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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 388-392
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Serum syndecan-1: a new independent prognostic marker in multiple
myeloma
Carina Seidel,
Anders Sundan,
Martin Hjorth,
Ingemar Turesson,
Inger Marie S. Dahl,
Niels Abildgaard,
Anders Waage, and
Magne Børset for the Nordic Myeloma Study Group
From the Institute of Cancer Research and Molecular Biology and the
Section of Hematology, University Hospital, Norwegian University of
Science and Technology, Trondheim, Norway; the Department of Medicine,
Lidköping Hospital, Lidköping, Sweden; the Department of
Medicine, Malmö University Hospital, Malmö, Sweden; Section
of Hematology, University Hospital, Tromsø, Norway; and the Department
of Medicine and Hematology, Aarhus University Hospital, Aarhus,
Denmark.
 |
Abstract |
Serum samples drawn at diagnosis from 174 myeloma patients were
analyzed for the presence of the heparin sulfate proteoglycan, syndecan-1. Syndecan-1 was elevated in 79% of patients (median, 643 units/mL) compared with 40 healthy controls (median, 128 units/mL), P < .0001. Serum syndecan-1 correlated with
the following: serum creatinine, secretion of urine M-component over
the course of 24 hours, soluble interleukin-6 (IL-6) receptor,
C-terminal telopeptide of type I collagen,
 2-microglobulin, percentage of plasma cells in the bone
marrow, disease stage, and serum M-component concentration. In order to
evaluate syndecan-1 as a prognostic marker in multiple myeloma, it was
entered into a multivariate Cox regression model. Data from 138 patients were available for this analysis. As a continuous variable,
syndecan-1 was an independent prognostic parameter in addition to serum
2-microglobulin and World Health Organization
performance status. When syndecan-1 was dichotomized by the best cutoff
(66th percentile, 1170 units/mL), the survival difference between the
groups was highly significant: "high" syndecan-1 group had a
median survival of 20 months, and the "low" syndecan-1 group had
a median of 44 months (P < .0001). We conclude that syndecan-1 is a new independent prognostic parameter in multiple myeloma, and its role in prognostic classification systems should be
further investigated.
(Blood. 2000;95:388-392)
© 2000 by The American Society of Hematology.
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Introduction |
Multiple myeloma is a B-cell malignancy characterized
by the accumulation of clonal malignant plasma cells. It is associated with the production of monoclonal immunoglobulins, bone destruction, anemia, hypercalcemia, and renal dysfunction.
Syndecan is a member of a family of integral membrane heparin sulfate
proteoglycans.1 It is known to participate in cell-matrix adhesion processes by binding cells to collagens,2-4
fibronectin,5 and thrombospondin.6 Syndecan can
also serve as a low-affinity receptor for heparin-binding growth
factors.7
Within the bone marrow, syndecan-1 is detected solely on cells of the B
lymphocyte lineage, and its expression changes at specific stages of
differentiation. In mice it is present on the surface of pre-B cells,
lost in mature B cells, and re-expressed in plasma cells.8
In the bone marrow of myeloma patients, syndecan-1 is reported to be
expressed on myeloma cells only9; it is also expressed on malignant plasma cells in peripheral blood.10
Syndecan-1 is rapidly lost by apoptotic myeloma cells.11
Since syndecan-1 is expressed on the surface of viable malignant plasma
cells, specific antibodies to syndecan-1 are used for identification and purification of myeloma cells from clinical
samples.9,12
Previous studies have shown that syndecan-1 is shed from the surface of
myeloma cells in culture13 and into human
serum.14 Measured by a semiquantitative method, syndecan-1
levels in serum of 7/20 myeloma patients were elevated compared with
normal controls. High levels were associated with a high percent of
bone marrow plasmocytosis and 2-microglobulin
levels.14
In this study, we analyzed serum levels of shed syndecan-1 in a large
well-characterized population of myeloma patients in order to determine
its relation to prognosis and other variables at the time of diagnosis.
| |
Patients and methods |
Study population
A total of 592 patients were entered in the Nordic Myeloma Study
Group (NMSG) randomized trial from June 1990 until November 1992. In
this study, patients were randomized to receive melphalan and
prednisone with or without the addition of low-dose  -interferon. The
diagnostic and eligibility criteria and results were previously described by NMSG.15 The following parameters were
registered for all patients at the time of diagnosis: age; sex;
Durie-Salmon16 stage; the World Health Organization (WHO)
performance status15; a grading of bone morbidity in 3 stages, as judged by X-ray abnormality (no changes, limited changes,
advanced changes); percentage of plasma cells in the bone marrow;
immunoglobulin (Ig) class; serum M-component protein
concentration; albumin; calcium; creatinine; total alkaline
phosphatase; 2-microglobulin; and secretion of urine
M-component over the course of 24 hours.
After completion of the study, approximately 400 sera drawn at
diagnosis were analyzed for interleukin-6 (IL-6), IL-6 receptor, C-reactive protein (CRP), osteocalcin, C-terminal telopeptide of type I
collagen (ICTP), and hepatocyte growth factor (HGF). A manuscript on
prognostic factors in the original larger patient material has been
published separately30. The present study was performed
after the closing of this study, and therefore data on syndecan-1 will
only be reported in this paper.
At the time of the present study, remaining serum samples from the time
of diagnosis of 174 patients were available for analysis of syndecan-1
levels. These patients constitute the study population. Their mean age
was 66.1 ± 8.8 years (mean ± SD, range 35-82). There were 102 males and 72 females. The distribution of myeloma characteristics with
respect to monoclonal component (M-protein) type was: IgG, 64%; IgA,
15%; IgD in 2 patients, 1.1%; and light chain disease, 20%.
According to the staging of Durie and Salmon,16 10% of
patients were in stage I, 41% in stage II, and 49% in stage III
disease. In regard to any of the studied parameters, no significant differences between the present study population and the original patient material were found. The survival of the 174 patients did not
differ significantly from the total study population. The median
follow-up period of surviving patients was 38 months.
Criteria for having achieved response included clear clinical
improvement, reduction in urinary or serum M-component,
absence of hypercalcemia, absence of anemia, stable serum creatinine, and no progression of osteolytic lesions.17 Control samples were obtained from 40 healthy age-matched and sex-matched individuals.
Syndecan-1 enzyme-linked immunosorbent assay
Human syndecan-1 enzyme-linked immunosorbent assay (ELISA) (Diaclone
Research, Besançon, France) was performed according to the
manufacturer's instructions. Briefly, 100 µL of samples and
standards and 50 µL of diluted biotinylated antibody were added into
precoated wells and incubated for 1 hour at room temperature. After 3 washes, 100 µL horseradish-peroxidase-streptavidin
conjugate was added, and the plate was incubated for 30 minutes at room temperature. After washing, 100 µL of substrate was added, and the
color was allowed to develop for 10-15 minutes. The reaction was
stopped with H2SO4, and the absorbance was read
at 450 nm. The entire procedure was performed in approximately 2 hours.
All samples were analyzed in duplicate. The standard curve was linear, from 30 to 1000 units/mL, and serum samples above this range were diluted. The interassay and intra-assay coefficient of variation was
< 14%.
Statistical analyses
All statistical analyses were done with the SPSSX/PC computer
program (SPSS, Chicago, IL). Results were considered statistically significant when P < 0.05. Skewed variables (Kurtosis
> 8) were transformed by the natural logarithm (ln) before entering
the multiple linear regression analysis and the Cox regression model. Comparisons between groups were performed with the Student t
test and the Mann-Whitney U test. Correlation between 2 parameters was
estimated by the Spearman rank correlation analysis. For investigation of linear correlations, multiple regression analysis was applied. Response to treatment was analyzed using multiple logistic regression techniques. The method of Kaplan and Meier was used to compute the
survival curves and to estimate the median survival18 and the log-rank test for significance. Survival was modeled with the Cox
regression analysis.19 In all multivariate models,
variables were entered by forward selection, where entry required a
maximum adjusted value of P = .05.
The NMSG study found no significant survival difference between the 2 arms of treatment.15 Thus it was possible to pool data from
the treatment arms to evaluate the prognostic significance for the
studied parameter.
| |
Results |
Serum analyses
The serum syndecan-1 values in patients at the time of diagnosis and
in controls are shown in Figure 1. The
distribution of syndecan-1 concentrations was skewed (kurtosis = 15).
The median syndecan-1 concentration (25th to 75th percentile) was
643 units/mL (401-2022) in the myeloma and 128 units/mL
(76-208) in the control sera. This difference was statistically
significant (P < .0001). The maximal syndecan-1 level
measured in a patient was 20 000 units/mL, ie, over 100 times higher
than the median level of normal controls. In 137 patients (79%), the
syndecan-1 levels were above the mean level +2SD of syndecan-1 in the
control group (> 370 units/mL), which is considered above the normal
range by conventional criteria.
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| Fig 1.
Syndecan-1 in serum by ELISA.
Serum syndecan-1 levels at diagnosis in 174 patients with multiple
myeloma. Horizontal line denotes median value of 643 units/mL and 40 healthy
age- and sex-matched controls (median,128 units/mL). The difference
between the groups is highly significant (P < .0001).
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Correlation to other parameters
A significant correlation coefficient (r) was obtained with respect
to serum creatinine, secretion of urinary M-component over 24 hours,
IL-6 receptor, ICTP, 2-microglobulin, percentage of
plasma cells in the bone marrow, disease stage, and serum M-component concentration (Table 1). By
forward selection of these variables, a multiple linear regression
yielded creatinine and the percentage of plasma cells in the marrow as
the best predictors of syndecan-1 (with an adjusted r2 of
0.18). There was no significant correlation between syndecan-1 and
pretreatment age, type of serum M-component, radiographic staging of
bone destruction, IL-6, CRP, calcium, HGF, albumin, alkaline
phosphatase, or osteocalcin (data not shown).
Relation to treatment response
When syndecan-1 was evaluated in a univariate logistic regression
model, it was a significant predictor of response to treatment (P = .01). However, in a multivariate model, it did not
retain significance.
Survival analyses
When syndecan-1 (transformed by the natural logarithm) was entered
in a univariate Cox regression analysis, it was a significant predictor
of mortality (P = .0006). Syndecan-1 was
therefore entered into a multivariate Cox regression analysis involving
the other factors in this patient material that held significant
(P < .05) prognostic information in a univariate Cox
regression analysis: serum calcium; soluble IL-6 receptor;
2-microglobulin; WHO performance status (0-2 versus
3-4); and ln [IL-6], ln [CRP], ln [creatinine], and ln [ICTP] (data not shown). Patients with missing variables were
excluded from the analysis. Complete data from 138 patients were available.
Table 2 demonstrates the result of the
multivariate Cox regression. Only 3 factors retained prognostic
significance: ln [syndecan-1] (P = .002);
2-microglobulin (P = .004); and WHO
performance, 0-1 versus 2-3 (P = .01). Thus, when syndecan-1
was included in the model, corrected serum calcium, IL-6, soluble IL-6
receptor, CRP, creatinine, and ICTP added no further prognostic
information. Without syndecan-1, the final model included
2-microglobulin, corrected serum calcium, and WHO
performance status. The difference between the models with and without
syndecan-1 was 4,2  2
(P < .05).
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Table 2.
Variables with independent prognostic importance for
survival according to a multivariate Cox regression analysis, with and
without syndecan-1 in the model
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Syndecan-1 was further evaluated as a dichotomous variable with respect
to survival. An evaluation of survival, using different cutoff levels,
is summarized in Table 3. The best
separation of the curves was with the cutoff point at the 66th
percentile of the syndecan-1 values ( 1170 units/mL). There was a
highly significant survival difference (P = .0001) between
the "high" syndecan-1 group ( 1170 units/mL, n = 58) and
"low" syndecan-1 group (< 1170 units/mL, n = 116). Median
survival was 20 and 43 months, respectively, as shown in Figure
2. The follow-up period of surviving
patients did not differ significantly between the high and low
syndecan-1 groups.
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| Fig 2.
Kaplan-Meier survival curves for 174 myeloma patients.
The curves are separated by: (A) "high" syndecan-1 levels
( 1170 units/mL, n = 58, median survival 20 months) versus (B)
"low" syndecan-1 levels (< 1170 units/mL, n = 116, median
survival 43 months). Open circles represent censored patients. The
survival difference was highly significant (P = .0001).
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Syndecan-1 high/low grouping (> / < 1170 units/mL) was applied
to stratify 2 established classification systems: Durie-Salmon stage16 (Figure 3) and CRP and
2-microglobulin20 (Figure 4). There was no survival difference
between patients in Durie-Salmon stage I and II, thus these data were
pooled. Syndecan-1 separated patients by both classsification systems,
in all risk categories. The separation was highly significant in the
medium-risk and high-risk patient groups.
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| Fig 3.
Kaplan-Meier survival curves for patients classified by
the staging system of Durie and Salmon.
The solid line represents high syndecan-1 levels ( 1170 units/mL),
and the dotted line represents low syndecan-1 levels (< 1170
units/mL). Open circles represent censored patients. (A) Patients in
Durie-Salmon16 stages I and II were separated by high
syndecan-1 levels (n = 21) and low syndecan levels (n = 68),
P = .20). (B) Patients in Durie-Salmon stage III were
separated by high syndecan-1 levels (n = 37) and low syndecan-1
levels (n = 48), P = .0006.
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| Fig 4.
Kaplan-Meier survival curves for patients
classified by the staging system of Bataille et al.20
The drawn line represents high syndecan-1 levels ( 1170 units/mL),
and the dotted line represents low syndecan-1 levels (< 1170
units/mL). Open circles (o) represent censored patients. Panels A, B,
and C depict the high and low levels of syndecan-1 for patients
classified by Bataille: (A) Stadium 1: CRP < 6 mg/L and
2-microglobulin < 6 mg/L; high levels (n = 64) were
separated from low levels (n = 21), P = 0.10. (B) Stadium
2: CRP 6 mg/L or 2-microglobulin 6 mg/L; high
levels (n = 33) were separated from low levels (n = 20),
P = 0.003. (C) Stadium 3: CRP 6 mg/L and
2-microglobulin 6 mg/L; high levels (n = 14) were
separated from low levels (n = 14), P = 0.05.
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| |
Discussion |
The main finding is that in a well-defined population of untreated
myeloma patients, the serum syndecan-1 level is a new and powerful
prognostic marker. A good prognostic system in multiple myeloma should
ideally form the basis for selecting the best treatment, and it should
include only variables with independent prognostic information. In
order to be useful in clinical practice, these should be available at
diagnosis and be measured with simple reproducible techniques. A number
of prognostic factors reflecting various aspects of the disease have
been identified in myeloma,21 relating to either the
intrinsic malignancy of the tumor, host-tumor interactions, renal
function, or tumor mass.22 Of these, serum
2--microglobulin concentration is regarded as one of the
most powerful prognostic factors.22-24 In our study,
we show that syndecan-1 provides substantial prognostic value in
a Cox regression model with proven prognostic markers, including
2 -microglobulin.
An important question is whether syndecan-1 can identify patients at
high risk who have a favorable prognosis by other classification systems. Our results, as illustrated in Figures 3 and 4, suggest that
this is indeed the case, especially in the medium-risk and high-risk
patient groups. Notably, for medium-risk patients, as classified by the Bataille20 system, with a concomitant
high syndecan-1 level, the median survival time was 17 months. This was shorter than the 19-month median survival of the Bataille high-risk group as a whole. However, our cutoff point for
syndecan-1 was derived from the present set of data. Thus,
additional studies must be performed to determine if these results are
reproducible in other populations of myeloma patients, with respect to
age and treatment regimes.
The NMSG study was a multicenter trial, with limitations in the
variables available for evaluation of prognosis. Thus our analysis
could not include data on some known powerful prognostic factors25-27 in these patients: plasma cell labeling index,
the percentage of circulating plasma cells, or karyotype abnormalities. Further studies should be designed to determine if syndecan-1 retains
independent prognostic information when these parameters are available.
Syndecan-1 correlated significantly with a number of variables in our
study (Table 1). These results are in accordance with previous
suggestions14 that soluble syndecan-1 reflects tumor mass
(as assayed by the percentage of plasma cells in the marrow, urine and
serum M-component levels,28 and soluble IL-6
receptor29). Also, it may reflect renal failure as
determined by increased levels of serum creatinine. However, the
multiple linear regression model suggests that approximately 20% of
the variability in syndecan-1 levels can be attributed to variations in
the percentage of plasma cells in the marrow and serum creatinine. The
fact that syndecan-1 contains prognostic information which is superior
to these variables could indicate that syndecan-1 not only reflects
tumor load and renal failure but also other biological aspects of the disease.
Syndecan-1 has been found to increase osteoblast development and
inhibit osteoclast formation in murine bone marrow cell cultures, suggesting that syndecan-1 may counteract bone
destruction.13 However, syndecan-1 expression does not
differ among patients with or without lytic bone lesions.10
Our study does not support a clear connection between syndecan-1 and
the degree of bone affection (as determined by serum calcium levels,
alkaline phosphatase, and osteocalcin). In fact, we found a significant
positive association between syndecan-1 and serum ICTP, which is a
marker of collagen degradation.
In culture, shed syndecan-1 has been shown to induce apoptosis of
myeloma cell lines through an unknown mechanism.13
Also, the development of myeloma cell tumors is retarded
in severe-combined-immunodeficiency mice injected with syndecan-1
positive as compared with syndecan-1 negative ARH-77
cells.13 These results suggest a beneficial effect of
syndecan-1 to the patient. Our study does not attempt to address the
biology of shed syndecan-1 in multiple myeloma. However, it clearly
shows that a high level of shed syndecan-1 in serum is associated with
an unfavorable prognosis for the patient.
We conclude that serum syndecan-1 is a new independent prognostic
parameter in multiple myeloma. Through a rapid and simple ELISA
procedure, it seems to provide additional prognostic information in
some commonly used classification systems. We suggest that syndecan-1
levels should be further explored in the prognostic classification of
myeloma to determine its clinical usefulness.
| |
Acknowledgments |
We are grateful to Berit Størdahl and Marie Rygh for excellent
technical assistance and to Professor Lars Vatten for his comments on
the statistical calculations.
We are also grateful to members of the Nordic Myeloma Study Group directory board: I. M. S. Dahl, P. Gimsing, E. Hippe, M. Hjorth, E. Holmberg, E. Löfvenberg, S. Magnusson, J. L. Nielsen, I. Palva, S. Rödjer, I. Talstad, I. Turesson, J. Westin, and F. Wisløff.
| |
Footnotes |
Submitted December 23, 1998; accepted September 4, 1999.
Supported by grants from the Norwegian Cancer Society;
Rakel and Otto Kr. Bruuns legat; and The Cancer Fund (Trondheim, Norway).
Reprints: Carina Seidel, Norwegian Cancer Society, Institute of
Cancer Research and Molecular Biology, Norwegian University of Science
and Technology, Medisinsk Teknisk Senter, N-7489 Trondheim, Norway.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction