Monoclonal Gammopathy of Undetermined SignificanceMonoclonal gammopathy of undetermined significance is a pre-malignantplasma cell proliferative disorder denoted by the presence of a monoclonalintact immunoglobulin in individuals with no evidence of multiple myeloma,AL amyloidosis, Waldenström's macroglobulinaemia or other related condi-tion [Table 1]. MGUS is found in around 3% of the general population over50 years [2] and is the most common of the monoclonal gammopathies. Anaudit at the Mayo Clinic, Rochester, NY, USA in 1992 showed that 56% of sam-ples with a detectable serum monoclonal protein were attributed to MGUS[3], 3 times more than multiple myeloma [Figure 1]. In a primary referralsample population in the UK, around 8-9 times as many patients are diag-nosed with MGUS compared to multiple myeloma each year. For the majorityof patients, the MGUS remains stable and asymptomatic and is unlikely tocontribute to their mortality. However, each year, 1% of patients progress tomultiple myeloma or another plasma cell cancer. Multiple myeloma is anincurable disease with a median survival of 3-4 years. Although the number ofpatients who progress is only a small proportion of the total number of MGUScases, management of these patients is difficult:

· when MGUS is first diagnosed it is impossible to distinguish betweenpatients who will remain stable and those who will progress to disease

· regular testing of all MGUS patients is important in order to prevent theunrecognised development of pathologic fractures and renal failure associat-ed with progression to undiagnosed multiple myeloma

· there is no decline in the risk of progression over time so patients requirelifelong follow-up. This may cause unnecessary distress to many that willnever develop multiple myeloma and also makes a significant contributionto cost and workload.

· in order to minimise treatment-related morbidity/mortality, therapy is onlygiven when disease develops.

Prognostic risk factorsMany studies have been undertaken to identify risk factors predicting pro-gression to malignancy. A large population-based study [4] evaluating morethan 13 potential risk factors concluded that only concentration and type ofmonoclonal (M) protein were predictors of progression (the most importantbeing the initial M protein concentration in the serum). The presence of amonoclonal urinary light chain was found not to be a risk factor.In contrast, in an Italian study of 1231 patients, Bence Jones proteinuria wasan important risk factor for malignant transformation [5]. When patientswith myeloma have good renal function, urine tests for monoclonal free lightchains may be normal. The same possibly applies to MGUS patients so serumconcentration may be a more reliable predictor of disease.

Serum free light chainsMonoclonal free light chains (traditionally termed Bence Jones Proteins) arehomogenous populations of kappa or lambda immunoglobulin light chainmolecules produced by malignant clones of B cells. There is now significantevidence indicating the benefit of these tumour markers in initial screeningfor monoclonal gammopathies [6], AL amyloidosis, nonsecretory and lightchain multiple myeloma patients missed by conventional methods, and rapidevaluation of treatment efficacy [7, 8, 9].

The clinical importance of elevated free kappa and lambda light chain con-centrations in the serum of individuals with MGUS was first noted in a pilotstudy at the Mayo Clinic a few years ago. The ratio of serum free kappa toserum free lambda (κ/λ) showed significantly different median values inpatients with and without progression.Rajkumar et al then conducted a case control study to investigate the value ofserum free light chains for prediction of disease progression [10]. 47 patientswith MGUS who had progressed to malignancy were compared with 50 whoremained stable over a 5 year period. In those patients who progressed, theκ/λ ratio was abnormal in 31/47 (66%) compared to 11/50 (22%) patientswithout progression. An abnormal κ/λ ratio was associated with a signifi-cantly higher risk of MGUS progression (relative risk 2.5%, 95% confidenceinterval: 1.6 - 4.0; P < 0.001). The increased risk was independent of the intactmono-clonal immunoglobulin concentration.

The significance of these findings led to a much larger study of 1148 patientswith MGUS, for whom long term follow-up data was available [11]. An

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Serum free light chain ratiopredicts outcome in MGUS

Monoclonal gammopathy of undetermined significance (MGUS) affects around 3% of the population over 50 years of age.

It is asymptomatic but each year around 1% of patients progress to multiple myeloma or a related malignancy. As the vast

majority of MGUS patients will not progress, patient management would be greatly improved if this population could be

more easily identified and given reassurance regarding likely outcomes. A recent study of 1148 MGUS patients showed that

the serum immunoglobulin free light chain ratio (kappa/lambda) is a clinically and statistically significant predictor of pro-

gression to disease.

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by C. Szarka

Table 1. MGUS diagnostic criteria: all three required [1].

Figure 1. Distribution in clinical diagnoses in 1026 patients with a serum monoclonalprotein detected at the Mayo Clinic in 1992.

as published in CLI December 2005

abnormal free light chain ratio (kappa/lambda<0.26 or >1.65) [Table 2] was detected in 379(33%) patients. This group had a significantlyhigher risk of progression compared to those witha normal κ/λ ratio [Figure 2], (hazard ratio, 3.5;95% confidence interval, 2.2 - 5.5; P <.001). Therelative risk of progression is also related to theextent to which the κ/λ ratio is abnormal. Therisk of progression to malignancy 10 years afterdiagnosis was 17% with an abnormal serum κ/λratio compared to 5% if patients had a normalratio. At 20 years the risk was 35% (abnormalratio) and 13% (normal ratio).

MGUS risk stratificationAddition of the free light chain data to the othertwo known prognostic factors (size and type of Mprotein) has enabled the creation of a risk stratifi-cation model [Table 3].

A large group of patients, around 40%(449/1148), were identified as low-risk, with onlya 2% lifetime risk of progression to malignancywhen competing causes of death were taken intoaccount. The remaining patients were stratifiedinto 3 further groups depending on the numberof abnormal risk factors. This model could beused to improve the difficult management ofMGUS patients. One proposal [Table 4] suggests

discharge of most low-risk patients whose MGUScould be reviewed when attending for other ill-nesses. The smaller high-risk group could bemore closely monitored before serious myeloma-related complications develop.

Free light chain MGUSThese recent data have raised questions regardingthe precursor of light chainmultiple myeloma and ALamyloidosis. MGUS isdefined by the presence ofserum monoclonal pro-teins of intactimmunoglobulins andthese patients progress tointact immunoglobulinplasma cell abnormalities.The large group of patientsstudied to assess the valueof the κ/λ ratio were previ-ously identified as MGUSby the presence of an M-spike (monoclonal pro-tein). Is there a "free lightchain MGUS" in the gener-al population that remainsunrecognised?

Katzmann et al. surveyed serum samples from 900outpatients (>50 years) as part of an epidemio-logical study [12]. These were selected on thebasis of negative serum protein electrophoresis(SPE). When assessed for serum free light chains12 of the samples were abnormal. These 12 serawith abnormal κ/λ ratios were carefullyreassessed by immunofixation electrophoresis. Ofthese, it is likely that 7 had detectable monoclon-al free light chains, possibly representing a previ-ously unknown entity of free light chain MGUS.Two patients with intact immunoglobulin M pro-teins missed in the original SPE tests were identi-fied by the serum free light chain assays.Long term follow-up studies are needed to deter-mine the significance of free light chain MGUS, tosee whether these patients progress to light chainmultiple myeloma or if the risk of progression is

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Figure 2. Risk of progression in patients with normal and abnormal κ/λ ratios. Theupper curve illustrates risk of progression of monoclonal gammopathy of undeterminedsignificance in patients with an abnormal kappa/lambda free light chain ratio (<0.26or >1.65). The lower curve illustrates the risk of progression in patients with a normalratio.

Table 2. Reference ranges for serum free kappa and lambda light chains.

as published in CLI December 2005

similar to intact immunoglobulin MGUS.

Guidelines for diagnosis and monitoring ofMGUS patients are currently under review by sev-eral working parties.

References1. Durie BG et al. Myeloma management guidelines: aconsensus report from the Scientific Advisors of theInternational Myeloma Foundation. The HematologyJournal 2003; 4: 379-398.

2. Kyle RA et al. Prevalence of monoclonal gammopathyof undetermined significance (MGUS) among OlmstedCounty, MN residents 50 years of age. Blood 2003; 102:934a. Abstract A3476.3. Bradwell AR, Mead GP, Carr-Smith HD. Serum FreeLight Chain Analysis. Pub: The Binding Site Ltd, POBox 11712, Birmingham B14 4ZB, UK: 2005.4. Kyle RA et al. A long-term study of prognosis in mon-oclonal gammopathy of undetermined significance.New England Journal of Medicine 2002; 346: 8: 564-569.5. Cesana C et al. Prognostic Factors for Malignant

Transformation in Monoclonal Gammopathy ofUndetermined Significance and Smouldering MultipleMyeloma. J Clin Oncol 2002; 20: 1625-1634.6. Bakshi NA et al. Serum Free Light ChainMeasurement Can Aid Capillary Zone Electrophoresisin Detecting Subtle FLC-Producing M Proteins. Am JClin Pathol 2005: 124: 214-218.7. United Kingdom Myeloma Forum. Guidelines on thediagnosis and management of AL amyloidosis. Brit JHaem 2004; 125: 6: 681-700.8. Drayson MD et al. Serum free light-chain measure-ments for identifying and monitoring patients withnonsecretory multiple myeloma. Blood 2001; 97: 9:2900-2902.9. Bradwell AR et al. Serum test for assessment ofpatients with Bence Jones myeloma. The Lancet 2003;361: 489-491.10. Rajkumar SV et al. Presence of monoclonal free lightchains in the serum predicts risk of progression in mon-oclonal gammopathy of undetermined significance. BritJ Haem 2004; 127: 308-310.11. Rajkumar SV et al. Serum free light chain ratio is anindependent risk factor for progression in monoclonalgammopathy of undetermined significance. Blood2005; 106: 3: 812-817.12. Katzmann JA et al. Monoclonal free light chains insera from healthy individuals: FLC MGUS. Clin Chem2003; 49: 6: Supp A74.

The authorColette SzarkaTechnical CommunicationsThe Binding Site LtdPO Box 11712Birmingham B14 4ZBUK

Table 3. Risk stratification model.

Table 4. Proposal for MGUS patient management.*Younger low-risk patients should be managed as for intermediate risk.** Increased risk associated with rising and more abnormal κ/λ ratio.

C ancer Prognosis as published in CLI December 2005