Publication Review - InSite 7
MGUS
A monoclonal gammopathy precedes multiple myeloma in most patients.
Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM. Blood 2009;113:5418-22
Monoclonal gammopathy of undetermined significance (MGUS) precedes Multiple Myeloma: a prospective study.
Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, et al. Blood 2009;113:5412-7
In the same edition of Blood, Weiss and Landgren both report analyses examining the evolution of MGUS into multiple myeloma (MM). For the first time, a pre-existing MGUS stage was shown to be present in the majority of patients prior to the diagnosis of MM. Patients with a light chain or non-secretory MM evolved from a light chain MGUS phenotype. Serum FLC and serum M-protein levels progressively evolved in 50 to 70% of patients during the MGUS phase prior to the diagnosis of multiple myeloma. Sequential serum FLC analyses may provide a useful biomarker in the routine follow-up of MGUS patients.
Renal
Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis.
Hutchison CA, Bradwell AR, Cook M, Basnayake K, Basu S, Harding S, et al. Clin J Am Soc Nephrol 2009;4:745-54
This prospective pilot study assessed the combination of standard chemotherapy with extended haemodialysis using a high cut-off dialyser (HCO-HD) on serum FLC concentrations and renal recovery in patients with biopsy-proven cast nephropathy and dialysis-dependent acute renal failure. Out of the 19 patients who met the study entry criteria, 13 received uninterrupted chemotherapy and extended HCO-HD and demonstrated sustained reductions in serum FLC concentrations and recovered renal function. Of the 6 patients who had chemotherapy temporarily withheld or discontinued, early reductions in serum FLC concentrations were not sustained and only one subsequently became independent of dialysis. A multi-centre, randomised control trial has commenced to address the hypothesis that extended HCO-HD increases the percentage of patients with cast nephropathy who become independent of dialysis.
Are renal reference intervals required when screening for plasma cell disorders with serum free light chains and serum protein electrophoresis?
Abadie, J.M., K.H. van Hoeven, and J.M. Wells, Am J Clin Pathol, 2009. 131(2): p. 166-71.
Recently, a modified renal reference range for the FLC κ/λ ratio (0.37-3.1) was proposed for patients with renal impairment (Hutchison et al. 2008). Abadie et al. evaluated this range when screening for plasma cell disorders. Overall, 78 plasma cell disorders were detected, with SPE/serum FLC tests detecting 2 additional patients missed by SPE/urine protein electrophoresis. Mildly increased κ/λ ratios were observed in patients with renal impairment and/or polyclonal hypergammaglobulinemia. The authors therefore recommend interpreting serum FLC in the context of renal function as application of the renal reference range increases assay specificity.
Screening
Utility of serum free light chain analysis when screening for lymphoproliferative disorders.
Robson, E.J.D., et al., Lab Med, 2009. 40(6): p. 325-329.
Robson et al. examined the utility of screening for lymphoproliferative disorders using a combination of serum protein electrophoresis (SPE) and serum FLC tests. Out of 653 serum samples, serum FLC analyses significantly contributed to the diagnosis in seven patients. This included two patients with intact immunoglobulin monoclonal (M)-proteins (1 x IgD MM, 1 x IgA MGUS) who had no obvious M-protein band by SPE and one case of chronic lymphocytic leukaemia. With urine provision of <5%, serum FLC analyses provided the most effective means of determining monoclonal FLC production in a diagnostic setting.
Inaccuracies in 24-hour urine testing for monoclonal gammopathies.
Siegel, D.S., et al., Lab Med, 2009. 40(6): p. 341-344.
Siegel et al. examine the relative merit of monitoring patients using serum and urine tests. In their analysis, fluctuations in renal function lead to aberrant changes in urine protein electrophoresis M-protein measurements, whereas serum measurements showed no fluctuations. The authors conclude that serum FLC analyses provide a more accurate assessment of clonal light chain burden and represent a reliable test to guide appropriate therapeutic management and avoid the pitfalls of inappropriate urine results.
Amyloidosis
Identification of amyloidogenic light chains requires the combination of serum-free light chain assay with immunofixation of serum and urine.
Palladini, G., et al., Clin Chem, 2009. 55(3): p. 499-504.
The authors analysed the diagnostic sensitivity of serum/urine IFE and the serum FLC assay in 121 AL amyloidosis patients. Although the serum FLC assay was more sensitive than commercial urine IFE (76 versus 67%), Palladini et al. describe 5 patients that were negative by serum tests but positive by urine IFE. These results were likely due to low tumour burden in combination with glomerular damage. In these circumstances, the reabsorptive capacity of the proximal tubules can be overloaded due to the increased passage of albumin and other serum proteins. Small amounts of monoclonal FLC may then be detected in a 24hr urine sample by IFE, but may be insufficient to alter the serum FLC concentration outside the normal range (Mead, G.P., et al., Comparison of serum versus urine for the identification of monoclonal free light chain production in 219 patients with AL amyloidosis. Hematology meeting reports, 2008. 2(2): abstract B12). Therefore, for 100% sensitivity, a combination of all serum and urine tests was required. This is also reflected in the International Myeloma Working Group guidelines, which recommend screening for monoclonal gammopathies with a serum-only panel of SPE, serum IFE and serum FLC assays, with the exception of AL amyloidosis which requires the serum tests and urine IFE (Dispenzieri et al. 2009).
