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Immunoreactive Interleukin-6 and Acute Phase Proteins as Prognostic
Factors in Multiple Myeloma
By Tarja-Terttu Pelliniemi, Kerttu Irjala, Kari Mattila, Kari Pulkki, Allan Rajamlki, Anri Tienhaara, Markku Laakso,
and Reino Lahtinen for the Finnish Leukemia Group
High serum levelof bioactive interleukin-6 (IL-6) is regarded
as a predictor of poorprognosis in multiple myeloma (MM).
On the other hand, the reported levels of immunoreactive
IL-6 have been highly variable, and the prognostic value of
immunoreactive IL-6 in MM is not clear. We have analyzed
the prognostic significance of serum immunoreactive IL-6,
as measured by a sensitive immunosorbent assay, in 210
patients with newly diagnosed MM subsequently treated
with intermittent melphalan and prednisone. The serum levels of acute phase proteins C-reactive protein (CRP), al-antitrypsin (alAT),and acid al-glycoprotein (orosomucoid; OM)
were evaluated as surrogates for IL-6. Serum IL-6, CRP,
d A T , and OM levels were raised in 42%, M%, 41%, and
24% of the patients, respectively. There was a significant
correlation between the clinical stage of the patients and
serum IL-6 (P = .006), a l A T (P = .001), and OM ( P = .004)
levels at diagnosis. At 3 years, 52% of the patients were
alive. Univariate logistic regression analysis showed that
high levels of 11-6 ( P = .002), CRP (P = .02), a1AT ( P < .
O
O
l
)
,
OM ( P = .007), P2-microglobulin (P2M; P < .001), and thymidine kinase (P < .M)
were allassociated with 3-year mortalIn multivariate regression analysis, PZM (P < .00011 and
a1AT ( P = .01) had independent prognostic significance. The
patients with high levels of both P2Mand a I A T or IL-6 were
at very high risk of dying within 3 years from diagnosis (16%
and 21% of thepatients in these groups were alive, respectively). When the patients werestratified according t o t h e
clinical stage, the prognostic significance of serum IL-6 and
a l A T was especially evident in stage I1 patients. When the
patients were divided into two groups according t o normal
or raised serum IL-6 levels, the patients with high 11-6 levels
had more frequent osteolytic bona lesions ( P = .03) and a
more aggreasive disease. We conclude that serum immunoreactive 11-6 is a significant prognostic marker in MM.
8 1995 by The American Society of Hematology.
M
ment arms. A serum sample drawn at diagnosis was available in
210 of these patients, and these patients form the study group for
this investigation.
The median age of the patients in the study group was 68 years
(range, 25 to 89 years). There were 102 males and 108 females. The
paraprotein heavy chain was IgG in 143 patients (68.1%), IgA in
42 (20.0%), and IgD in one (0.5%). Twenty patients (9.5%) had
light chain disease, and four (1.9%) were nonsecretory. Clinical
stage according to Dune and Salmon'' was distributed as follows:
stage IA, 26.6%; IIA, 43.2%; IIB, 5.6%; IIIA, 18.0%;and IIIB,
6.6%. Lytic bone lesions were found at diagnosis in 66% of the
patients. All of the patients have been observed for 3 years or until
death. At 3 years, 109 patients (52%) were alive.
Serum samples were drawn at diagnosis, stored frozen, and after
thawing, clarified by centrifugation (Beckman Airfuge Ultracentrifuge; Beckman Instruments Inc, Palo Alto, CA). L 6 concentration
was measured by a sensitive sandwich-type ELISA (Quantikine; R&
D Systems, Minneapolis, MN), with a detection limit of 0.4 ng/L
and upper reference limit of 3.2 ng/L in 35 healthy controls (range,
less than 0.4 to 3.2 ng/L; median, 1.4 ng/L). CRP was measured by
particle-enhanced nephelometry (NA Latex CRP Kit; Behringwerke
AG, Marburg, Germany), and alAT, OM, and a2-macroblobulin
ULTIPLE MYELOMA (MM) is a clonal disorder
where terminally differentiated B cells and plasma
cells infiltrate the bone marrow, produce the monoclonal
Ig, and secrete osteoclast-activating factors leading to bone
lesions. The growth of myeloma cells is regulated by a cytokine network where interleukin-6 (E-6) plays a key role.'
IL-6 may act as an autocrine2 or paracrine3 growth factor
for myeloma cells. Measurements of serum L - 6 concentrations by a sensitive bioassay have demonstrated raised levels
in about one third of MM patients at diagnosis! High concentration of serum bioactive IL-6 in MM patients has been
associated with poor
On the other hand, the
reported levels of immunoreactive IL-6 have been varied
and even ~ndetectable,~-"
and the prognostic significance of
immunoreactive IL-6 is, thus, unresolved.
By applying a sensitive enzyme-linked immunosorbent
assay (ELISA) we have recently reported raised serum levels
of IL-6 in 30% of a small cohort of patients with newly
diagnosed ".I2
In the present study, we have analyzed
the prognostic significance of immunoreactive IL-6 in 210
patients included in the clodronate study of the Finnish Leukemia Group.I3As L - 6 is a pleiotropic cytokine that, among
other functions, induces the synthesis of acute phase proteins
in the liver,I4 we also evaluated the prognostic significance
of serum C-reactive protein (CRP),al-antitrypsin (alAT),
and acid al-glycoprotein (orosomucoid; OM) as surrogates
for IL-6. The prognostic significance of IL-6 and acute phase
proteins was evaluated together with that of previously
established prognostic factors, serum P2-microglobulin
(P2M)'5-'7 and thymidine kinase (TK)."
MATERIALS AND METHODS
The Finnish Leukemia Group clodronate trial included 350 patients entered between March 1986 and August 1989. The patients
were treated with melphalan and prednisone and randomized to receive oral clodronate or placebo. The median survival time, calculated from the onset of chemotherapy, was 36 months for both treat-
Blood, Vol 85. No 3 (February l ) , 1995: pp 765-771
ity.
Fromthe Departments of Hematology and Clinical Chemistry,
Turku University Central Hospital, Turku; and the Department of
Medicine, Kuopio University, Kuopio, Finland.
Submitted June 20, 1994; accepted October 3, 1994.
Supported in part by grants from Huhtamdki O y , Leiras, Turku,
Finland: Orion O y , Orion Diagnostica, Helsinki, Finland; and Wallac O y , Turku, Finland.
Address reprint requests to Tarja-Terttu Pelliniemi, MD, Department of Hematology, Turku University Central Hospital, FIN-20520
Turku, Finland.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"adve~sement" in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
Q 1995 by The American Society of Hematology.
0006-4971/95/8503-0$3.00/0
765
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PELLlNlEMl ET AL
766
Table 1. Serum IL-6 and Acute Phase Proteins in MM at Diagnosis
Mean
IL-6 42
(ng/L)
<0.4-107
2.8 9.6 5.4
11.4
CRP (mg/L)
2.7
alAT
1.2
OM (g/L)
35
Albumin (g/L)
SD Range Median
26.8
0.9
0.5
6.8
4.0
2.6
1.1
36
%*
<2.0-284
40
410.6-6.1
240.4-4.1
21 18-73
Upper reference limits were as follows: IL-6, 3.2 ng/L; alAT, 2.7 g/
L; and OM, 1.5 g/L. Cut-off limit for CRP was 6 mg/L20.”; for albumin,
30 g/L.
Proportion of patients with raised (IL-6, CRP, alAT, OM) or decreased (albumin) values. Thenumber of patients for IL-6 and albumin
was 210 and for others, 209.
(a2M) bynephelometricassays(Behringwerke
AG). Serum P2M
concentrationwasmeasuredbytime-resolvedfluoroimmunoassay
(Delfia;Wallac, Turku, Finland),TK by radioenzymatic assay(Sangtec Medical, Bromma, Sweden).
Forstatistical analyses, comparisonsbetweengroupswereperformed by Mann-Whitney U test, x’ test, or one-sided analysis of
variance when appropriate. The significance of prognostic factors in
determining the 3-year mortalitywas evaluated by univariate logistic
regression analysis. Theparametersthatshowedstatistical
significanceintheunivariateanalysiswereincludedinthemultivariate
logistic regression analysis. Survival analyses were performed with
the product-limit method (Kaplan-Meier), and the log rank test was
used to comparesurvival curves. Theseanalysesweredonewith
SPSSX/PC+ (SPSS Inc, Chicago, L) or BMDP statistical software
(BMDP Statistical Software Inc, Los Angeles, CA). A P value less
than .05 was considered statistically significant.
RESULTS
Serum concentrations of IL-6 and acute phase proteins.
The serum concentration of immunoreactive IL-6 was above
the upper reference limit of the healthy controls in 42% of
the MM patients at diagnosis (Table l). Regarding acute
phase proteins, serum CRP level was above 6 m&, the
prognostic cut-off level in earlier studies,”.” in 40% of the
patients. The other two acute phase proteins, a l A T (upper
reference limit, 2.7 g L ) and OM (upper reference limit, 1.5
g/L), were raised in 41% and 24% of the patients, respectively. Serum albumin was decreased in 21% of the patients.
The distribution curves for IL-6 and CRP levels were
strongly skewed, as indicated by the discrepancy between
the meanand median values (Table 1). Therefore, in the
Table 3. Serum 11-6 and Acute Phase Proteins in MM at Diagnosis
by Clinical Stage
-
Stage 111
Stage II
Stage I
In = 57)
(n =
(n = 52)
100)
P
IL-6(ng/L)
Mean t SD
Median
Range
CRP fmg/L)
Mean t SD
Median
Range
alAT
Mean f SD
Median
Range
OM
Mean f SD
Median
Range
Albumin (g/L)
Mean f SD
Median
Range
5.2 ? 7.4
2.6
<0.4-44.6
5.9 -t 6.2
3.6
0.4-31.7
,006
13.5 IT 39.2
6.0
12.0-284
,162
12.0-92
12.0 t 24.0
4.0
<2.0-139
2.5 ? 0.7
2.4
0.8-4.2
2.7 5 0.9
2.5
0.6-5.9
3.1
5 1.0
2.8
1.4-6.1
,001
1.0 r 0.4
1 .o
0.4-2.1
1.2 t 0.5
1.4 2 0.5
1.2
0.5-2.8
,004
37 i- 5.6
37
26-56
36 t 7.5
35
18-73
35 f 6.3
35
19-47
,171
5.1 f 14.5
2.0
<0.4-107
8.3 f 15.7
2.0
1.1
0.4-4.0
For analysis of variance, IL-6 and CRP were logarithmically (base
e) transformed. The number of patients was 209.
linear regression analyses the values for IL-6 and CRP, as
wellas for P2M and TK, were logarithmically (In) transformed. Among the acute phase proteins, Cl” showed the
strongest correlation with serum IL-6 concentration (Table 2).
When the patients were stratified according to the clinical
stage, a significant correlation could be shown between the
stage and serum levels of L - 6 , alAT, and OM, butnot
between clinical stage and serum CRP or albumin (Table 3).
Survival. The median survival time of the 350 patients
entering the Finnish Leukemia Group clodoronate study was
36 months, and 52% of the 210 patients included in this
analysis were alive at 3 years. The common risk factors that
might predict the 3-year mortality in MM are listed in Table
4. The patients who survived 3 years were younger, had
lower serum creatinine, urate, and calcium concentrations,
Table 4. Common Risk Factors at Diagnosis as PredictorsOf %Year
Mortality
Table 2. Linear Correlations Between the Serum Concentrations of
IL-6 (In-transformed)and Acute Phase Proteins, p2M. and TK
r
In CRP
<.001
alA
T
OM<.001
<.001
In P2M
In TK
Albumin
<.001
,677
.507
,637
,412
,037
-212
P
Risk Factor
Age (v)
(28-89)
66 (25-86)
69
Hemoglobin level (g/L)115(78-154)
Creatinine level
(pnol/L)
(55-505)
.02
(59-475)
104 97
Urate concentration
(pmol/L)
NS
<.Ol
Abbreviations: In, logarithmically (base e) transformed; NS, not significant.
Calcium concentration
(mmol/L)
Albumin level (g/L)
Dead
Alive
101 (56-156)<.001
(31-7641
(111-666)
378
333
(1.61-3.23)
2.52 (1.69-4.03)
2.64 <.001
(18-73)
36 (19-47)
35 .29
Values are medians (ranges).
P
.02
,008
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767
IL-6 AND ACUTE PHASE PROTEINS IN M M
Table 5. IL-6, Acute Phase Proteins, B2M. and TK at Diagnosis as
Risk Factors in Predicting the 3-Year Mortality
Alive
IL-6 (ng/L)
CRP (mg/L)
alAT (g/L)
OM (g/L)
P2M (mg/L)
TK
Dead
2.3 (<0.4-107)
3.0 (<2-284)
2.4 (0.9-5.6)
1.0 (0.5-4.1)
3.2 (1.4-31.7)
4.0 (1.0->40)
P
3.6 (<0.4-45)
5.0 (<2-139)
2.9 <.001
(0.6-6.1)
<.001
(0.4-2.7)
1.2
(1.8-31.5)
<.001
5.4
4.8 (1.O->40)
.03
<.001
.02
Values are medians (ranges).
and higher blood hemoglobin levels than the patients who
died during the 3-year follow-up. Serum concentrations of
immunoreactive IL-6 and acute phase proteins (CRP, alAT,
and OM) were significantly higher in the patients who had
died during the 3-year follow-up as compared with those
who were alive at 3 years (Table 5). The level of a2M, a
suggested carrier for IL-6," was not different between the
two groups (median values, 2.4 g/L and 2.5 g/L for the
patients who were alive or had died at 3 years, respectively;
P = .67). The serum concentrations of P2M and TK were
also higher in the patients who had died during the 3-year
observation period (Table 5). In univariate logistic regression
analysis, serum concentrations of immunoreactive IL-6,
acute phase proteins (CRP, a1AT and OM), P2M, and TK
were all statistically significant predictors of 3-year mortality
(Table 6). In multivariate logistic regression analysis with
IL-6, P2M, TK, CRP (all four logarithmically transformed),
a 1AT, and OM as covariates, P2M and a 1AT were statistically significant independent predictors of 3-year mortality
(Table 7). If age, blood hemoglobin level, and serum creatinine, urate, and calcium concentrations were also included
in the multivariate analysis, P2M (P = .006), calcium ( P
= .013), and a l A T (P = .05) had statistical or borderline
significance.
When the patients were divided in two groups according
to the serum IL-6 or a l A T levels at diagnosis, a significant
survival benefit was seen for the patients with low levels of
IL-6 (Fig 1) or a l A T (Fig 2), respectively. When the patients
were stratified in four groups according to serum P2M and
IL-6 levels (Fig 3) or P2M and a l A T levels (Fig 4), those
with high levels for both P2M and IL-6 or P2M and a1AT
were high-risk patients, with only 21% and 16% surviving
at 3 years, respectively.
Table 6. Predictors of 3-Year Mortalii by Univariate Logistic
Regression Analysis
~~
0 Coefficient
,002 In IL-6
In CRP
.02
ulAT
<.001
,007 OM
<.001
In P2M
In TK
0.460
0.248
0.642
0.834
1.349
0.308
P
Table 7. Predictors of 3-Year Mortality by Mukivariete Logistic
Regression AnalysisWith IL-6, Acute Phase Proteins,
B2M. and TK as Covariates
0 Coefficient
<.0001
In P2M
.01 u l A T
.29 OM
.44 In IL-6
In CRP
.53 In TK
P
1.296
0.640
-0.554
0.174
-0.142
0.111
.47
If the patients were stratified in three groups according to
the clinical stage, the prognostic significance of IL-6 (Fig 5)
and a1AT (Fig 6) was especially seen in stage I1 patients
(stage 11, high v low L - 6 levels, P = .0004; stage 11, high
v low a l A T levels, P = .0002, respectively).
Distribution of other prognostic factors according to serum ZL-6 concentration. Several possible prognostic parameters were compared in the two patient groups defined
according to normal or raised serum IL-6 concentration (Table 8). Patients with raised serum IL-6 levels were older and
had more advanced disease, more frequent osteolytic lesions,
lower blood hemoglobin and serum albumin levels, and
higher serum creatinine, urate, and calcium concentrations.
Also the serum levels of P2M and acute phase proteins were
higher in the patients with raised IL-6 levels, whereas serum
TK concentration was not significantly different between the
two groups.
DISCUSSION
Intermittent melphalan and prednisone is still the common
first-line chemotherapy regimen in MM. In randomized studies combination chemotherapy protocols have not signifi-
L
LL
2o
1
IL-6 IOW
p = 0.0002
1
o !
0
I
l
l
1
10
20
30
40
MONTHS
Fig 1. Survival curves of 210 MM patients according to serum IL6 level at diagnosis. Low IL-6 indicates values less than 3.3 ng/L; high
<.05
IL-6, r3.3 ng/L. The number of patients with low 11-6 values was
123; with high values, 87.
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768
PELLlNlEMl
ET AL
r - 1
p < 0.0001
loo
.......
"
1 B2M low,
2o
l
o !
0
p
0.0001
2o
I
I
1
i
10
20
30
40
i
alAT low
-"
-
L.
'
B2M low, alAT high .........
B2M high, alAT low
-----
B2M high, alAT high
---
0 1
0
'7
I-
-l"
I
I
I
I
10
20
30
40
MONTHS
MONTHS
Fig2. Survival curves of 209 MM patienta according to serum
alAT level at diagnosis. Low alAT indicates valuesless than 2.8 g/
L; high alAT, r2.8g/L. The number patlents
of
with low alATvalues
was 123; with high values, 86.
Fig 4. Survival curves of 209 MM patients stratified according to
serum p2M and alAT levels at diagnosis. The cut-off level for P M
was 6 mg/L; for alAT, 2.8 g/L. The number of patients in each group
was as follows: p2M low, alAT low: 94; p2M low, alAT high: 51;
p2M high, alAT low: 33; and p2M high, alAT high: 31.
cantly improved the outcome of MM patients. Intensive
treatment including rescue by autologous bone marrow or
peripheral blood stem cell transplantation is a newpromising
option in the management of MM. To offer the patients
an appropriate treatment modality and to correctly stratify
patients in clinical trials, careful analysis of prognostic factors is mandatory. In the Finnish Leukemia Group clodronate
trial, all patients were primarily treated with melphalan and
prednisone, and thus, this cohort of myeloma patients allowed us to evaluate the prognostic significance of various
pretreatment characteristics.
As IL-6 plays a keyrole in the cytokine network regulating
the growth of myeloma cells, its serum concentration might
reflect the biologic characteristics of MM. When sensitive
bioassays have been applied, increased serum concentrations
of IL-6 have been shown in MM patients at diagnosis and
in advanced d i ~ e a s e . ~ .On
~ . 'the
~ other hand, various immunoassays either have shown normal or even undetectable levels
of serum IL-6 in MM patient^"^'" or have shown raised
levels in MM patients in studies where the serum concentration of IL-6, even in the controls, has been very high.",25
By applying a sensitive immunoassay, we observed in the
2>
IL-6
IL-6
IL-6
II, IL-6
Ill, IL-6
40
-
n
L l"
B2M low, IL-6 high ..........
B2M high, IL-6 low - - - - B2M high, IL-6 high ---
7L
"
l"
0
30 10
20
MONTHS
Fig 3. Survival curves of 210 MM patients stratified according to
serum p2M and IL-8 levels at diagnosis. The cut& level for p2M
was 8mg/L for 11-6.3.3 ng/L. The number of pcrtients in each grwp
was as follows: p2M low, IL-6 low: 98; P M low, IL-8 high 48; p2M
high, IL-6 low: 23; and p2M high, IL-6 high 41.
..:
..........'
L"
- --
IOW-
......
..............
high
IOW- - - "- high ---
I-
L
low ..........
Ill, IL-6 high
-
0
0
40
""k-L
""
LL
a
B2M IOW,
IL-6 IOW
I I
60
3
bp
-.
I
A
30 10
20
40
MONTHS
Fig 5. Survival curves of 210 MM patients stratified according to
clinical stage and serum IL-6level at diagnosia. The cut-off level for
11-6 was 3.3 ng/L. The number of petlenta in esch group was as
follows: stage 1.11-6 low: 40; stage 1.11-6 high: 17; stage II, 11-6 low:
60; stage II, IL-6 high: 4
0
; stage 111, IL-6 low: 24; stage HI, IL-6 high:
29.
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IL-6 ANDACUTEPHASEPROTEINS
769
IN MM
and P2M had independent prognostic significance. In the
present study, plasma cell labeling index was not measured,
but we assayed instead the activity of TK, which is an enzyme involved in cell proliferation. Serum levels of TK are
increased in MM patients who also have high plasma cell
labeling index and poor p r o g n ~ s i s , "and
~ ~TK
~ ~may
~ ~ provide
. .\additional prognostic information after P2M stratification in
"I,
melphalan-treated MM patients." Our results in 210 melphaI, a l A T low - - lan-treated patients show that immunoreactive IL-6, P2M,
I, a l A T high - and TK are significant prognostic markers in MM. When
11, a l A T low - - - - these three parameters together with the acute phase proteins
11, a l A T high --were included in the multivariate analysis, P2M and a l A T
Ill, a 1 A T low .........
(but not TK) had independent prognostic value. Thus, serum
Ill, a l A T high alAT, reflecting the biologic effects of IL-6, provides addi"
l
tional prognostic information to the tumor mass and renal
0
10
20
30
40
function represented by serum P2M. This result agrees with
MONTHS
the earlier observation that among acute phase proteins,
a1AT had the strongest correlation with survival.34However,
Fig 6. Survival curves of 209 MM patients stratified according to
stratification of the patients according to the clinical stage
clinical stage and serum a l A T level at diagnosis. The cut-off level for
showed that the prognostic significance of IL-6 and a1AT
a l A T was 2.8 g/L. The number of patients in each group was as
follows: stage 1, alAT low: 38; stage 1, a l A T high: 19; stage II, a l A T
was concentrated in stage I1 patients. In agreement with the
low: W;stage II, alAT high: 40; stage 111, d A T low: 22; stage 111,
results of Bataille et a12" on serum P2M and CRP levels,
alAT high: 30.
we also found that a powerful prognostic stratification of
myeloma patients can be based on serum levels of P2M and
either IL-6 or a 1AT.
present study increased levels of serum IL-6 in 42% of paStratification of the MM patients into two groups with
tients with newly diagnosed MM. The range of serum ILeither normal or raised serum IL-6 concentration showed
6 concentrations and the proportion ofMM patients with
increased IL-6 levels agree well with the bioassay r e s ~ l t s . ~ that several other prognostic factors were associated with
the IL-6 level. The lower serum albumin concentrations in
As IL-6 induces the synthesis of acute phase proteins in
patients with raised IL-6 levels is in agreement with the
the liver,14.z6*z7
the serum levels of acute phase proteins might
serve as surrogates for IL-6 activity in vivo.',zo The close
correlation between IL-6 activity and the serum concentraTable 8. Prognostic Variables in MM by Serum IL-6 Level
tion of acute phase proteins is supported by the finding that
in vivo administration of anti-IL-6 antibody causes a rapid
IL-6 Level
decrease2' and administration of recombinant IL-6 a sharp
13.3 ng/L
~ 3 . ng/L
3
increasez9in serum C m concentration. The results in our
(n = 1231
Variable
In = 87)
P
MM patients show that serum IL-6 level correlates with the
Age ( v )
65 (28-86)
70 (40-89)
<.001
concentration of acute phase proteins and that the correlation
Stage 1/11/111 (no.)
17/41/29
40/60/23
.02
was strongest with CRP. A correlation between the serum
Osteolytic lesions
levels of CRP and bioactive IL-6 has previously been docu60.2
74.4
.03
(present, %)
mented in severe burns3' and rheumatoid arthriti~.~'
Hemoglobin level
Several pretreatment characteristics, eg, age, hemoglobin
111 (73-156)
103 (56-154)
.01
(g/L)
level, stage of the disease, renal function, P2M concentraCreatinine
tion, and plasma cell labeling index, give prognostic informaconcentration
tion in MM.l5.16.l9.32,~3Serum P2M level reflecting the tumor
(pmol/L)
97 (58-449)
107 (55-505)
.03
Urate concentration
mass and renal function is usually regarded as the most
(prnol/L)
338 (66-669)
374 (31-764)
,007
significant single prognostic factor in MM.I5-l7Also, in our
Calcium
patients P2M level was strongly associated with survival
concentration
and came out first in the multivariate analysis. Previous stud(mmol/L)
2.53 (1.69-3.93)
(1.61-4.03)
2.63 .01
ies have resulted in contrasting data about the value of other
37 (22-56)
Albumin level (g/L)
35 (18-73)
.02
prognostic parameters in addition to P2M. Bataille et alZo CRP level (mg/L)
1.5 (1.0-33.0)
(1.0-284)
11
<.001
showed that serum CRP level gave prognostic information
nlAT level (g/L)
2.3 (0.8-5.1)
(0.6-6.1)
<.001
3.2
in addition to P2M and proposed a stratification system
OM level (g/L)
0.9 (0.4-2.3)
(0.6-4.1)
<.001
1.4
based on P2M and CRP levels. Merlini et a134 confirmed the
3.5 (1.4-18.5)
(1.9-31.7)
5.1<.001
P2M level (mg/L)
prognostic significance of acute phase proteins, but in their
TK level (U/L)
4.4 (1.0->40)
4.7 (1.0->40)
.53
study, a1AT was more powerful than CRP. Greipp et a121
Concentrations are expressed as medians with ranges in parenthereported that CRP was a significant prognostic marker, but
ses. The number of patients was 209 for CRP, nlAT, and OM; 210 for
in the multivariate analysis, only plasma cell labeling index
other variables.
p < 0.0001
I
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
770
PELLlNlEMl ET AL
observation that IL-6 in vitro decreases the synthesis of albumin in human hepato~ytes.’~~~’
The stratification also showed
that the patients with raised IL-6 levels had more frequent
osteolytic lesions than the patients with normal IL-6 levels.
This is in agreement with the proposed critical role of IL-6
in the activation of osteoclasts in MM.37
We conclude that the serum concentration of immunoreactive IL-6 is a significant prognostic marker in MM, particularly in stage I1 patients, and that acute phase proteins, especially alAT, provide a good surrogate for IL-6
measurements in MM.
APPENDIX
Participating centers in the Finnish Leukemia Group: Turku University Central Hospital (T.-T. Pelliniemi, A. Rajam*, K.
Remes),
Helsinki University Central Hospital (I. Elomaa, E. Elonen, T. Parkkali, T. Ruutu, P. Virkkunen), Kuopio University Hospital (A. Hbninen, M. Laakso, R. Lahtinen, T. Nousiainen), Oulu University Central Hospital (P. Koistinen, T. Timonen), Tampere University
Hospital (G. Jarventie, E. Koivunen, M. Lehtinen, T. Leino), Joensuu
Central Hospital (E. JWenpZi), Jyvaskyla Central Hospital (H. Hallman), Kajaani Central Hospital (M. KWiilnen), Kemi Central Hospital (P. Nylanden), Kokkola Central Hospital (S. Rosengkd), Lappeenranta Central Hospital (K. Soininen), Mikkeli Central Hospital
(A. Laitinen), Pori Central Hospital (H. Kilpi, H. Makela), Rovaniemi Central Hospital (M. Ilvonen), Savonlinna Central Hospital
(T. Pulli), Seinajoh Central Hospital (J. Jouppila), Vaasa Central
Hospital (A. Almqvist), Aland Central Hospital (D. Nyman), Hatanpail Hospital (I. Palva), Lohja District Hospital (J. Valtonen), Malmi
District Hospital (B. Isomaa), Porvoo District Hospital (B. Rask),
and Ahtiiri District Hospital (E. Korpi).
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Immunoreactive interleukin-6 and acute phase proteins as prognostic
factors in multiple myeloma. Finnish Leukemia Group
TT Pelliniemi, K Irjala, K Mattila, K Pulkki, A Rajamaki, A Tienhaara, M Laakso and R Lahtinen
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