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Prepublished online as a Blood First Edition Paper on July 18, 2002; DOI 10.1182/blood-2002-05-1406.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Institute of Cancer Research and Molecular
Biology, Faculty of Medicine, Norwegian University of Science and
Technology, Trondheim, Norway; Department of Haematology,
Lund University Hospital, Lund, Sweden; Department of
Hematology, Ullevål University Hospital, Oslo, Norway;
and Division of Pathology, Institute of Microbiology, Pathology and
Immunology, Karolinska Institute, Huddinge University Hospital,
Stockholm, Sweden.
Insulinlike growth factor 1 (IGF-1) has growth-promoting effects on
myeloma cells in vitro as well as in vivo. In this study, we measured
the concentration of IGF-1 and its major binding protein, IGF- binding
protein 3 (IGFBP-3), in serum from 127 patients with multiple myeloma.
Serum had been drawn at the time of diagnosis, before treatment with
high-dose melphalan. IGFBP-3 in myeloma patients (1.6 ± 0.73
µg/mL; mean ± SD) was significantly decreased compared
to healthy age- and sex-matched controls (2.2 ± 0.42 µg/mL).
However, IGFBP-3 had no prognostic value in this study. The mean IGF-1
level did not differ between myeloma patients (17.8 ± 7.7 nM) and
controls (17.3 ± 5.6 nM). Nevertheless, IGF-1 was a strong indicator
of prognosis. After 80 months of follow-up, myeloma patients with low
levels (< 13 nM) of serum IGF-1 had not reached median survival. In
the patient group with IGF-1 levels above 13 nM, median survival was 62 months (P = .006). These findings support the hypothesis
of a role for IGF-1 in myeloma disease progression.
(Blood. 2002;100:3925-3929) Multiple myeloma (MM) is a B-cell malignancy that
is characterized by accumulation of clonal plasma cells in the bone
marrow. The disease is associated with production of monoclonal
immunoglobulins and painful bone destruction. In recent years, the role
of cytokines in the development of MM has been the focus of many
studies. Although interleukin 6 (IL-6) is the best documented growth
factor in this malignancy, it is now clear that several cytokines
induce MM cell proliferation and possibly promote disease development.
Insulinlike growth factor (IGF) is mainly produced by hepatocytes in
response to growth hormone stimulation but is also produced locally in
many other tissues (eg, by chondroblasts, fibroblasts, and
osteoclasts).1 IGF-1 can be detected in high (nanomolar) concentrations in serum, where 90% is bound to IGF-binding protein 3 (IGFBP-3). This protein inhibits IGF-1 by rendering it inaccessible to
the receptor.1 Substantial evidence suggests a role
for IGF-1 in the growth and survival of MM cells. In vitro,
IGF-1 induces proliferation of several MM cell
lines.2-4 IGF-1 can also enhance the growth-promoting
effect of IL-6 on MM cells.2,3,5 MM cell lines express the
IGF-1 receptor, and stimulation of the receptor activates a distinct
signal transduction cascade. This results in proliferation of MM cells
as well as protection against apoptosis.6 A mouse model of
myeloma indicates that IGF-1 in the bone marrow can act as a
chemoattractant for myeloma cells in vivo.7 This suggests
that IGF-1 may contribute to the recruitment and homing of myeloma
cells to the bone marrow compartment. Moreover, in mice with severe
combined immunodeficiency inoculated with MM cells, administration of
IGF-1 increases the growth rate of the tumor cells.6
The probable functional interaction between IGF-1 and MM cells made us
examine the levels of IGF-1 and IGFBP-3 in serum of patients with MM
and to compare them to the concentration in healthy controls. We
further wished to relate serum levels of IGF-1 and IGFBP-3 to other
disease variables at the time of diagnosis and to disease outcome. In a
few patients, serum samples drawn at intervals during the course of the
disease were analyzed retrospectively. We here demonstrate that in a
large, well-defined population of patients with MM the levels of
IGFBP-3 in serum are decreased. We further show that patients with low
IGF-1 levels have a favorable disease prognosis.
Treatment protocol
Patients
The median age of the patients (82 men, 45 women) in the study population was 52 years (range, 28-59 years). The distribution of myeloma characteristics with respect to monoclonal component (M-protein) type was IgG in 66%, IgA in 18%, IgD in 1.6%, and light chains only in 14%. According to the staging of Durie and Salmon,34 1.5% of the patients were in stage I, 29.5% in stage II, and 69% in stage III disease. The median survival was 68 months. None of these characteristics differed significantly from the original population of 274 patients. Registered parameters at diagnosis were age, sex, Durie-Salmon stage,
World Health Organization (WHO) performance status, grade of bone
morbidity (3 severity levels as judged by x-ray analyses), percentage
of plasma cells in the bone marrow, immunoglobulin class, urine
immunoglobulin per 24 hours and serum M-protein concentration, blood
hemoglobin, serum albumin, serum calcium, serum creatinine, serum
lactate dehydrogenase, serum Four additional patients from whom serum had been drawn at regular intervals (> 1 sample/10 months) were included for a detailed analysis of change in IGF-1 and IGFBP-3 over time. Serum M-protein concentration and treatment periods were registered from their medical records. These patients received treatment according the NMSG 5/94 protocol and samples from them were obtained from the Section of Hematology, University Hospital of Trondheim. Control samples were obtained from 42 healthy age- and sex-matched individuals. IGF-1 and IGFBP-3 measurements Serum IGFBP-3 was measured by enzyme-linked immunosorbent assay (ELISA). An antibody pair (R & D Systems, Minneapolis, MN) was used according to the manufacturer's instructions, with the modification that horseradish peroxidase (HRP)-conjugated streptavidin from Diaclone (Besançon, France) was used to increase sensitivity. The standard curve was linear between 2 and 40 ng/mL, and samples were diluted to concentrations within this range. All samples were run in duplicate. Human IgG does not interfere with the assay. The intra-assay and interassay variation coefficients were 3.3% and 5.5%, respectively. Total serum IGF-1 was measured by IGF-1 immunoradiometric assay (IRMA; Nichols Institute Diagnostics, San Juan Capistrano, CA) at the Department of Clinical Chemistry at the University Hospital of Trondheim, Norway. The detection limit was 7 nM IGF-1. IGFBP-3 does not interfere with analysis. Intra-assay and interassay variation coefficients were 4% and 11.6%, respectively.Statistical analyses All statistical analyses were done with the SPSSX/PC computer program (SPSS, Chicago, IL). Results were considered statistically significant when P .05. Skewed variables were
transformed by the natural logarithm before making analyses requiring
normal distribution. Comparisons between groups were performed with the Student t test or one-way ANOVA analyses. Correlation
between 2 parameters was estimated by the Spearman rank correlation
analysis. For investigation of linear correlations multiple regression
analysis was performed. Survival was modeled with the Cox regression
analysis, variables were entered by forward selection where entry
required a maximum P of .05. The method of Kaplan and Meier
was used to compute the survival curves and to estimate the median
survival. To compare the survival curves (test for significance) the
log-rank test was used.
Serum analyses Serum IGF-1 and IGFBP-3 levels in patients at the time of diagnosis and in controls are shown in Figure 1. The IGF-1 concentrations in myeloma and control sera were 17.8 ± 7.7 nM (mean ± SD) and 17.3 ± 5.6 nM, respectively (Figure 1A). This difference was not significant. The mean IGFBP-3 concentration was 1.6 ± 0.73 µg/mL in myeloma patients and 2.2 ± 0.42 µg/mL in control sera (Figure 1B). This difference was highly significant (P < .001). Serum levels in 41% of the patients were lower than mean 2
SD in the control population (< 1.4 µg/mL), and could
therefore be considered abnormal by conventional criteria.
In 4 patients, consecutive serum samples from the time of diagnosis
until point of death or last follow-up were analyzed. Patient no. 1 (Figure 2A) was followed for 2.5 years
and had normal IGFBP-3 (2.9 µg/mL) and IGF-1 (21.4 nM) levels at
diagnosis. The patient responded to treatment with a fall in serum
M-protein levels of more than 50%, and a concomitant reduction in
IGF-1 levels of 30% was observed. IGFBP-3 levels temporarily decreased (1.3 µg/mL), rising to levels within "normal range" 4 months
after treatment. Levels of serum M-protein and IGF-1 remained stable throughout the follow-up period.
Patient no. 2 (Figure 2B) had normal IGFBP-3 (2 µg/mL) and IGF-1 (21 nM) at the time of diagnosis. He responded to treatment with a fall in serum M-protein level of 90%. The serum M-protein levels remained stable for 4 years after treatment, but then increased (relapse). IGFBP-3 and IGF-1 levels varied within normal range during the follow-up period of 5 years. Patient no. 3 (Figure 2C) had normal IGFBP-3 (2.5 µg/mL) and IGF-1 (24.1 nM) levels at the time of diagnosis. The serum M-protein levels were stable until death 11 months after diagnosis. The patient responded to treatment as judged by clinical observations, but within 2 months after termination of treatment new treatment (chemotherapy) was initiated due to relapse. IGFBP-3 levels increased in the responsive period (3.5 µg/mL), and thereafter tended to decline. IGF-1 levels increased the last month before death. Patient no. 4 (Figure 2D) had a normal IGFBP-3 level (2.8 µg/mL) at diagnosis. IGF-1 concentration was 33 nM, which is above "normal range." The patient did not respond to treatment, and both serum M-protein levels and IGF-1 levels increased until death 4 years after diagnosis. IGFBP-3 levels declined, but remained within "normal range" (above 1.4 µg/mL) during the whole period. Correlation with other parameters We wished to correlate IGF-1 and IGFBP-3 at diagnosis to other registered parameters (see "Patients, materials, and methods"). IGF-1 correlated significantly only to IGFBP-3 (r = 0.39, P < .001). IGF-1 was likewise correlated to IGFBP-3 in the healthy population (r = 0.45, P = .004).IGFBP-3 correlated significantly to IGF-1 (r = 0.39,
P < .001), the concentration of M-component in serum
(r = By forward selection of significantly related variables, a multivariate linear regression analysis yielded IGF-1 and presence or absence of serum M-component as the best predictors of IGFBP-3 (adjusted r2 = 0.19). Overall survival IGFBP-3 did not predict mortality in a univariate Cox regression analysis. Patients with low levels of IGFBP-3 had a survival similar to those with normal IGFBP-3 levels (data not shown).When IGF-1 values for all 127 included patients were entered in a
univariate Cox regression analysis, IGF-1 was a significant predictor
of overall survival (P = .004). Of the 127 patients, 94 received the intended high-dose protocol with stem cell support, and
IGF-1 was likewise a predictor of mortality in this group (P = .02). Therefore, IGF-1 was entered as a continuous
variable in a multivariate Cox regression analysis together with the
other factors that held significant (P < .05) prognostic
information: natural logarithm (Ln) of
IGF-1 was further evaluated as a dichotomous variable with
respect to survival. The best separation of curves was seen with the
cutoff point at the 25th percentile of IGF-1 levels. As shown in Figure
3A, there was a highly significant
survival difference between patients with "low" IGF-1 (< 13 nM)
compared to the remaining patients (IGF-1
IGF-1 is an important growth and antiapoptotic factor for the cancer cells in several malignancies.9-14 In colorectal adenomas and breast cancer IGF-1 in serum has prognostic value.15,16 Here we demonstrate that IGF-1 is a prognostic factor in MM. We found that healthy individuals and myeloma patients at diagnosis have similar amounts of IGF-1 in the circulation. Nevertheless, MM patients with low serum IGF-1 levels have a favorable prognosis. This finding is in keeping with the observed biologic effects of IGF-1, which includes promotion of myeloma cell growth and survival. It is possible that in patients with low levels of IGF-1, paracrine growth stimulation of myeloma cells is minimal due to reduced availability of IGF-1 in the bone marrow microenvironment. In this way reactivation of the malignant clone after completion of chemotherapy could possibly be delayed. Serum levels of IGF-1 are increased in patients with breast cancer
compared to healthy individuals16,17 although this is not
the case in all studies.18 Also, in patients with
high-risk colorectal adenomas, serum IGF-1 levels seem to be elevated
compared to patients with normal colonoscopy.15 In this
study IGF-1 levels hold prognostic value even though the serum IGF-1
concentrations in the group of patients with MM did not differ from
those of the healthy population. This is in contrast to other
prognostic markers in myeloma, for example, IL-6,19 serum
We correlated IGF-1 to a number of disease parameters registered at
diagnosis, including the concentration of serum M-component, The bioavailability of IGF-1 is in part regulated by binding proteins. Of these IGFBP-3 is the most abundant, binding 90% of IGF-1 in the circulation. IGF-1 action is inhibited when it is bound to IGFBP-3. Enhanced proteolysis of IGFBP-3 has been observed in patients with breast cancer,26 colon cancer,27 and prostate cancer.28 The resulting fragments have a reduced binding affinity for IGF-1, as seen when IGFBP-3 is cleaved by, for example, plasmin.29 The expression of proteases cleaving IGFBP-3 by MM cells could provide an explanation for the reduced levels of IGFBP-3 in patients with MM found in this study. Urokinase-type plasminogen activator (uPA) is a serine protease capable of converting plasminogen to its active form plasmin, which then cleaves IGFBP-3. Myeloma cells express both uPA and its receptor uPAR.30 Another protease associated with MM31 and known to digest IGFBP-3 is ADAM 12 (a disintegrin and metalloprotease domain 12).32,33 One could speculate that reduced levels of IGFBP-3 increase the amount of biologically active IGF-1 and in this way contribute to increased cancer cell growth. However, the biologic relevance of the reduced levels of IGFBP-3 is uncertain, because IGFBP-3 had no prognostic value in this study. IGF-1 and IGFBP-3 in serial samples from a small number of myeloma patients were also studied. We wished to examine if there was a trend toward increasing IGF-1 levels and decreasing IGFBP-3 levels in periods of active disease. However, as seen in Figure 2, no clear picture emerged from these analyses. As for IGF-1 this may not be surprising because IGF-1 is probably not produced by the myeloma cells and not related to tumor burden. However, a well-defined, prospective approach in the examination of serial patient samples is needed to reach a conclusion on this matter. This study highlights the importance of IGF-1 and its binding protein in the setting of MM. The in vivo and in vitro biologic effects of IGF-1 in MM seem to translate into a favorable prognosis for patients with low IGF-1 levels in serum.
We are grateful to Anne Hole at the Department of Clinical Chemistry at the University Hospital of Trondheim, Norway for IGF-1 laboratory analyses.
Submitted May 14, 2002; accepted July 8, 2002.
Prepublished online as Blood First Edition Paper, July 18, 2002; DOI 10.1182/blood-2002-05-1406.
A complete membership list of the Nordic Myeloma Study Group appears in the "Appendix."
Supported by grants from the Norwegian Cancer Society (T.S., C.S., M.B., A.S.); the Norwegian Research Council (grant 139615/300); the Cancer Fund, St Olav's Hospital, Trondheim; the Swedish Cancer Society (C.S.); and the Wallenberg Foundation (C.S.).
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.
Reprints: Therese Standal, Norwegian University of Science and Technology, Institute of Cancer Research and Molecular Biology, Olav Kyrresgt 3, N-7489 Trondheim, Norway; e-mail: therese.standal{at}medisin.ntnu.no.
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Other members of the Nordic Myeloma Study Group responsible for trial no. 5/94, include the following individuals. Sweden: Martin Hjorth, Lidköping; Ingemar Turesson, Malmö; Jan Westin, Lund; Kristina Carlson, Uppsala; Margaretha Carlsson, Lindköping; Eva Löfvenberg, Umeå; Stig Rödjer, Göteborg. Norway: Lorentz Brinch, Oslo; Inger Marie S. Dahl, Tromsø; Jon Lamvik, Trondheim; Ingerid Nesthus, Bergen. Denmark: Johan Lanng Nielsen, Århus; Peter Gimsing, København; Erik Hippe, Herlev; Hans Johnsen, Herlev.
© 2002 by The American Society of Hematology.
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| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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Abstract
Introduction
2b was given as maintenance therapy.
2-microglobulin, C-reactive protein in serum, number of leukocytes and thrombocytes, and hepatocyte growth factor (HGF).
; s-M protein, 
; IGF-1,
; and +, death.
2 of the model was 25.
13 nM). Median survival
was not reached in the patient group with low IGF-1, compared to a
median survival of 62 months in the remaining patients
(P = .006). This difference was also evident in the 94 patients treated with the intended protocol (median survival not
reached compared to 70 months; P = .03; Figure 