Serum free light chain ratio predicts outcome in MGUS

lab technologyC ancer PrognosisSerum free light chain ratiopredicts outcome in MGUSby C. Szarkaas published in CLI December 2005Monoclonal 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 vastmajority of MGUS patients will not progress, patient management would be greatly improved if this population could bemore easily identified and given reassurance regarding likely outcomes. A recent study of 1148 MGUS patients showed thatthe serum immunoglobulin free light chain ratio (kappa/lambda) is a clinically and statistically significant predictor of progressionto disease.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 condition[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 sampleswith 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 diagnosedwith 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 associatedwith 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.Table 1. MGUS diagnostic criteria: all three required [1].Prognostic risk factorsMany studies have been undertaken to identify risk factors predicting progressionto 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 concentrationsin 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 significantlyhigher 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.Figure 1. Distribution in clinical diagnoses in 1026 patients with a serum monoclonalprotein detected at the Mayo Clinic in 1992.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

C ancer Prognosisas published in CLI December 2005Table 2. Reference ranges for serum free kappa and lambda light chains.abnormal free light chain ratio (kappa/lambda1.65) [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 50 years) as part of an epidemiologicalstudy [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 monoclonalfree light chains, possibly representing a previouslyunknown entity of free light chain MGUS.Two patients with intact immunoglobulin M proteinsmissed in the original SPE tests were identifiedby the serum free light chain assays.Long term follow-up studies are needed to determinethe significance of free light chain MGUS, tosee whether these patients progress to light chainmultiple myeloma or if the risk of progression isFigure 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 (1.65). The lower curve illustrates the risk of progression in patients with a normalratio.

C ancer Prognosisas published in CLI December 2005Table 3. Risk stratification model.similar to intact immunoglobulin MGUS.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.Guidelines for diagnosis and monitoring ofMGUS patients are currently under review by severalworking 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 monoclonalgammopathy of undetermined significance.New England Journal of Medicine 2002; 346: 8: 564-569.5. Cesana C et al. Prognostic Factors for MalignantTransformation 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 measurementsfor 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 monoclonalgammopathy 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