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2794
CORRESPONDENCE
INTERLEUKIN-6 IS A PROGNOSTIC FACTOR IN MULTIPLE MYELOMA
To the Editor:
Interleukin-6 (IL-6) is a pleotropic cytokine with a broad range
of biologic effects. These effects include the production of acutephase proteins by hepatocytes,' the activation of T and natural
killer (NK) cells, the induction of pluripotential hematopoietic
progenitors to enter the cell cycle: and enhanced differentiation of
more committed progenitor cells into granulocytes and macrophages.) IL-6 is probably involved in the establishment and
maintenance of in vivo peritoneal pristane-induced BALBic plasmocytoma4and in the induction of Castleman's disease, a systemic
lymphoproliferative disorder.s
Recent reports indicate that IL-6 also functions as a growth
factor in multiple myeloma, but whether it acts in an autocrine or
only in a paracrine fashion is still subject to dispute:' To test that
proposed growth-inducing activity of IL-6, we analyzed, retrospectively, the survival times of myeloma patients with regard to their
serum levels of IL-6 at the time of diagnosis.
Forty-two patients with multiple myeloma or plasma cell leukemia (30 female, 12 male; 29 IgG, 5 IgA, 8 light chain) were studied.
They constituted the entire group of myeloma patients diagnosed
at our center between 1980 and 1982 and had been under
observation long enough to render reliable survival times. The
distribution of the disease stages are shown in Table 1. Within the
same time span, five subjects were referred to us as possible
myeloma cases but were diagnosed as presenting with monoclonal
gammopathy of undetermined significance (MGUS). All sera were
obtained at the time of diagnosis, stored at -7O"C, and tested
simultaneously. IL-6 concentrations were determined by means of
the IL-&dependent hybridoma cell line assay, as previously described.8
As expected from a previous report,' the median levels of IL-6
increased significantly ( P < .005, Kruskal-Wallis test) with more
advanced stages of the disease at the time of diagnosis (Table 1).
The most important result of our investigation, however, has (to
our knowledge) not yet been reported. Survival times differed
highly significantly (P < .002, Breslow as well as Mantel-Cox test)
between patients whose IL-6 levels were at the time of diagnosis
below 7 pglmL and those with IL-6 concentrations of 7 pg/mL or
higher. The 50% survival rate in the former category was 53.7
months as compared with only 2.7 months in the latter category of
patients with high IL-6 levels (Fig. 1). No death has been observed
in the group of patients with MGUS; they were lost to follow-up
after a median of 26 (range; 4 to 49) months.
This pronounced shortening of survival time in myeloma patients
with high initial IL-6 levels is in accordance with the reported
capacity of that cytokine to induce proliferation and differentiation
in human B cells and with the observation of increased IL-6 serum
levels in patients with fulminating m ~ e l o i n a . It
~.~
remains to be
clarified whether the observed excessive amounts of IL-6 in some
myeloma patients are produced by the malignant cell clone or by
accessory cells of the bone marrow such as fibroblasts, endothelial
cells, or macrophages in response to IL-1, tumor necrosis factor, or
other stimulators. It would also be interesting to investigate the
Table 1. Serum Levels of IL-6 According to Stage of the Disease
Multiple Myeloma
MGUS
Numberof cases
IL-6 (pg/mL)
Median
Range
5
2
0-5
Stage I
13
1.5
0-10
Stage II
Stage 111
12
16
3
0-14
7
0-20
Plasma Cell
Leukemia
1
30
Fig 1. Myeloma patients whose IL-6 serum concentration at the
time of diagnosis was less than 7 pg/mL (-)
showed significantly
(P < ,002) longer survival times than patients whose IL-6 level was 7
pg/mL or higher (--). The respective 50% survival rates were 53.7
months as compared with only 2.7 months.
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2795
CORRESPONDENCE
kinetics of IL-6 levels during the course of the disease and under
various forms of treatment, in particular under interferon and
glucocorticosteroids. Besides the potential of IL-6 findings at the
time of diagnosis to serve as a prognostic factor, anti-IL-6
antibodies might be therapeutically exploited and may possibly
help to curb disease progression in patients with multiple myeloma.
H. LUDWIG
D. M. NACHBAUR
E. FRITZ
First Department of Medicine and Oncologv
Whelminen Hospital
Vienna, Austria
M. KRAINER
II. Department of Medicine
University of Vienna
Austria
H. HUBER
Department of Hematology and Oncologv
University of Innsbruck
Austria
REFERENCES
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Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci
USA 84:9035,1987
3. Wong GG, Witek-Giannotti JS, Temple PA, Kriz R, Ferenz
C, Hewick RM, Clark SC, Ikebuchi K, Ogawa M: Stimulation of
murine hemopoietic colony formation by human IL-6. J Immunol
1403040,1988
4. Van Snick J, Vink A, Cayphas S, Uyttenhove C InterleukinHP1, a T cell derived hybridoma growth factor that supports the in
vitro growth of murine plasmacytomas. J Exp Med 165:641,1987
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Castelman’s disease in mice. J Clin Invest 86592, 1990
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Aarden L, Piechaczyk M, Bataille R: Paracrine rather than
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interleukin-6. Blood 73:517, 1989
7. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwafo K,
Asaoku H, Tang B, Tanabe 0, Tanaka H: Autocrine generation
and requirement of BSF-UIL-6 for human multiple myelomas.
Nature 332233,1988
8. Van Damme J, Opdenakker G, Simpson RJ, Rubira MR,
Cayphas S, Vink A, Billiau A, Van Snick J Identification of the
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hybridomdplasmocytoma growth factor induced by interleukin 1
and tumor necrosis factor. J Exp Med 165:914,1987
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1991 77: 2794-2795
Interleukin-6 is a prognostic factor in multiple myeloma [letter] [see
comments]
H Ludwig, DM Nachbaur, E Fritz, M Krainer and H Huber
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