New tools for detecting occult monoclonal gammopathy, a cause of secondary osteoporosis

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Screening for MGUS in the general osteoporotic population is not warranted, since its prevalence (2.1%) is similar to that in the general population (2.9%) of women age 50 or older and 5.3% to 7.5% of all persons age 70 years or older.15,16 However, testing for monoclonal gammopathies is warranted when clinical or laboratory findings—eg, subtle hints such as an unexplained elevation in the erythrocyte sedimentation rate or a low anion gap—trigger diagnostic suspicion. Unexplained hypercalcemia, renal insufficiency, unexplained anemia, hypo- and hypergammaglobulinemia, skeletal problems (eg, widespread osteoporosis, unexplained back or bone pain), and distal, symmetric polyneuropathy are the usual signs of underlying plasma cell neoplasia.

Signs of multiple myeloma: the CRAB mnemonic

Patients should be screened for multiple myeloma if they have any of the following presenting features not attributable to another disorder, using the mnemonic CRAB17:

Calcium elevation (serum calcium ≥ 11.5 mg/dL)

Renal insufficiency (serum creatinine > 1.73 mmol/L)

Anemia (normochromic, normocytic anema, with a hemoglobin value lower than 10 g/dL or more than 2 g/dL below the lower limit of normal)

Bone disease (lytic lesions, widespread osteoporosis, or bone fractures on skeletal survey, or a decline in bone mineral density or evidence of osteoporosis on DXA).

For the diagnosis of multiple myeloma to be made, the patient must have at least 10% clonal bone marrow plasma cells, evidence of a monoclonal protein in the serum or urine, and CRAB-related organ damage. When in doubt, referral for a hematologic evaluation is advised. Patients with signs of myeloma-related organ damage warrant prompt treatment.

Electrophoresis is not 100% sensitive

As the clinical cases above illustrate, standard testing for the monoclonal protein is not 100% sensitive for multiple myeloma, as some patients do not secrete the protein in the serum or urine.

In more than 97% of patients, the plasma cells that proliferate clonally produce a measurable monoclonal protein, such as an intact immunoglobulin only (eg, IgG kappa, IgA lambda), a light chain only (kappa or lambda), or intact immunoglobulins and free light chains. In the rest, no detectable monoclonal protein is produced, a disease subtype called nonsecretory multiple myeloma.

Of patients who secrete an intact immunoglobulin, 90% to 95% also produce excess free light chains.18,19 From 15% to 20% of patients with multiple myeloma secrete only light chains.1,20

Classically, serum and urine protein electrophoreses are the diagnostic tools used to evaluate monoclonal gammopathy, but urine electrophoresis detects only about 50% of myelomas.19


While serum and urine protein electrophoreses are still the standard for screening for MGUS or multiple myeloma if one strongly suspects it, additional testing with serum free light chain analysis should be considered if patients exhibit CRAB-related features of myeloma-related organ damage, such as hypercalcemia, renal insufficiency, anemia, or bone loss.

Serum assays for free kappa and free lambda light chains can detect circulating clonal free light chains in most patients with nonsecretory multiple myeloma. In one study,21 elevated concentrations of either kappa or lambda free light chains (and abnormal kappa-lambda ratios) were detected in the sera of 19 of 28 patients with nonsecretory multiple myeloma, such that the diagnosis could be changed to oligosecretory disease.

Several studies have also found serum light chain panels to be highly sensitive for the diagnosis of MGUS or multiple myeloma.22–24 Clonal light chains must be present in a concentration of at least 500 mg/L to be detected by serum protein electrophoresis, or at least 150 mg/L to be detected by serum immunofixation. 25 In contrast, free light chain immunoassays can measure free light chain concentrations of 3 mg/L or lower, and can therefore detect light-chain-related disorders despite negative results on serum protein electrophoresis or immunofixation.14

Cost-effectiveness of free light chain analysis

Serum free light chain assays appear to be more cost-effective than urine tests in screening for monoclonal gammopathy: Medicare reimbursement is $38 for the serum free light chain assay vs $71 for the urine assay, which includes total urine protein, urine protein electrophoresis, and urine immunofixation electrophoresis.22

The kappa-lambda ratio

Normal values for serum free light chains are:

  • Kappa 3.3–19.4 mg/L
  • Lambda 5.7–26.3 mg/L
  • Kappa-lambda ratio 0.26–1.65.

The kappa-lambda ratio is an indication of clonality.26,27 A ratio greater than 1.65 suggests a kappa free light chain monoclonal gammopathy; a ratio less than 0.26 suggests a lambda free light chain monoclonal gammopathy.

Importantly, in patients with renal impairment but no monoclonal gammopathy, the kappa-lambda ratio is often slightly higher—up to 3:1 because of reduced renal light chain clearance.26

However, not all patients with a monoclonal gammopathy have an abnormal free light chain ratio. Only one-third of patients with MGUS do, and these patients are at greater risk of progression to other plasma cell dyscrasias. 28 The free light chain ratio is normal in 5% to 10% of patients with intact immunoglobulin multiple myeloma.29,30 In a study of 116 patients with plasmacytoma, serum protein electrophoresis demonstrated an M-spike in half of patients, serum immunofixation was abnormal in two-thirds, and the kappa-lambda ratio was abnormal in half.31

A risk exists that MGUS will progress to multiple myeloma in patients who have an abnormal free light chain ratio. Thus, patients should be referred to a hematologist-oncologist for evaluation and monitoring if an abnormal kappa-lambda ratio is detected by serum free light chain assay.

Patients with abnormalities in the kappa-lambda ratio and no other evidence of monoclonal protein may harbor light-chain-related diseases only (eg, light chain multiple myeloma, primary amyloidosis, or light chain deposition disease) or a newly described entity, free light chain MGUS.14,19,27 An abnormal kappa-lambda ratio has also been noted in variable percentages of patients with chronic lymphocytic leukemia and malignant lymphoma.32

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