Curcumin for monoclonal gammopathies what can we hope for, what should we fear

Critical Reviews in Oncology/Hematology 84 (2012) 350–360
Curcumin for monoclonal gammopathies. What can we hope for, what
should we fear?
A.J.M. Vermorken
a,∗
,J.Zhu
a
, W.J.M. Van de Ven
a
, E. Andrès
b
a
Laboratory for Molecular Oncology, Department of Human Genetics, KU Leuven, Belgium
b
Department of Internal Medicine, Diabetes and Metabolic Disorders, University Hospital of Strasbourg, Strasbourg, France
Accepted 25 April 2012
Contents
1. Introduction 351
1.1. Curcumin and health 351
1.2. Monoclonal gammopathies 351
2. Curcumin for monoclonal gammopathies 352
2.1. The first results with curcumin 352
2.2. Reflecting on possible targets 352
2.3. Curcumin does not influence the paraprotein level in all patients 352
3. Can curcumin lower the risk for emergence of MGUS in some inflammatory diseases? 353
4. Curcumin might work on immune cells rather than on the bone marrow directly 353
5. Curcumin for prevention of progression of MGUS and SMM, reasons for concern? 354
5.1. Both curcumin and myeloma act on dendritic cells and induce immunosuppression 354
5.2. Increased susceptibility to infections 354
5.3. Does curcumin suppress the immune response against (pre)malignant cells in MGUS? 356
5.4. Could curcumin stimulate clonogenic growth of tumor cells? 356

5.5. Could curcumin induce a more malignant phenotype? 356
6. Conclusions 356
Conflict of interest 357
Reviewers 357
Acknowledgements 357
References 357
Biographies 359
Abstract
Over the last decades there has been an increasing interest in a possible role of curcumin on cancer. Although curcumin is considered
safe for healthy people, conclusive evidence on the safety and efficacy of curcumin for patients with monoclonal gammopathies is, so far,
lacking. The present paper reviews the literature on molecular, cellular and clinical effects of curcumin in an attempt to identify, reasons for
optimism but also for concern. The results of this critical evaluation can be useful for both patient- selection and monitoring in the context of
clinical trials. Curcumin might be helpful for some but certainly not for all patients with monoclonal gammopathies. It is important to avoid
∗
Corresponding author at: KU Leuven, Herestraat 49 BOX, 602, BE-3000 Leuven, Belgium. Tel.: +32 16 3 46076; fax: +32 16 3 46073.
E-mail addresses: (A.J.M. Vermorken), (J. Zhu),
(W.J.M. Van de Ven), (E. Andrès).
1040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.
/>A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360 351
unnecessary detrimental side effects in some in order to safeguard curcumin for those that could benefit. Parameters for patient monitoring,
that can be used as early warning signs and as indicators of a favorable development have therefore been suggested.
© 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Monoclonal gammopathy; Multiple myeloma; Clinical trials; Immunosuppression; Dendritic cells; Curcumin; Inflammation; Clonogenic growth
1. Introduction
1.1. Curcumin and health
During thelast twenty years curcumin has been discovered
by modern science, in particular molecular biology, as a sub-
stance with a potential role in the treatment of cancer. Almost
1700 papers were published, only 22 in the first decade and
more than 500 in the year 2011 alone. About thirty papers

were related to multiple myeloma. Besides this increasing
interest in the scientific community there is an increasing
exchange of information on internet forums among citizens
about the spice and its alleged positive health effects. The
substance is commercialized and widely available.
In traditional medicine in India, turmeric, containing cur-
cumin is known for its anti-inflammatory properties [1].
Curcumin (diferuloylmethane), is the main curcuminoid
(>75%) in the Indian spice turmeric (see Fig. 1 for the struc-
tural formulas of the three main curcuminoids). Since it is
extracted from a food component that has been used for cen-
turies it is considered safe. Indeed the results of some clinical
Fig. 1. Structural formulas of the three main curcuminoids in turmeric.
trials indicated that even doses of up to 8 g per day of extracted
curcumin provoked only minimal toxicity in healthy peo-
ple. Food components might, however, be less safe for
patients as thought by the general public. Legislation does
not require companies producing supplements to show evi-
dence of health benefits. Modern medicine has confirmed the
anti-inflammatory effect of turmeric and curcumin, however,
their bioavailability is different [2]. Chronic inflammation can
predispose to cancer and non-toxic anti-inflammatory com-
pounds could thus have a place in prevention and in delay
of progression. The anti-inflammatory activity of curcumin
comes, however, at a price: immunosuppression. The immune
system also forms an important element in cancer prevention.
Any decision to treat with curcumin must therefore take the
balance between limiting inflammation and reducing immune
competence in consideration.
1.2. Monoclonal gammopathies

Monoclonal gammopathy of undetermined significance
(MGUS) is a common plasma cell disorder with an unknown
etiology and with a life-long increased risk of malignant pro-
gression. Prevalence of monoclonal gammopathy, without
evidence of malignant disease, increases from below two per-
cent in fifty to sixty year old people to above six percent over
the age of eighty [3]. The main risk factors for progression
of MGUS are size and type of the serum monoclonal protein
and presence of an abnormal serum free light chain (FLC)
ratio [4,5]. Diminished life expectancy of MGUS patients
can, however, not be explained by progression to lympho-
proliferative disorders alone. Other causes of death, both due
to malignant and non-malignant diseases are also increased,
especially in the first years after diagnosis [6]. When com-
peting causes of death are taken into account, the risk of
progression is around 0.5% per year [5]. MGUS is therefore
monitored regularly (“watchful waiting”) in order to assure
an early diagnosis of malignant progression [7].Inviewof
the relatively small overall risk for progression “watchful
waiting” is prudent since intervention may pose the risk to
disturb a possibly delicate balance keeping the gammopathy
from progressing. The above mentioned risk factors allow
distinguishing groups according to the risk for progression.
Patients with an abnormal serum FLC ratio and a high serum
monoclonal protein level (>15 g/L) have an almost 10 times
higher risk for progression as compared to patients without
these risk factors [4]. When monoclonal protein levels are
30 g/l or greater and the proportion of plasma cells in the
bone marrow is above 10 percent but there is no associated
organ damage, the diagnosis smoldering malignant myeloma

352 A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360
(SMM), a more advanced (pre)malignant condition, is made
[8]. The overall risk of progression to a malignant condition
is 10% per year for the first 5 years, it diminishes gradually
thereafter [9]. Because myeloma is a devastating incurable
condition while MGUS and SMM are often asymptomatic,
patients with a high-risk MGUS and with SMM are candi-
dates for preventive strategies. It is absolutely essential for a
preventive approach that it does not itself increase the risk of
progression.
2. Curcumin for monoclonal gammopathies
2.1. The first results with curcumin
Curcumin has recently been (re)discovered by modern sci-
ence as a therapeutic agent. It is currently used in human
clinical trials for a variety of conditions, including psoria-
sis, Alzheimer’s disease and several types of cancer [10].
Doses of up to 8 g/day of extracted curcumin provoked only
minimal toxicity in healthy volunteers [11]. The question
whether curcumin is also safe for patients with monoclonal
gammopathies remains, however, to be answered.
Patients with MGUS are often without symptoms. Preven-
tive strategies can therefore not use the effect of intervention
on symptoms as early indicators of “success”. Because the
annual risk for progression is relatively low, early endpoints
are, however, needed. Preliminary studies performed so far
[12,13] have used the above mentioned prognostic factor:
size of the serum monoclonal protein peak, which is con-
sidered to be proportional to the size of the (pre)malignant
clone, as well as the decrease in a urinary marker of bone
turnover as indicators. MGUS is associated to osteoporosis

[14] and excess of bone resorption was associated to earlier
progression to malignancy [15]. These studies revealed that
curcumin was able to decrease the paraprotein level in about
half the patients having a high concentration (of > 20 g/L)
[13]. About a quarter of the patients had a > 25% decrease
in the urinary marker of bone turnover [13]. A very recent
paper by the same group, a randomized double-blind placebo-
controlled study, used one additional parameter: the FLC ratio
[16]. In this study there was no influence on the average size
of the monoclonal protein peak, although most patients had
high paraprotein concentrations. On the other hand, curcumin
was reported to modestly decrease the average FLC ratio.
Even if the results in some individual patients are encour-
aging it has at this stage apparently not yet been possible to
identify patient selection criteria that could lead to clinically
significant effects in patient groups.
It must be kept in mind that the methodology used by
the above authors, in their work on curcumin for patients
with MGUS, is not standard. Moreover, patient numbers were
small and the duration of the studies short. The rather modest
effect on the FLC ratio should therefore be interpreted with
caution. It should be kept in mind that in multiple myeloma,
so far, no significant activity of curcumin has been noted
in clinical trials in which the validated endpoints used for
other myeloma drugs [17] were applied to adjudicate efficacy
of therapy. More studies on larger numbers of patients and
probably a more accurate definition of criteria for selection
of patients that could potentially benefit will be necessary,
before more definitive conclusions can be drawn.
2.2. Reflecting on possible targets

The original idea leading to the use of curcumin for pre-
vention of progression of MGUS [13] was based on its
capacity to down-regulate interleukin-6 (IL-6) [1], a growth
factor for both osteoclasts and myeloma cells [18] and to
inhibit osteoclastogenesis. It was hoped that curcumin would
inhibit effects of the abnormal plasma cells and normalize the
increased activity of octeoclasts in patients with monoclonal
gammopathies [18].
Serum levels of IL-6 are indeed increased in myeloma
and correlate with stage and survival. Myeloma patients with
osteolytic bone lesions have increased IL-6 levels. Inhibition
of the IL-6 signaling pathway with specific antibodies led to
in vitro and in vivo anti-multiple myeloma activity suggest-
ing that it could contribute to control tumor burden and bone
disease [19]. Curcumin has also been shown to inhibit osteo-
clastogenesis through the suppression of receptor activator of
nuclear factor kappa-B ligand (RANKL) signaling [20], the
expression of which is known to be increased in myeloma
[21].
The mechanisms of action that could explain the effects
on the paraprotein level, the FLC ratio and the bone turnover
markers remain so far uncertain. Moreover, biological find-
ings and even results in animal studies cannot always be
extrapolated to the situation in patients. Empiric evidence
from controlled studies using validated endpoints remains
therefore necessary before therapy in the clinic is justified.
Such data are, so far, lacking.
It is therefore of the utmost importance to carefully ana-
lyze the effects on patients in trials and to report the outcome
as soon as possible. This can both give indications as to

the mechanism(s) involved but also allow identifying early
warning signs of possible adverse effects in patients with
(pre)malignant conditions.
2.3. Curcumin does not influence the paraprotein level
in all patients
An important early finding is that curcumin decreases the
paraprotein load only in a limited group of patients with
MGUS [13]. It cannot be excluded that this means that cur-
cumin acts on some but not all cytogenetic subtypes of MGUS
and SMM. A more probable explanation seems that curcumin
does not act directly on the abnormal plasma cells. It could act
indirectly on secondary mechanisms that play an increasingly
important role in later stages of MGUS.
As mentioned above, curcumin is known to downregulate
IL-6, an inflammatory cytokine. IL-6 regulates differentiation
A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360 353
of dendritic cells (DCs), important antigen presenting cells
[22]. In patients with multiple myeloma the serum IL-6
level is a marker of high tumor burden. In patients with
MGUS serum IL-6 levels are not always increased but it
can be increased in relation to inflammatory parameters [23].
This is the reason that IL-6 cannot be used to differentiate
MGUS from myeloma. Increased C-reactive protein- (CRP)
and erythrocyte sedimentation rate- (ESR) values (indicators
of systemic inflammation) that can be increased in myeloma
as well as MGUS are independent prognostic factors for sur-
vival in myeloma [24,25]. This is understandable since IL-6
may induce inflammation.
The above data suggest that curcumin could be beneficial
in patients with MGUS and SMM in which inflammation is

present as witnessed by increased CRP and/or ESR. Indeed
long-term curcumin treatment significantly reduces CRP lev-
els [26] in agreement with its known anti-inflammatory
activity. Regrettably, neither indicators of systemic inflam-
mation nor IL-6 were measured in the earlier mentioned
clinical studies on the effect of curcumin on MGUS and SMM
[12,13,16].
3. Can curcumin lower the risk for emergence of
MGUS in some inflammatory diseases?
IL-6 is not the only growth factor for malignant plasma
cells [27]. B-cell activating factor belonging to the TNF fam-
ily (BAFF) and a proliferation-inducing ligand (APRIL) are
two members of the TNF ligand superfamily that can protect
myeloma cells from apoptosis induced by IL-6 deprivation
[27]. BAFF levels are significantly increased in myeloma
[28] and targeting BAFF is considered a therapeutic option
in B-cell malignancies [29].
BAFF is also increased in inflamed target organs in
autoimmune disease such as for example: rheumatoid arthri-
tis and systemic lupus erythematosis (SLE) [30]. In SLE,
BAFF levels are associated to CRP [30]. In osteoarthritis,
in which autoimmunity is not supposed to play a role, both
CRP and IL-6 are significant predictors of knee osteoarthri-
tis [31]. BAFF has not yet been measured in osteoarthritic
joint tissue but blood levels are increased in seronegative
osteoarthritis [32] and the expression of furin, the pro-protein
convertase responsible for the processing of pro-BAFF into
the active form, is increased in osteoarthritic cartilage [33].
All three conditions mentioned have a slightly increased risk
for developing MGUS [34,35].

Not all patients with monoclonal gammopathies have
increased levels of CRP or ESR but these levels are indicators
for prognosis. If indeed like in SLE the activity of the BAFF
pathway would be correlated to CRP or ESR [30] in some or
all patients with monoclonal gammopathies, curcumin could
be helpful and CRP and ESR would be very useful indicators
for success of intervention. Curcumin has also been shown to
directly suppress BAFF expression in cultured cells, proba-
bly by interfering with NF-kB signaling [36] but it is doubtful
whether the concentrations needed therefore are reached in
other tissues than the intestine [12]. In this context it is note-
worthy that IL-6 induces NF-kB activation, for example in
intestinal epithelia [37]. Both NF-kB and IL-6 are involved
in a positive feedback-loop that can be initiated by an inflam-
matory signal. It has been claimed that this can lead to an
epigenetic switch from nontransformed to cancer cells [38].
The logical consequence of the above would be that rela-
tively simple tests like CRP and ESR would be predictive for
the functioning of NF-kB signaling and thus of inflammatory
cytokines [39] produced in inflamed organs and thus for the
risk of developing MGUS. Traditional methods for measuring
CRP were developed for measuring the rather strong fluctu-
ations as induced by bacterial infections. Recent techniques
allow more refined determination, even within the previous
reference ranges and moderately elevated levels of CRP could
already be associated to colorectal cancer [40]. Interestingly
BAFF and moderate CRP elevation could also be related to
FLC levels. These are on average increased in autoimmune
disease [40]. Abnormal FLC ratios were detected in patients
with risk factors for progression only [40]. It is suggested that

an abnormal ratio could be a more sensitive marker of clon-
ality when this is still restricted to the site of inflammation
[41].
Since curcumin is helpful in chronic inflammatory states
like autoimmune disease [42] the above suggests that cur-
cumin could have a preventive effect on the development of
MGUS in chronic inflammatory conditions. However, this
is not easy to prove and would need long term monitoring
of large groups of patients. Trials about prevention of the
emergence of MGUS with curcumin in a context of chronic
immune stimulation and low grade inflammation could be
useful and should undoubtedly include measuring ESR as
well as CRP with high sensitivity. It is important to note that
curcumin concentrations in the inflamed target organs are per-
haps not of determining importance. Crucial for a favorable
outcome is probably the influence of curcumin on circulating
immune cells. These could be confronted to higher curcumin
concentrations in the gut and migrate to target organs. Rel-
atively low doses of curcumin would therefore probably be
effective.
4. Curcumin might work on immune cells rather
than on the bone marrow directly
In the context of prevention of progression of high-risk
MGUS and SMM the situation is probably quite different.
Multiple myeloma cells adhere to bone marrow stromal cells
[43]. While myeloma cells do not seem to produce IL-6,
bone marrow stromal cells do [43]. When myeloma cells
were adhered to the stromal cells, IL-6 secretion increased
strongly [43]. BAFF secretion is also much higher in stro-
mal cells than in myeloma cells, and tumor cell adhesion to

stromal cells further augments BAFF secretion by 2- to 5-
fold [44]. Moreover, BAFF increases adhesion of myeloma
354 A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360
Table 1
Immunosuppression induced by curcumin has elements in common with that by multiple myeloma.
Immunosuppression induced by curcumin References Immunosuppression induced by cancer and multiple myeloma References
Curcumin suppresses a Th1-type immune
response
[45] A reduced Th1/Th2 ratio has been reported in myeloma. Inflammation
driven by tumor specific Th1 cells is believed important for preventing
B-cell cancer
[46,47]
Curcumin inhibits the maturation and
modulates the cytokine pattern of DCs.
IL-12 production is inhibited. Curcumin
prevents DCs from inducing CD4+ T cell
proliferation
[45] DCs fail to mature, as caused by immunosuppressive factors TGFbeta and
IL-10 produced by many tumor types. This is suspected to form a critical
mechanism to escape immune surveillance. Immature DCs induce
immunosuppressive CD4 + T cells while mature DCs induce
immunostimulatory CD4 + T cells
[48,49]
Curcumin-treated bone marrow derived DCs
induced differentiation of naïve CD4+ T
cells into regulatory T cells (Tregs) similar
to those present in the intestine
[50,51] Immature DCs can maintain peripheral T cell tolerance by the induction
and stimulation of Treg populations
[49]

Curcumin treated DCs are not only
immature, they are also maturation
resistant. This means that curcumin
treated DCs do not mature under
inflammatory conditions
[51] Tregs negatively modulate DC maturation thereby contributing to the
immune tolerance of cancer
[48]
Maturation resistant DCs can find application
in the field of organ transplantation as a
means to down-regulate anti-donor T cell
responses but they are disadvantageous for
protection against bacterial infections
[51] Tumor cells appear able to convert DCs into cells that secrete bioactive
TGF-beta and stimulate proliferation of Tregs. These DCs secreting TGF
beta were called regulatory DCs. They suppress the development of
antitumor immune responses
[52]
Regulatory DCs, which accumulate in patients with different types of
cancers, are involved in the generation of Tregs, in turn these latter cells,
that expand during tumor progression, negatively modulate DC maturation
thereby contributing to the immune tolerance of cancer
[53]
Curcumin provokes Foxp3 expression in
Tregs.
[51] DCs matured with inflammatory cytokines can also induce Tregs. These
Tregs express Foxp3 protein and exert suppression through cell-cell
contact. Tregs induced by immature DCs secrete IL-10 as a suppressive
factor
[54]

Inflammatory cytokines in myeloma could lead to maturation of DCs and
to the induction of Foxp3 expressing regulatory T cells
[55]
Curcumin treated DCs are defective in both
migration and endocytosis.
[45] Multiple myeloma reduces the percentage and numbers of both myeloid
and plasmacytoid DCs while the percentages of Tregs, both with and
without expression of Foxp3 are strongly increased
[55,56]
Warning: Multiple myeloma patients with higher percentages of regulatory T cells lived shorter suggesting a role in facilitation of
disease progression and/or infectious complications. Higher percentages of regulatory T cells were correlated to death caused by
infectious complications.
[56]
cells to bone marrow stromal cells in a dose-dependent man-
ner [44]. High doses of curcumin are apparently necessary
to impact on the paraprotein level in patients. Moreover, the
effect is found in some but not all patients [13]. If curcumin
concentrations in the bone marrow would be sufficient for
a local effect one would expect a favorable effect in many
patients. If, however, the effect of curcumin would be related
to influence on immune cells elsewhere in the body, it is con-
ceivable that patients with high levels of circulating IL-6,
that can induce inflammation in other tissues, would benefit
most.
Wehave so far seen that there are reasons for being hopeful
about the potential of curcumin to be beneficial for prevention
of monoclonal gammopathies in patients with inflammatory
conditions. The influence on inflammatory symptoms could
form early indicators of success. For high risk MGUS and
SMM high doses are needed to provoke an effect on the

paraprotein load and this, even more, obliges to anticipate
the possibility of side effects. It is therefore mandatory to
discuss reasons for potential concern.
5. Curcumin for prevention of progression of MGUS
and SMM, reasons for concern?
5.1. Both curcumin and myeloma act on dendritic cells
and induce immunosuppression
Curcumin has immunosuppressive properties that resem-
ble immunosuppression in patients with myeloma. In both
cases DCs are involved. Table 1 summarizes the effects on
DCs. The effects of curcumin on DCs lead to several rea-
sons for concern in the context of treatment of monoclonal
gammopathies with curcumin.
5.2. Increased susceptibility to infections
Patients with MGUS, but less so than those with myeloma,
have an increased risk of infection [57]. Peripheral blood DCs
in patients with MGUS show significant abnormalities in the
distribution, phenotype and pattern of secretion of inflamma-
tory cytokines [58]. Abnormal DC maturation had previously
A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360 355
Table 2
Elements to consider before and during treatment of a patient with a monoclonal gammopathy with curcumin.
Reasons for optimism Reasons for concern Parameters helpful in patient monitoring
Curcumin: Curcumin:
General parameters associated with malignant
progression: (list is not comprehensive).
Bone marrow plasma cell infiltration.
Free light chain ratio.
Serum paraprotein level
Bence Jones proteinuria

Polyclonal serum Ig reduction
Bone turnover markers
ESR, CRP.
Etc.
Is a food component that has been used for
centuries. Has also been used for centuries as
an anti-inflammatory substance.
There is no need to provide evidence of safety or
health benefits for food supplements.
Is rather insoluble which leads to low plasma
values and thus low toxicity.
Attempts to increase absorption and increase of the
dose might also increase toxicity. Some food
components, like e.g. piperine in pepper increase
bioavailability.
Provoked only minimal toxicity in healthy
volunteers at doses of up to 8 g/day
Is often regarded as efficient and safe, also in the
scientific literature. However, proof for both
efficiency and safety for patients with monoclonal
gammopathies remain to be proven.
Reduces the paraprotein load in some patients Does it increase the paraprotein load in some
patients?
Paraprotein load and FLC ratio
Reduces markers of bone turnover in some
patients.
Does it increase markers of bone turnover in some
patients?
Markers of bone turnover and FLC ratio
Has anti-inflammatory properties. ESR, CRP, IL-6, FLC absolute values.

Reduces the expression of toll like receptors and
thus induces immunesuppression.
Total Gammaglobulins, IgG, IgA, IgM and
subclasses thereof.
Determine absolute numbers of B-cells and
percentages of switched memory B-cells.
Interferes with NF-␬B signaling which can
reduce inflammation. Down-regulates
interleukin-6 an inflammatory cytokine that
inhibits the maturation of dendritic cells by
activation of the STAT3 pathway.
Limits the Th1 cytokine response useful for cancer
immunosurveillance. Could therefore reduce the T
cell response against (pre)malignant cells present in
MGUS but not in myeloma.
Th1 cytokines, IL-2 and IFN gamma.
Th2 cytokines, IL-4, IL-5, IL-10.
IL-6.
Inhibits the STAT3 pathway which is activated
by IL-6
Renders dendritic cells maturation resistant. ESR, CRP, IL-6
Might prevent maturation of dendritic cells by
inflammatory cytokines and so reduce the
induction of regulatory T cells.
Leads to the induction of regulatory T cells which
can reduce immune protection against infections and
cancer.
Numbers of regulatory T cells
Could through induction of increased numbers of
immature dendritic cells stimulate clonogenic

growth of myeloma cells. (Bone marrow of
myeloma patients has more iDCs as compared to
MGUS patients).
Paraprotein level and FLC ratio
Inhibits osteoclastogenesis. If the number of iDCs would be increased in the
bone marrow by curcumin, myeloma cells could
induce the transformation of immature dendritic
cells into more osteoclasts.
Markers of bone turnover
Has anti-angiogenic properties. Could lead to resistance against anti-angiogenic
therapy and thus induce a more malignant phenotype
Paraprotein level, FLC ratio, markers of bone
turnover
been found in myeloma and the effect had been ascribed to
IL-6 although other factors are probably also involved. Indeed
IL-6 is a potent inhibitor of DC maturation through activation
of signal transducer and activator of transcription-3 (STAT3)
[22]. Curcumin inhibits the STAT3 pathway [59]. Curcumin
can thus on the one hand attenuate the inhibitory effect of
IL-6 on DC maturation while it can on the other hand have
an inhibitory effect itself.
The risk of increased susceptibility to infections should
be anticipated when treating MGUS patients with curcumin.
This is particularly true for patients with a compromised
immune system. We encountered a case in which a daily
intake of turmeric for intestinal complaints repeatedly led
to bronchitis. Analysis of patient’s immune competence
revealed a familiar selective IgG1 deficiency [60]. Patients
with common variable immunodeficiency (CVID), have toll
like receptor (TLR)-mediated B-cell defects. In a milder form

this is caused by impaired interferon-alpha production by
plasmacytoid DCs [61]. This effect seems to be caused by a
selected impairment of both plasmacytoid DCs and B cells to
respond to TLR7 and TLR9 agonists. These are the predom-
inant TLRs expressed in plasmacytoid DCs and B cells. The
result is a loss of cell activation, proliferation, and cytokine
production by B cells and plasmacytoid DCs [61]. Curcumin
is known to inhibit the expression levels of TLR2, TLR4
and TLR9 and may thus further reduce immune competence
in patients with immunodeficiency [62]. In this context it
should be noted that one quarter of patients with MGUS have
hypogammaglobulinemia [3]. Moreover, most patients with
monoclonal gammopathies including those with MGUS have
356 A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360
significantly lower percentages of plasmacytoid DCs and in
myeloma patients this is not improved by treatment [55].
5.3. Does curcumin suppress the immune response
against (pre)malignant cells in MGUS?
As discussed earlier the immune system develops T cell
responses to tumors, but this response can either improve
immunosurveillance when it is brought about by mature DCs
and their cytokine profile or induce tolerance by the induction
of regulatory T cells by immature DCs [63]. A direct effect
of plasmacytoid DCs on the tumor has recently also been
demonstrated [64]. Patients with monoclonal gammopathies
have lower percentages of these cells [55]. Nevertheless
patients with MGUS develop a vigorous T cell response
against the (pre)malignant cells. Patients with myeloma fail
to do so [65]. It is to be feared that curcumin, since it
induces maturation-arrested DCs that expand regulatory T

cells in vitro and in vivo [51], could suppress the T cell
response in MGUS. If this would be confirmed it would imply
a risk for accelerated progression to malignancy.
5.4. Could curcumin stimulate clonogenic growth of
tumor cells?
Curcumin may also influence the close interaction
between bone marrow stromal cells and malignant plasma
cells. Both DCs and osteoclasts support the growth of normal
plasmablasts, the precursors of plasmacells. Only osteoclasts,
however, support growth of plasmacells [66]. DCs are known
to penetrate tumor tissue and this has been correlated to a
worse prognosis. While this has originally been ascribed to
the induction of immune tolerance by DCs it has recently
become clear that there is a more direct interaction with the
tumor cells. Myeloma cells cultured in the presence of DCs
have an altered phenotype and miss the plasma cell differ-
entiation marker CD138 [67]. DCs enhance the clonogenic
growth of myeloma cells [67]. This was particularly so for
immature DCs [68]. While doing so these latter cells display
osteoclast-like features and are able to resorb bone [69]. Bone
marrow of myeloma patients contains more immature DCs
as compared to that of MGUS patients. Cell to cell contact of
myeloma cells with immature DCs led to their transforma-
tion into osteoclasts. Plasma cells of MGUS patients did not
induce this transformation [69].
5.5. Could curcumin induce a more malignant
phenotype?
Curcumin is also known to have anti-angiogenic prop-
erties in several systems [70,71]. Its mechanism of action
includes the inhibition of the gene expression of vascular

endothelial growth factor (VEGF) [72]. Anti-angiogenetic
agents are already applied in modern treatment strategies
for solid tumors and for myeloma [73]. Unfortunately, the
period of clinical benefit that often follows anti-angiogenetic
Table 3
Memorandum.
(1) If low doses of turmeric or curcumin improve a chronic
inflammatory condition, this might, on the longer term, reduce the
risk for emergence of MGUS.
(2) Before starting therapy of a monoclonal gammopathy it is crucial to
establish whether it is stable of evolving.
(3) Indicators of (low-grade)-inflammation should be measured before
and during treatment.
(4) It is so far unknown whether curcumin could do any good in
patients without inflammation. If such patients are entered into a
trial, close monitoring is advised.
(5) Any lack of coherence in the evolution of the different parameters
for monitoring should be considered suspect. Interruption of
treatment should be considered.
(6) Risk of increased susceptibility to infections should be carefully
monitored.
(7) Patients with common variable immunodeficiency should probably
not be treated with curcumin.
(8) If a patient has even a mild hypogammaglobulinemia, it seems wise
to determine cellular immunity before treating with curcumin.
(9) It seems important to measure numbers and percentages of
regulatory T cells before and during curcumin treatment.
(10) Curcumin can inhibit osteoclastogenesis but it might also be able
to induce the formation of osteoclasts. Increased bone turnover
should be interpreted as a warning sign. Immediate interruption of

treatment should be considered.
(11) It should be realized that treatment with curcumin could pose the
risk of inducing a more malignant phenotype.
treatment does usually only result in delay of progression due
to the development of resistance to the therapy [74]. Unfortu-
nately the relapsing tumors often appear more invasive than
the original ones. So far no drug has yet resulted in enduring
efficacy in terms long-term tumor shrinkage or survival [74].
6. Conclusions
Curcumin is a pleiotropic substance with many targets of
which only the most pertinent ones have been discussed in
the present paper. This is why it often works like a double-
edged sword [75]. In its application to cancer there is a bright
side that has received a lot of attention in the last decade.
There is, unfortunately also a dark side [76]. In this respect
there is, despite the fact that curcumin is derived from a food
component, no fundamental difference with other treatments.
Future research will establish more clearly the benefit-risk
profile of curcumin.
The preliminary data available so far suggest that cur-
cumin, in those patients that respond, probably works
indirectly on factors playing a role at later stages of dis-
ease. Inflammation is a known risk factor for the emergence
and progression of cancer. In advanced cancer there is often
inflammation. It is conceivable that curcumin could act on
inflammation. Indicators of inflammation should therefore
absolutely be monitored. Unfortunately this has not happened
in the clinical studies published so far. Other parameters like
FLC ratio, the paraprotein load, markers of bone turnover
and others (Table 2) should be looked at together. Any lack

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360 357
of coherence in their evolution should be considered suspect.
Blind optimism could damage the chance to identify the cri-
teria for selection of patients that could benefit. Since there is
still a serious lack of knowledge, doctors and patients should
be cautious. (Table 3).
Whether curcumin will find an established place in the
management of a subgroup of patients with monoclonal gam-
mopathies will depend on results of controlled clinical trials
with validated clinical endpoints. Only positive empiric evi-
dence gathered in the course of such clinical studies will allow
the validation of the vast quantity of biological findings pub-
lished during the last decades. So far such convincing data
are lacking and therapy in the clinic is therefore today not
justified. The International Myeloma Working Group 2010
guidelines stipulate that patients diagnosed with MGUS and
SMM should not be treated outside of clinical trials [8]. Cur-
cumin is being tested in clinical trials for a variety of other
indications [10]. It seems wise to exclude patients with mono-
clonal gammopathies from such trials. Patients should realize
that higher doses of the food component turmeric, which
contains curcumin, are also not without risk.
Before markers, allowing to accurately predict which
patients will progress to malignant disease, have been found,
[77] and as long as adequate criteria for selection of patients
that could benefit from curcumin have not been identified,
“watchful waiting”, whatever frustrating it may be, may still
be the wisest choice. This is particularly true for stable mon-
oclonal gammopathies without inflammation.
Conflict of interest

The authors declare no conflict of interest.
Professor E. Andrès is a member of the French Commis-
sion of Pharmacovigilance. However, the present paper is
not associated with this commission (personal view). He has
received several grants for lectures, studies or expertise from
laboratories (AMGEN, ROCHE, CHUGAI, GSK, VIFOR,
FERRING, SHERRING, GENZYME, ACTELION), but this
present work is free of any such association.
Reviewers
Ramaswamy Narayanan, Ph.D., Professor and Associate
Dean for Res&Ind Relations, Florida Atlantic University,
Charles E. Schmidt College of Science, 777, Glades Road,
Boca Raton, FL 33431, United States.
S. Vincent Rajkumar, M.D., Professor of Medicine, Mayo
Clinic, Division of Hematology, Rochester, MN 55905,
United States.
Acknowledgements
This research was supported by ‘Geconcerteerde Onder-
zoeksactie’ (GOA-08/016), Project 324000 of K.U. Leuven
Research & Development, the ‘Fonds voor Wetenschap-
pelijk Onderzoek Vlaanderen’ (FWO), the Foundation for
Biochemical and Pharmaceutical Research and Education,
the “Industrieel Onderzoeksfonds” (IOF-HB/06/040) of K.U.
Leuven, and the Belgian Federation against Cancer. These
funding bodies had no role in the study design, in the collec-
tion, analysis and interpretation of data; in the writing of the
manuscript; and in the decision to submit the manuscript for
publication.
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Biographies
Professor Alphons Vermorken in 1977, received his PhD
degree in Molecular Biology, with the greatest distinction,
at the University of Nijmegen, the Netherlands. In 1988 he
obtained a postdoctoral degree in toxicology.He was awarded
the Nijmegen, Faculty of Sciences price for research in 1973,
the Shell price in 1977 and the “Young Investigators Award”
during the International Congress of Pediatric Laboratory
Medicine in Jerusalem, Israel in 1980. He was head of the
Research Unit for Cellular Differentiation and Transforma-
tion in Nijmegen from 1978 onwards. In that function he was
recruited as advisor to three pharmaceutical companies. In
1986, he was nominated Professor on Steroid Biochemistry
at the University of Montpellier in France. In 1989, he was
nominated Professor at the University of Leuven, Belgium.
Between 1987 and 2005 he was involved in the coordina-
tion of Health Research, at the European level, as a civil
servant at the European Commission in Brussels, Belgium.
In 2005 he again joined the University of Leuven where he
was nominated Professor of Molecular Oncology. In 2009,
he was also nominated visiting Professor at the Northwest
University, Xi’an, China.
Jingjing Zhu M.Sc. did two bachelor’s degrees, on Bio-
science and Technology and on Foreign-oriented English
translation. She subsequently completed her master’s degree
in Biochemistry and Molecular Biology at the Northwest
University in Xi’an, China, in June 2009. During her master’s
study, she participated in the 5th Annual Congress of Inter-
national Drug Discovery Science and Technology in 2007

in Xi’an and she followed a three months training period
at the University of Leuven in Belgium. She studied the
Japanese language. After her study on the expression and
purification of GST fusion proteins using magnetic nanopar-
ticles at the Northwest University, she joined the Laboratory
for Molecular Oncology at the University of Leuven in
Belgium where she follows a PhD program on biomedical
360 A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360
research on Cancer. Her subject deals with physiological
mechanisms in the regulation of the proprotein convertase
furin.
Professor Wim J.M. Van de Ven Upon completion of his
PhD in viral oncology at the University of Nijmegen, The
Netherlands, Dr. Van de Ven joined in 1979 the National
Cancer Institute of the United States, where he participated
as a post-doc in basic cancer research. In 1983, he joined
the faculty of the Biochemistry Department of the Univer-
sity of Nijmegen. This led to the discovery and cloning
of the FUR gene and his pioneering work led to the iden-
tification of the function of furin as the first and long
elusive mammalian proprotein convertase. The furin enzyme
was then used in developing a precursor protein processing
technology for application for the enhanced production of
relevant protein-based biopharmaceuticals. Furin pro-protein
processing technology has been patent protected by the Uni-
versity of Leuven, covering countries of major markets. In
1987, he joined the Medical School of the University of Leu-
ven in Belgium, where he is a full professor in Molecular
Genetics and Biotechnology. At the Department of Human
Genetics, he focused his research on genes involved in benign

tumor formation. This led to the discovery of two novel
gene families, i.e. the HMGA and the PLAG gene family,
respectively, and both of these are involved in multiple tumor
types (Nature Genetics 10, 436-444,1995; Nature Genetics
15, 170-174, 1997). Subsequently, he generated a versatile
PLAG1 transgenic mouse strain that is instrumental in specif-
ically mimicking various human tumor types. In 2009, he was
invited as visiting professor at the Northwest University in
Xi’an, P.R. China.
Professor Emmanuel Andrès In 1996, received his MD
degree in Internal Medicine, at the University of Strasbourg,
France. He worked as an associated professor in the Uni-
versity Hospital of Strasbourg, France. In 1998 he worked
as PhD in Molecular Biology in the Laboratory of Profes-
sor Hoffmann (2011, Nobel Prize of Medicine) in the field
of cationic antimicrobial peptides and pathogens – host rela-
tions. In 2002, he was nominated Professor at the University
of Strasbourg, France. He also was in the head of an Inter-
nal Medicine Department (of > 60 beads) in the University
hospital of Strasbourg, France. He was awarded the French
Society of Hematology, price for research in the field of
anemia related to cobalamin or folate deficiencies in 2004.
Achievements include development of research in: all type
of anemia, neutropenia and thrombocytopenia, particularly
drug-induced neutropenia and agranulocytosis or thrombo-
cytopenia; haematopoietic growth factors; and cobalamin
deficiencies. His recent works also include research and
development on human sounds analysis, electronic stetho-
scope, e-auscultation, and e-medicine. In that function he was
recruited as advisor to several pharmaceutical companies or

start-up. In 2007, he was nominated in the French National
Commission of Pharmacovigilence.