ORIGINAL ARTICLE

B cell-activating factor: its clinical significance

in multiple myeloma patients
M. Fragioudaki & A. Boula & G. Tsirakis & F. Psarakis &
M. Spanoudakis & I. S. Papadakis & C. A. Pappa &
M. G. Alexandrakis
Received: 7 January 2012 / Accepted: 2 April 2012
#Springer-Verlag 2012
Abstract B cell-activating factor (BAFF) is a cytokine that
plays a major role in the maintenance of normal B-cell
development and homeostasis. It has been suggested that
in multiple myeloma (MM) it might have regulatory effects
on the proliferation and viability of malignant plasma cells.
The aim of this study was to evaluate serum levels of BAFF
in 52 newly diagnosed MM patients, with varying disease
severity, in order to see the correlations between BAFF and
indices of MM activity, such as interleukin-6, C-reactive
protein, lactate dehydrogenase, and beta-2 microglobulin,
and to explore the clinical significance of BAFF in predict-
ing the disease activity of MM. We found increased BAFF
serum levels in MM patients, increased in advanced stages,
and decreased in plateau phase. We also found significant
correlations between BAFF serum levels with the above
parameters of disease activity. We conclude that BAFF
may play an important role in pathogenesis of MM, could
be used as a marker of disease activity, and a possible
therapeutic target.
Keywords Multiple myeloma
.
Bcell-activating factor
.
Cytokines
.
Prognosis
Introduction
Multiple myeloma (MM) is a mostly incurable B-cell neo-
plasia characterized by the malignant proliferation of mono-
clonal plasma cells (PC) in the bone marrow (BM). MM
usually is preceded by monoclonal gammopathy of undeter-
mined significance (MGUS), a premalignant tumor that
progresses to MM at an average of about 1 % per year [1].
The molecular basis for the progression to MM is quite
complex. Progression events that can occur in all the differ-
ent molecular subtypes of MM include both genetic aberra-
tions in MM cells (cytogenetic and epigenetic abnormalities,
activating mutations of signaling pathways, p53 deletion or
mutation) and evolving interactions between different cell
types within the BM microenvironment [24]. When MM
cells bind to BM stroma cells, adhesion molecules can
activate intracellular signaling cascades in MM cells and
can increase stromal cell secretion of cytokines involved in
tumor cell proliferation. Some of the growth and survival
factors produced by the BM microenvironment include
interleukin-6 (IL-6), insulin-like growth factor-1, vascular
endothelial growth factor, osteopontin, stromal derived fac-
tor 1, B cell-activating factor (BAFF), and a proliferation-
inducing ligand (APRIL).
BAFF, also called B lymphocyte stimulator, is 285-amino
acid cytokine, member of tumor necrosis factor (TNF) fam-
ily, with a central physiologic role in maintenance of normal
B-cell development and homeostasis [5, 6]. It shares signif-
icant homology with APRIL, another TNF family member,
that stimulates tumor cell growth. BAFF is expressed by a
variety of cell types, mainly innate immune cells, like neu-
trophils, macrophages, monocytes, and dendritic cells but
also some T and B lymphocytes [7]. Several other non-
hematopoietic cells express this cytokine, probably modu-
lating B-cell function in the tissue microenvironment [7].
M. Fragioudaki
:
G. Tsirakis
:
M. Spanoudakis
:
M. G. Alexandrakis (*)
Hematology Department, University Hospital of Heraklion,
PO Box 1352, Heraklion, Crete, Greece
e-mail: alexandm@med.uoc.gr
A. Boula
:
C. A. Pappa
Hematology Department,
Venizelion General Hospital of Heraklion,
Heraklion, Greece
F. Psarakis
:
I. S. Papadakis
:
M. G. Alexandrakis
Hematology Laboratory, University Hospital of Heraklion,
Heraklion, Greece
Ann Hematol
DOI 10.1007/s00277-012-1470-x
Three receptors for BAFF have been identified: BAFF re-
ceptor 3, transmembrane activator and calcium modulator
and cyclophylin ligand interactor (TACI), and B-cell matu-
ration antigen [79]. All three receptors are potent stimula-
tors of the nuclear factor-B (NF-B) pathway [10].
The striking roles of BAFF, APRIL, and their receptors in
normal B-cell homeostasis and in several tumor models
raised the possibility that they may be involved in the
pathogenesis of B-cell malignancies. Some studies reported
aberrant expression of BAFF and APRIL by tumor B cells
isolated from a subset of patients with chronic lymphocytic
leukemia [11, 12]. Another study showed that patients with
follicular lymphoma had increased levels of soluble BAFF
in their serum, which seemed to favor B-cell survival [13].
Recent studies provided evidence that myeloma cell lines
and primary myeloma cells express BAFF and APRIL and
their receptors and that both of them are myeloma cell growth
factors [14]. It was also shown that they can rescue myeloma
cells from dexamethasone-induced apoptosis [15]. The pur-
pose of the study was to evaluate serum levels of BAFF in
normal persons and in MM patients with varying severity of
disease, in order to see whether there was any correlation
between BAFF at diagnosis and some prognostic biological
parameters of MM patients and explore the clinical signifi-
cance of BAFF in predicting the disease activity of MM.
Materials and methods
Patients
Fifty-two previously untreated MM patients were enrolled
in this study. Of them, 53.8 % were women and 46.2 % men,
with a mean age 66.610.5 years (range 4082 years).
Accordingly to the International Staging System (ISS),
28.8 % had ISS-1 disease, 36.5 % ISS-2, and 34.6 % ISS-
3. Monoclonal immunoglobulins IgG, IgA, and light chain
disease were found in 57.6, 34.6, and 7.7 %, respectively.
We also studied 25 of them, who reached the plateau phase
after effective treatment. From them, nine had received the
combination of bortezomib plus dexamethasone, five the
MPV (melphalan, prednisone, bortezomib), four the VAD
(vincristine, pegylated liposomal doxorubicin, dexametha-
sone), three the MP (melphalan, prednisone), and three the
PAD regimen (bortezomib, pegylated liposomal doxorubi-
cin, dexamethasone). Twenty age and sex-matched healthy
volunteers were used as controls. Informed consent for the
study was obtained from all subjects.
Methods
Venous blood samples were collected for laboratory-based
studies. To eliminate interassay variability, all serum
samples from patients and controls were aliquoted into
separate vials and stored at 70 C until assayed on the
same day.
Serum BAFF and IL-6 determination
BAFF and IL-6 serum levels were analyzed by enzyme
linked immunosorbent assay (ELISA), using commercially
available kits (Quantikine Human BAFF and IL-6; R&D
Systems, Minneapolis, MN, USA) according to the manu-
facturers protocol.
Biochemical markers assay
Serum 2-microgobulin (2M) was measured with a micro-
ELISA method using the commercially available kit from
Abbot (IMX, Abbot Park, IL, USA). Serum C-reactive
protein (CRP) levels were measured by nephelometry (Dade
Behring, Marburg, Germany). Lactic dehydrogenase (LDH)
serum levels were measured using a commercially available
kit (Olympus System Reagent 500 from Olympus Diagnos-
tics GmbH Co., Clare, Ireland).
Statistical analysis
All calculations were performed on a Microsoft computer,
using SPSS software. Results are expressed as meanSD.
Statistical analysis was performed using KruskalWallis
test, to assess the existence of differences between differ-
ent disease stages. A post hoc multiple comparisons test,
StudentNewmanKeuls, was carried out to determine
differences between means. Statistical comparisons be-
tween MM group and control group were made using
the nonparametric MannWhitney test. Correlations were
assessed using the Spearmans rho correlation coefficient.
Survival analysis was performed using the KaplanMeier
method. A p value <0.05 was considered statistically
significant.
Results
Mean (SD) serum values of BAFF in both patients and
controls are shown in Table 1. Serum levels of BAFF were
significantly higher in MM patients in comparison to con-
trols (p<0.001). BAFF concentrations were significantly
elevated at disease stage III compared to stages I and II
(p<0.0001, Table 1). Similarly, mean serum values of IL-6
were significantly increased in untreated MM patients in
comparison to controls (p<0.001); moreover, statistically
significant differences were found among the levels of IL-
6 in disease stages I, II, and III (p<0.001). Regarding the
acute phase protein studied, CRP, the mean serum levels
Ann Hematol
were significantly higher in the patients sera than in healthy
controls (p<0.001) and also with advancing disease stage.
LDH and 2M increased significantly with advancing stage
of disease (p<0.001 and p<0.009, respectively).
In the pretreatment group, serum levels of BAFF corre-
lated positively with IL-6 (r00.399, p<0.003; Fig. 1), LDH
(r00.443, p<0.001; Fig. 2), and CRP (r00.287, p<0.04;
Fig. 3). A trend to correlate was found between BAFF levels
and 2M (p<0.07). Furthermore, IL-6 correlated with LDH,
CRP, and 2M values, LDH with CRP and 2M values,
and CRP with 2M value.
Data from the posttreatment patients are shown in
Table 2. We compared the values of the above param-
eters only for the patients who achieved plateau phase.
BAFF levels in the pretreatment group decreased signif-
icantly after treatment (p<0.001). Furthermore, there
was also a significant decrease of IL-6, LDH, 2,
and CRP in the group of posttreatment patients com-
pared to their pretreatment levels. Additionally, we
found that pretreatment MM patients with serum BAFF
values higher than the median (792.7 pg/ml) had signif-
icant shorter survival than patients with lower BAFF
value (p<0.02).
Discussion
Recent studies support the notion that BAFF is essential for
the survival of normal immature and mature B cells, as well
as normal plasmablastic cells. Importantly, dysfunctional
BAFF signaling occurs in many B-cell neoplasias with an
autocrine loop stimulating tumor cell growth and survival
[12, 16]. Previous studies showed a potential role for BAFF
in the progression of lymphoid malignancies. BAFF levels
have been found higher in the serum of patients with
non-Hodgkin lymphomas, where BAFF seems to pro-
mote the survival of lymphomatic B cells [15]. Similar
results have been observed in B-cell chronic lymphocyt-
ic leukemia (B-CLL) where also BAFF protects B-CLL
cells against apoptosis and, as such, may play an im-
portant role in promoting the survival and expansion of
B-CLL [11]. BAFF is expressed in MM cells and can
be detected in the serum of MM patients, suggesting an
autocrine loop of stimulation from these tumor cells as
well [14, 15]. It has been reported that BAFF is mainly
secreted by bone marrow stromal cells, where plasma
cell adhesion to them augments its secretion, resulting
NF-B activation [17] and MAPK and AKT phosporylation
Table 1 MeanSD values of B cell-activating factor (BAFF) in the group of untreated multiple myeloma patients, according to disease stages and
in controls
Patients (n052) Stage I (n015) Stage II (n019) Stage III (n018) Controls (n020)
BAFF (pg/ml) 988.6720.3 557.4308.9 966.3533.2 1371925.8* 279.8164.3**
*p<0.0001 between stage III and stages I and II; **p<0.001 between patients and controls
Fig. 1 Correlation between B
cell-activating factor (BAFF)
with interleukin-6 (IL-6) in
myeloma patients
Ann Hematol
[15]. The biological role of BAFF on myeloma cell survival is
both direct and indirect, affecting bone marrowmicroenviron-
ment via affecting bone resorption [18].
In this study we have shown that BAFF levels are sig-
nificantly higher in MM patients compared to normal con-
trols. This finding confirms previous observations indicating
increased serum levels [15] and mRNA expression [19] of
BAFF in patients with MM. However we have extended this
observation by showing that BAFF significantly increases
with advancing disease stage, since patients in stage III had
significantly higher levels of BAFF compared to those in
stage I and II, and decreases when the disease gets inactive,
in plateau phase. MM cells are highly dependent upon the
presence of various growth factors. Most importantly of
them all is IL-6, a pleiotropic cytokine with multiple bio-
logical activities in vitro and in vivo, including human
myeloma cell proliferation, differentiation, and protection
against drug-induced cytotoxicity [2023]. Furthermore,
IL-6 has a potential diagnostic role in both MGUS and
MM, since it is significantly higher in these patients [24].
IL-6 can be considered as a significant prognostic marker in
MM patients: not only is it higher in patients with advanced
stages or with progressive disease but it also shows a strong
correlation with several parameters of disease activity [25].
Fig. 2 Correlation between B
cell-activating factor (BAFF)
with lactate dehydrogenase
(LDH) in myeloma patients
Fig. 3 Correlation between B
cell-activating factor (BAFF)
with C-reactive protein gCRP)
in myeloma patients
Ann Hematol
In the present study, we have shown that serum levels of
BAFF correlated strongly with IL-6. This may be explained
by the fact that IL-6 could induce BAFF gene and enhance
protein expression level [26]. This is also interesting since
IL-6 is the major growth factor for human myeloma cells
and a potent regulator of the acute phase response. BAFF
levels also correlate with LDH and CRP, which are well-
known markers of disease activity. Therefore, it could be
suggested that BAFF serum levels might also have diagnos-
tic value; although our sample is small to reach definite
conclusions, we showed that increased BAFF levels are
associated with disease progression.
There are certain laboratory parameters with prognos-
tic value in MM. One of them is CRP, a sensitive
systemic marker of inflammation and tissue damage.
CRP values are elevated in a variety of situations, such
as infections, inflammations, tissue necrosis, and malig-
nancies. CRP is an acute phase protein, secreted by
hepatocytes in response to inflammatory cytokines, such
as IL-1 and IL-6, being both elevated in patients with
active MM. It has been shown that CRP, as well as
dexamethasone, upregulate myeloma cell secretion of
IL-6. Both IL-6 and CRP seem to protect myeloma
cells from dexamethasone-induced apoptosis, creating a
vicious circle where IL-6 and CRP interfere in the
survival of myeloma cells [27]. In our study, we found
increased values of CRP in pretreatment patients, decreased
values in the plateau phase, and a significant correla-
tion, as expected, with IL-6 values. We also found
significant positive correlations with other markers of
disease activity, such as 2M and LDH. Moreover, it
is of importance that CRP values also correlated to
BAFF levels, suggesting an indirect relation between them.
As far as we know, this is the first study in the literature
correlating CRP values with serum BAFF levels in MM
patients.
Another important prognostic variable in several hema-
tological malignancies is LDH. In MM patients, LDH con-
centration is a reflection of the tumor-bearing status and
may be used as a predictor for therapeutic outcomes and
prognosis [28]. In our study, as expected, LDH concentra-
tions were higher in MM patients compared to controls,
increased significantly with advanced disease stage, also
decreased significantly when disease was inactive, in
plateau phase, and correlated with parameters of disease
activity, such as 2M and CRP. It is of importance that
LDH levels significantly correlated with BAFF concentra-
tions. Since there is a positive correlation of BAFF serum
levels with LDH, a known marker of disease activity, we
have another indirect indication that BAFF serum levels
might be a significant factor of disease activity.
We also examined the association of serum BAFF levels
with 2M, another prognostic factor of MM. Although
2 levels were, as expected, higher in pretreatment
patients compared to controls and posttreatment ones, as
well as in advanced disease stages, we only found a trend
to correlate with BAFF serum levels. This may be due to the
small number of analyzed cases.
Since serum levels of IL-6, LDH, and CRP reflect the
activity of MM, it is possible that the elevated serum BAFF
concentrations found in advanced MM stages may be relat-
ed to the growth of myeloma cells. The positive correlation
found between serum BAFF concentrations and serum IL-6,
LDH, and CRP values corroborates this suggestion. This is
an expected finding, since BAFF is a known stimulator
factor for B-cell homeostasis and survival, through activa-
tion of NF-B pathways. It is of interest that neutralization
of BAFF protein by specific BAFF antibody decreases MM
cells survival in vitro. Furthermore, the use of LY2127399,
a human anti-BAFF antibody, in a phase I study, when used
in combination with bortezomib, caused an overall response
rate to 55 % in previously treated patients, despite prior
bortezomib use in 65 % of them [29]. Moreover, atacicept,
a fusion protein composed of the human IgG Fc portion and
the extracellular, ligand-binding portion of the TACI recep-
tor, neutralizes both BAFF and APRIL, and its addition to
primary myeloma cells abrogates proliferative effects and
induces apoptosis [15]. Furthermore, atacicept has inhibited
the growth of primary myeloma cells with high expression
of TACI, when cocultured with osteoclasts [30]. The use of
atacicept, in a phase I study of relapse/refractory myeloma
or active Waldenstrm macroglobulinemia, showed clinical
and biological activity consistent with its mechanism of
action [31]. All these observations agree that BAFF and its
receptors have regulatory effects on the proliferation and
viability of myeloma PC suggesting a role in pathogenesis
of the disease [17].
In conclusion, we found increased serum BAFF lev-
els in newly diagnosed MM patients, being correlated to
disease stage and known factors of disease activity. We
also noted decrease of BAFF serum levels after treat-
ment, in plateau phase, when the disease is inactive. All
these data show that BAFF is well implicated in the
pathogenesis of MM. Our results suggest that serum
BAFF levels might be used in future prognostic models
for MM. They also provide the rationale to target the
BAFF pathway in novel therapeutics.
Table 2 MeanSD values of B cell-activating factor (BAFF) and
interleukin-6 (IL-6) in myeloma patients before and after treatment
BAFF (pg/ml) IL-6 (pg/ml)
Pretreatment 883.3690.5 5.91.7
Posttreatment 315.6159.0 2.91.2
p value <0.001 <0.001
Ann Hematol
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