What conditions are associated with elevated free kappa light chains?

Conditions Associated with Elevated Free Kappa Light Chains

Free kappa light chains are elevated in plasma cell disorders including multiple myeloma, AL amyloidosis, light chain deposition disease, monoclonal gammopathy of undetermined significance (MGUS), and smoldering multiple myeloma, as well as in renal impairment where decreased clearance causes accumulation. 1

Primary Plasma Cell Disorders

Multiple Myeloma and Related Conditions

• Multiple myeloma is the most common cause of elevated free kappa light chains when the kappa/lambda ratio is abnormal (>1.65), with the malignant plasma cell clone secreting unstable immunoglobulin light chains 2, 1
• Light chain myeloma presents with elevated free light chains without heavy chain expression, representing a more aggressive variant 1
• Nonsecretory multiple myeloma shows elevated free kappa light chains in 68% of cases (19 of 28 patients), making serum free light chain testing essential for diagnosis and monitoring in this population 3
• Smoldering multiple myeloma (SMM) demonstrates elevated free light chains with abnormal ratios but without end-organ damage, requiring close monitoring for progression 1

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Light chain MGUS is defined by abnormal free light chain ratio with increased involved light chain, no heavy chain expression, <10% bone marrow plasma cells, and absence of end-organ damage 1
• This condition has the lowest progression risk at only 0.27% per year, substantially lower than conventional MGUS at 1% per year 1
• The International Myeloma Working Group incorporates the free light chain ratio into risk stratification models for MGUS 1

AL Amyloidosis

• AL amyloidosis involves a slowly proliferating bone marrow plasma cell clone secreting unstable immunoglobulin free light chains that infiltrate peripheral organs (kidneys, heart, GI tract, liver, nervous system) causing organ dysfunction 2
• The serum free light chain assay detected abnormalities in 91% of untreated AL patients within 120 days of diagnosis, compared to only 69% for serum immunofixation 4
• More than 69% of AL patients already have multiple organ involvement at diagnosis, making early detection critical 2

Light Chain Deposition Disease (LCDD)

• LCDD presents with elevated free kappa light chains (kappa is more common than lambda) causing nonfibrillar tissue deposits in kidneys and other organs 5, 4
• The free light chain assay is more sensitive than immunofixation for detecting this condition 4

Renal Impairment

Decreased Clearance

• Renal impairment causes decreased clearance of both kappa and lambda free light chains, leading to elevation even with a normal kappa/lambda ratio (0.26-1.65) 1, 6
• In severe renal impairment (CKD stage 5), the normal kappa/lambda ratio range expands to 0.34-3.10 6
• Free light chain measurements can be affected by renal function, potentially leading to false elevations 1

Light Chain Cast Nephropathy

• Acute kidney injury from light chain cast nephropathy occurs when serum free light chains exceed 80-200 mg/dL, particularly with high urinary excretion 1
• Free light chain levels >150 mg/dL with urine M-spike >200 mg/day and albuminuria <10% strongly suggest light chain cast nephropathy 6
• Rapid reduction of serum free light chains by at least 50-60% is essential for renal recovery, with better outcomes when achieved by day 12 versus day 21 of treatment 1

Monoclonal Gammopathy of Renal Significance (MGRS)

• MGRS involves monoclonal immunoglobulins causing kidney damage without meeting criteria for multiple myeloma, requiring light chain testing for diagnosis 1, 7

Diagnostic Approach

Initial Workup

• Perform serum protein electrophoresis (SPEP) and immunofixation (SIFE) to identify and quantify monoclonal proteins 6, 7
• Obtain 24-hour urine collection for electrophoresis and immunofixation to assess urinary light chain excretion (Bence Jones protein) 6, 7
• Measure serum creatinine, eGFR, and electrolytes to evaluate renal function 6, 7
• Assess kappa/lambda ratio: abnormal ratio ≥100 (involved kappa) or <0.01 (involved lambda) is a myeloma-defining event 1

Further Evaluation When Abnormal

• Bone marrow aspirate and biopsy with immunohistochemistry to determine plasma cell percentage and clonality 7
• Cytogenetic studies including FISH for prognostic markers (17p13, t(4;14), t(14;16)) 7
• Skeletal survey or advanced imaging (MRI or PET-CT) to assess for bone lesions 1, 7
• Cardiac biomarkers (troponin T, NT-proBNP) if AL amyloidosis suspected, as these determine transplant eligibility 6

Critical Management Considerations

Urgent Intervention Required

• For light chain cast nephropathy, initiate bortezomib-containing regimens immediately to decrease production of nephrotoxic clonal immunoglobulin 1, 6
• Bortezomib/dexamethasone can be administered without dose adjustment in severe renal impairment 6
• Provide adequate hydration and urine alkalinization 6
• Avoid nephrotoxic medications such as NSAIDs in all patients with elevated light chains 6, 7

Monitoring

• Use the same serum free light chain assay throughout treatment to ensure accurate relative quantification 1, 6
• Serial measurements track disease activity, with the kappa/lambda ratio near normal (1.2-9.1) in plateau phase but ranging from 19-460 in progressive kappa myeloma 8