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Letter to the Editor |
Address communications to Dr Indra Ramasamy, Department of Chemical Pathology, Newham University Hospital, Glen Road, Plaistow, London, E13 8SL, United Kingdom.
To the Editor:
In a recent issue of this journal, Abadie et al [1] reported on the use of serum free light chain (FLC) assays in the diagnosis of B-cell dyscrasias in a veteran’s hospital population. Although we are in general agreement with their findings, we wish to present additional data that are relevant to the clinical interpretation of serum FLC results.
Prior publications have shown the diagnostic utility of monoclonal serum FLC assays for identifying monoclonal gammopathies in patients with primary systemic amyloidosis (AL), non-secretory multiple myeloma (NSMM), and light chain myeloma (LCM) [2]. The FLC ratio (the ratio of free kappa (
) to free lambda chains (
)) has been included as part of a risk assessment panel, which predicts progression to malignant conditions in patients with monoclonal gammopathy of undetermined significance (MGUS) [3].
A previous article has supported the use of FLC measurements in the follow-up of patients with intact monoclonal immunoglobulin multiple myeloma (IMM) [4], while another report has expressed reservations about the use of the assay in the routine laboratory [5]. The International Myeloma Working Group [6] recommends serum light chain assay as a sensitive method of detecting light chain disease, NSMM, AL, or solitary plasmacytoma. Myeloma management guidelines [7] recommend the use of serum FLC for serial monitoring but require the additional measurement of Bence-Jones protein. The UK Myeloma Forum and Nordic Myeloma Study Group state that quantification of serum FLC levels and computation of the / ratio can be used as an alternative to quantifying urinary light chains [8]. Some authors comment that the clinical utility of serum FLC measurement to monitor IMM remains to be demonstrated [9,10].
In this letter we present the results of a 2-yr prospective study on the use of serum FLC, in addition to serum protein electrophoresis, in the follow-up of patients with B-cell dyscrasias.
Materials and Methods
The primary study cohort consisted of 27 IMM (mean age: 75 yr; range 51–90; 16 M, 11 F) and 54 MGUS (mean age: 74 yr; range: 47–99; 23 F; 31 M) patients, who were diagnosed according to the criteria established by International Myeloma Working Group [6].
Additional samples were from patients with (a) biclonal gammopathies, MGUS (mean age: 82 yr, range: 58–98; 3 F; 2 M); (b) LCM (median age 77 yr; range: 49–100; 1 F, 2 M); (c) amyloidosis (age 76 yr, 1 M); and (d) other B-cell derived malignant disease. The last group consisted of lymphoma (mean age: 72 yr; range: 56–85; 6 M, 1 F), myelodysplasia (age 91 yr, 1 F), treated spinal myeloma (age 64 yr, 1 M), and cryoglobulinemia (age 69 yr, 1 M). A single patient (age 74 yr, F) with an oligoclonal response observed with serum protein electrophoresis was included for comparison purposes.
Serum FLC assays were measured using an immunoturbidimetric assay on the Olympus AU600 analyzer. The interassay CV was <7% for both and assays. Serum electrophoresis, urine electrophoresis, and immunofixation were performed with a Sebia Hydrasys electrophoresis system.
Results
The results of the first serum sample for each patient are shown in Table I
. Among the 34 patients with MGUS and light chain type , FLC- was increased in 25/34 (73.5%); of these FLC- was increased in 6/34 (17.6%) and / ratio was increased in 13/34 (34.2%). Among the 20 patients with MGUS and light chain type , FLC- was increased in 12; of these FLC- was also increased in 4 and / ratio was decreased in 8. Unusually, a single patient with IgG/ of 14.3 g/L showed an increased FLC- of 44.8 mg/L and FLC- of 14.1 mg/L. Exceptional ratios (>30, IgG/ =13.6 g/L in 80 yr, F and 0.02, IgA/ = 12 g/L in 90 yr, F) were found in 2 patients clinically classified as MGUS.
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, 18 had raised FLC- and raised / ratio. Ten patients showed a suppressed FLC-. Two patients with chronic renal failure had raised FLC-. A single patient who had received cyclophosphamide therapy had FLC values and / ratio within the reference ranges and IgA/ value of 14.0 g/L. Of the 8 IMM patients with light chain type , 7 had raised FLC- and decreased / ratio. Four patients showed a decreased FLC- value. Serum FLC results were at the lower reference range in a single patient with an IgG/ value of 9.1 g/L and previous chemotherapy. At diagnosis free light chains were >500 mg/L in 3 patients with IMM.
Although serum FLC concentrations and ratios overlapped for IMM and MGUS patients, the means differed for both groups (p <0.05), suggesting a greater severity of the disease in IMM. A single patient with non-Hodgkin’s lymphoma (NHL) with an IgG/ monoclonal band showed discrepant results with a raised / ratio. Interestingly, the FLC / ratio was >44 in a patient with cryoglobulinemia, confirming monoclonal FLC production. The / ratio varied in biclonal gammopathy (Table I
); the ratio reflected the largest M protein found in the serum. FLC ratios were abnormal when both bands were of the same light chain type. The ratio may be of limited clinical value as a marker in this patient group. Raised serum FLC concentrations and / ratio of 0.63 were observed in a single patient with oligoclonal bands.
Where urine samples were available for analysis, immunofixation (IFE) detected Bence-Jones protein (BJP) in 2/3 MGUS, 2/4 IMM, and 0/2 lymphoma patients with raised serum FLC and abnormal / ratios. All patients with detectable BJP had raised serum FLC concentrations. FLC concentrations were within the reference range and BJP was negative by IFE in 4/4 MGUS, 1/1 IMM, and 2/2 lymphoma patients.
Of the 54 patients with MGUS, 52 had stable disease over a period of 2 yr, as determined by the level of monoclonal protein (M protein), FLC, and / ratio; variations in these values were <10% of basal values. In 2 patients (2/54) classified as MGUS, the abnormal FLC concentration increased (158% and 58% over the basal level) over a period of 1 yr, with a similar increase in / ratio (155%, 51%), while the M protein remained stable.
In the IMM patients the serological plateau reached by the serum FLC values, as a result of therapy initiated prior to the study or due to therapy started during the 2 yr study period, was either within the reference range (2/27) or remained raised, indicating residual disease (25/27). Of the 27 IMM patients, serial samples were available in 9 who had treatment, initiated either following diagnosis or as a result of relapse, during the period of follow-up. In 5/9 patients, following treatment, FLC decreased to 18.2–50.3% (mean 33.1%) of the basal value. Reductions in concentrations of the M protein and FLC occurred in parallel in 4/9 patients. In 1/9 patients the FLC decreased in advance of the M protein. During follow-up prior to initiation of therapy, an increase in the abnormal FLC (500% above basal level, with similar changes in / ratio), with stable M protein values, was observed in 1/9 (or 1/27) patients. In 1/9 patients following chemotherapy during which both FLC and the M protein fell to a plateau, a progressive rise in FLC and / ratio (50% above the basal value) was observed. In this patient the M protein concentration remained stable. In a further patient (1/9) the FLC remained high, as did the M protein, suggesting a poor response to therapy. Response to chemotherapy in 1/9 (or 1/27) patients was followed using the M protein, as the FLC value was, surprisingly, at the lower reference range, suggesting that in this case, the M protein was the more useful tumor marker.
In 2/27 IMM patients, following treatment, the FLC concentrations normalised despite the persistence of monoclonal serum immunoglobulin. Despite rising monoclonal immunoglobulin concentrations, in one of these patients, the abnormal FLC concentration remained at the lower reference range. In 2/27 IMM and 2/54 MGUS patients FLC concentrations increased while the M protein remained stable. In addition, in 2/100 patients with B-cell dyscrasias / ratios were discordant with the M protein light chain type. The reasons for the lack of reactivity in the latter patients are speculative, but may be due to the lack of antigenic sites on the abnormal light chain.
In this study BJP was detected in 44% of patients with B-cell dyscrasias and raised serum FLC. This difference in the incidence of serum and urine FLC detection may at least in part be due to the renal capacity to absorb and catabolize filtered FLC. As a consequence of this, BJP measurement may be a relatively insensitive method of detecting the presence of abnormal FLC in serum. Further, serum FLC assays offer a technical advantage over BJP measurement. Current methods for measuring BJP in urine are cumbersome and inaccurate.
In conclusion, this study demonstrates the clinical utility of serum FLC assays in monitoring B-cell dyscrasias in a routine laboratory. The present study additionally evaluates the range of serum FLC values found in MGUS, IMM, and other B-cell dyscrasias, including cryoglobulinemia and biclonal gammopathies. Normalisation of serum FLC ratio has been suggested as a stricter indicator of clinical remission and may correlate well with extended response duration [11]. Our study shows that serum FLC assays cannot be used in isolation, neither for the diagnosis nor for monitoring and follow-up of IMM, as the results may be misleading in a small percentage (4% in this study) of patients. Both serum FLC and the M protein levels are required for effective diagnosis and monitoring of B-cell dyscrasias.
References
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