What to do next in a patient with elevated serum free light chains, normal Serum Protein Electrophoresis (SPEP) and Urine Protein Electrophoresis (UPEP)?

Elevated Serum Free Light Chains with Normal SPEP and UPEP

Perform serum immunofixation electrophoresis (SIFE) and urine immunofixation electrophoresis (UIFE) immediately, as these are more sensitive than standard electrophoresis and may detect monoclonal proteins missed by SPEP/UPEP. 1, 2

Initial Confirmatory Testing

The next critical step is to complete the monoclonal protein screen with immunofixation studies, as approximately 10-15% of plasma cell disorders can be missed by electrophoresis alone but detected by immunofixation. 3

• Order SIFE and UIFE to identify small monoclonal proteins that may not produce visible spikes on standard electrophoresis 1, 2
• Verify the serum free light chain (FLC) ratio is truly abnormal and confirm the absolute elevation of the involved light chain, not just an abnormal ratio 2, 4
• Assess renal function carefully (serum creatinine, BUN, eGFR) as renal impairment can cause false-positive FLC elevations with ratios up to 3.1 even without plasma cell disorders 4
• Evaluate for polyclonal hypergammaglobulinemia which can also cause mildly abnormal FLC ratios 4

Risk Stratification Based on FLC Abnormality

The degree of FLC abnormality guides urgency and next steps:

• Markedly abnormal FLC ratio (kappa/lambda >100 or <0.01): Proceed urgently to bone marrow biopsy regardless of immunofixation results, as this strongly suggests a plasma cell disorder 2
• Moderately abnormal ratio (>3.1 or <0.26) with normal renal function: High suspicion for plasma cell disorder; proceed with bone marrow evaluation 2, 4
• Mildly abnormal ratio (1.65-3.1 or 0.10-0.26) with renal impairment or inflammation: May represent physiologic elevation; repeat testing after addressing underlying condition 4

Comprehensive Hematologic Workup

If immunofixation is negative but FLC remains abnormal with normal renal function:

• Bone marrow aspiration and biopsy with immunohistochemistry and/or flow cytometry to quantify clonal plasma cells and assess for light chain-only myeloma or AL amyloidosis 1, 2
• Cytogenetic studies including FISH analysis for del(13), t(4;14), t(14;16), del(17p), and 1q21 amplification to assess risk stratification 1, 2
• Complete blood count with differential to evaluate for cytopenias suggesting bone marrow involvement 1, 2
• Comprehensive metabolic panel including calcium, creatinine, albumin, LDH, and beta-2 microglobulin to assess for end-organ damage (CRAB criteria) 1, 2

Imaging and End-Organ Assessment

• Skeletal survey (whole body low-dose CT or MRI preferred over plain radiographs) to detect lytic lesions 1, 2
• Consider cardiac evaluation if clinical suspicion for AL amyloidosis exists (unexplained heart failure, LV wall thickness ≥14mm, low voltage ECG) - this includes echocardiography, troponin, and NT-proBNP 1
• Evaluate for other amyloid involvement if suspected: fat pad aspirate, rectal biopsy, or tissue biopsy of affected organs 1

Common Diagnostic Pitfalls to Avoid

Critical caveat: The serum FLC assay has a sensitivity of only 41% for detecting monoclonal proteins when used alone, meaning normal SPEP/UPEP with elevated FLC does not rule out significant disease. 3

• Do not assume renal disease explains all FLC elevations - while renal impairment increases FLC levels, it should not cause extreme ratio abnormalities (>3.1) unless a plasma cell disorder coexists 4
• Do not delay bone marrow biopsy in patients with markedly abnormal FLC ratios even if immunofixation is negative, as light chain-only myeloma and AL amyloidosis may not produce detectable monoclonal proteins by standard methods 2, 5
• Remember that 3% of myeloma patients have non-secretory disease where FLC may be the only measurable marker 1
• Inflammatory conditions and other hematologic disorders can cause mildly abnormal FLC ratios; clinical context is essential 3, 4

Monitoring Strategy

If initial workup reveals a plasma cell disorder:

• Use serum FLC for monitoring response as it detects changes approximately 3 months earlier than SPEP/UPEP (median 1.94 months vs 5.39 months to detect response) 6
• Continue 24-hour urine collections if measurable urinary M-protein is eventually detected, as FLC cannot replace UPEP for monitoring urinary disease 1, 2
• Serial FLC measurements must use the same assay for accurate comparison over time 1, 2

If no plasma cell disorder is identified but FLC remains abnormal, repeat complete evaluation in 3-6 months as early disease may evolve. 2