What is the differential diagnosis (DDx) for serum free light chain elevation?

Differential Diagnosis for Serum Free Light Chain Elevation

Serum free light chain elevation occurs in plasma cell disorders (multiple myeloma, light chain myeloma, AL amyloidosis, MGUS, smoldering myeloma), lymphoproliferative disorders (Waldenström macroglobulinemia, B-cell lymphomas), monoclonal gammopathy of renal significance (MGRS), and importantly, renal impairment which causes polyclonal elevation of both chains. 1, 2

Malignant Plasma Cell Disorders

Multiple Myeloma

• Active (symptomatic) myeloma presents with abnormal serum FLC ratio, often with an involved/uninvolved ratio ≥100 serving as a myeloma-defining event even without CRAB criteria 1, 2
• Abnormal FLC concentrations are detected in 96% of MM patients at presentation 3
• The FLC ratio is abnormal in 26 of 29 patients (90%) with MM 4
• Malignant forms show abnormally increased dimerization of monoclonal FLC with higher clonality values compared to premalignant conditions 5

Light Chain Myeloma (Bence Jones Myeloma)

• Produces only monoclonal light chains without intact immunoglobulin 3, 6
• Serum FLC assay is particularly critical for diagnosis and monitoring in these patients 2, 6

AL Amyloidosis

• 96% have monoclonal immunoglobulin deposits, but only 16% have detectable monoclonal immunoglobulin on standard testing 1
• Displays abnormally increased FLC dimerization patterns similar to MM 5
• Serum FLC assay is essential as traditional protein electrophoresis often misses these cases 6

Non-Secretory Myeloma

• Produces minimal or no detectable monoclonal protein on electrophoresis 3, 6
• Serum FLC assay is the primary monitoring tool 2, 6

Premalignant Plasma Cell Disorders

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Light chain MGUS is defined by abnormal FLC ratio, increased involved light chain level, no heavy chain expression, <10% bone marrow plasma cells, and absence of end-organ damage 2
• Does not show the abnormal FLC dimerization patterns seen in malignant forms 5
• Progresses to MM at 1% per year 1

Smoldering Multiple Myeloma (SMM)

• High-risk SMM defined by FLC ratio ≥100, with 72% risk of progression to MM within 2 years 7
• 98% of patients with FLC ratio ≥100 develop progressive disease during follow-up 7
• Does not show abnormal FLC dimerization patterns characteristic of malignant disease 5

Lymphoproliferative Disorders

Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma)

• Produces monoclonal IgM with associated FLC elevation 1
• Serum FLC testing is not advised in routine practice for WM as its relevance is still under evaluation 1
• Accounts for 24-56% of type I cryoglobulinemic glomerulonephritis cases 1

B-Cell Lymphomas and Chronic Lymphocytic Leukemia

• Can produce monoclonal immunoglobulins with associated FLC elevation 1
• Represent the "other" category in MGRS-associated conditions 1

Monoclonal Gammopathy of Renal Significance (MGRS)

Light Chain Cast Nephropathy

• 100% have detectable monoclonal immunoglobulin 1
• Requires prompt bortezomib-containing regimens to decrease nephrotoxic clonal immunoglobulin production 2

Monoclonal Immunoglobulin Deposition Disease (MIDD)

• 78-100% associated with MM, but only 0-20% have detectable monoclonal immunoglobulin on standard testing 1

Light Chain Proximal Tubulopathy (Fanconi Syndrome)

• 61-80% associated with MM, with 12-33% having detectable monoclonal immunoglobulin 1

Other MGRS Entities

• Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID): 96% MGRS 1
• Type I cryoglobulinemic glomerulonephritis: 47-52% MM, 24-56% other lymphoproliferative 1
• Crystal-storing histiocytosis, immunotactoid glomerulonephritis, and C3 glomerulopathy with monoclonal gammopathy 1

Non-Monoclonal Causes

Renal Impairment (Critical Pitfall)

• Most important non-malignant cause of FLC elevation 1, 2
• Free light chains are cleared by the kidney; impaired function causes polyclonal elevation of both κ and λ chains 1
• Normal FLC ratio (0.26-1.65) can rise to 0.34-3.10 in severe renal impairment (CKD stage 5) 1
• A normal κ/λ ratio with elevated absolute values suggests polyclonal activation or renal impairment rather than monoclonal disease 2
• 36 of 203 patients with renal impairment or polyclonal immunoresponse had abnormal κ/λ ratios, but none had ratios <0.05 or >10 4

Polyclonal Immunoresponse

• Inflammatory conditions, infections, and autoimmune diseases can cause polyclonal FLC elevation 4
• Maintains normal or near-normal κ/λ ratio despite elevated absolute values 2, 4

Diagnostic Algorithm

When encountering elevated serum FLC:

1. Assess the κ/λ ratio first 1, 2

   • Ratio <0.26 suggests λ clone
   • Ratio >1.65 suggests κ clone
   • Ratio 0.26-1.65 suggests polyclonal elevation or renal impairment

2. Evaluate renal function 1, 2

   • Check creatinine, eGFR, and creatinine clearance
   • Adjust interpretation of FLC ratio based on CKD stage

3. Perform comprehensive protein studies 1, 2

   • Serum and urine protein electrophoresis with immunofixation
   • 24-hour urine collection for protein quantification
   • Quantification of IgG, IgA, IgM by nephelometry

4. Obtain bone marrow evaluation if monoclonal gammopathy suspected 1, 2

   • Assess plasma cell percentage and clonality
   • Perform FISH for high-risk cytogenetics [t(4;14), del(17p), t(14;16)]

5. Assess for end-organ damage (CRAB criteria) 1

   • Hypercalcemia, renal insufficiency, anemia, bone lesions
   • Consider advanced imaging (MRI, PET-CT) for focal lesions

6. Consider kidney biopsy if MGRS suspected with unexplained renal dysfunction 1

Critical Pitfalls to Avoid

• Never rely on serum FLC assay alone; always combine with protein electrophoresis and immunofixation 2, 4
• Use the same FLC assay (FreeLite vs. N Latex) for serial monitoring as results are mathematically inconvertible 1, 2
• Do not perform urine FLC assays; use 24-hour urine protein electrophoresis instead 2
• Recognize that small declines in renal function can impair FLC clearance, not just CKD stage 5 1
• Extreme ratios (<0.01 or ≥100) are highly specific for malignant plasma cell disorders 2, 7
• Abnormal FLC dimerization patterns help distinguish malignant (MM, AL) from premalignant (MGUS, SMM) conditions 5

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