critical Pitfall to Avoid
The most dangerous error is assuming that an FLC ratio <100 means "no myeloma" and stopping the diagnostic evaluation. 2, 4
- Patients with FLC ratios between 8-100 still have significantly elevated progression risk from smoldering to active disease 1, 2
- A recent study showed that among patients with FLC ratio ≥100, those with urine monoclonal protein <200 mg/24h had similar progression risk to patients with FLC ratio <100, emphasizing that the FLC ratio must be interpreted in clinical context 4
- The FLC ratio ≥100 criterion was designed to identify ultra-high-risk patients for early intervention, not to exclude myeloma in those below this threshold 2
Sensitivity of FLC Testing
The FLC assay has 96.3% sensitivity for detecting abnormalities in newly diagnosed myeloma, which is higher than serum protein electrophoresis (85.5%) or immunofixation (93.9%). 6 However, this refers to detecting any FLC abnormality, not specifically the ≥100 threshold.