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Clinical Impact of Discordance in Serum Albumin Measurements on Myeloma International Staging System

Division of Hematology, Mayo Clinic, Rochester, MN

Christine L.H. Snozek

Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

Colin Colby, Dirk R. Larson

Division of Biostatistics, Mayo Clinic, Rochester, MN

Jerry A. Katzmann

Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

S. Vincent Rajkumar, Philip R. Greipp

Division of Hematology, Mayo Clinic, Rochester, MN

To the Editor:

The International Staging System (ISS) for multiple myeloma (MM) has been widely accepted, easily adopted, and validated since its publication in this journal 3 years ago.¹ It has advanced the importance of serum albumin, one of the variables used in predicting MM patient survival. Serum albumin level is a prerequisite for staging myeloma patients. However, discordance among assays for albumin measurement has suggested that the method of albumin measurement may be an issue in minimizing variation and staging inaccuracy in MM. The most common methods for measurement of serum albumin level are agarose gel serum protein electrophoresis (PEL), which is universally available because it provides both the albumin value and the monoclonal (M) protein estimate, and the bromcresol green (BCG) and bromcresol purple assays, which are the methods used when serum albumin is ordered in a chemistry panel. In the original ISS data set, each patient had either a PEL or chemistry albumin. However, a direct comparison between methods could not be made because each patient was studied by one method only.

In terms of accuracy, a recent study showed good correlation of the BCG assay with immunonephelometric quantification (considered the gold standard), independent of the M spike in MM patients; in contrast, PEL overestimated albumin in the presence of large M spikes.² Our goal was to determine whether measuring albumin by BCG translates to a superior prognostication of patients by ISS compared with PEL albumin.

We studied a cohort of 696 previously untreated MM patients for whom both BCG and PEL albumin values were available. The absence of β₂-microglobulin, the other variable used in ISS, precluded the staging of 200 patients, but the survival of this group was not statistically different (P = .3476) from the remaining cohort of 496 patients. The median age of the cohort of 496 patients was 65 years, and 60% were male. These 496 patients were assigned an ISS stage for each of the two albumin assays. Patients who were classified as stage I or stage II by both albumin values were designated as true stage I and true stage II patients, respectively. Patients with discrepant ISS stages were assigned to either group A (those patients categorized as stage I based on BCG albumin but as stage II based on PEL albumin) or group B (patients classified as stage II based on BCG albumin but as stage I based on PEL albumin). Comparisons between the true stage patients and groups A and B were performed using one-way analysis of variance. The threshold for statistical significance was P = .05. Data were collected from May 1986 through December 1998. Survival was defined as the time from the start of treatment for MM to death or last follow-up. Estimates were created using the Kaplan-Meier method, and the curves were compared using log-rank tests. All analyses were performed with SAS version 8.2 (SAS Institute Inc, Cary, NC).

Using only BCG albumin values, ISS staging was validated in this cohort on obtaining statistically significant differences in survival between the three stages (P < .0001), with median survival times of 42, 35, and 18 months for ISS stages I (n = 143), II (n = 207), and III (n = 146), respectively. Similarly, PEL albumin alone showed statistically significant differences between stages I (n = 132), II (n = 218), and III (n = 146), with median survival times of 45, 34, and 18 months, respectively (P < .0001). Note that the median survival time for stage III patients is unaffected by the albumin method because this stage is defined only by β₂-microglobulin. On comparison of stages I and II, discrepancy in staging by BCG compared with PEL was noted in 69 patients. Forty patients were assigned ISS stage I based on BCG assay but ISS stage II by PEL assay (group A); in contrast, 29 patients were deemed stage II by BCG assay but stage I by PEL (group B). No difference in survival was observed between group A patients (median, 34 months) compared with true stage I patients (n = 103, P = .2818) or true stage II patients (n = 178, P = .5250; Fig 1A). Similarly, there was no difference in survival between group B patients (median, 48 months) compared with true stage I (P = .6377) or true stage II (P = .2920) patients (Fig 1B). As expected, a statistically significant difference was found between the M spikes of group B and true stage I and II patients, suggesting that elevated M spikes led to overestimation of albumin by PEL in group B patients, resulting in falsely low staging.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Comparison of survival curves of myeloma patients staged by the International Staging System using chemistry (bromcresol green [BCG]) albumin and electrophoretic (protein electrophoresis [PEL]) albumin (group A patients: stage I based on BCG albumin but stage II based on PEL albumin; group B patients: stage II based on BCG albumin but stage I based on PEL albumin).

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Supported by National Cancer Institute Grant No. CA62242.

REFERENCES

1. Greipp PR, San Miguel J, Durie BG, et al: International staging system for multiple myeloma. J Clin Oncol 23:3412-3420, 2005[Abstract/Free Full Text]

2. Snozek CL, Saenger AK, Greipp PR, et al: Comparison of bromcresol green and agarose protein electrophoresis for quantitation of serum albumin in multiple myeloma. Clin Chem 53:1099-1103, 2007[Abstract/Free Full Text]

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