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Long term use of curcumin in two smoldering multiple myeloma (SMM) patints

Authors:

Abstract

Introduction: Smoldering Multiple Myeloma (SMM) is an asymptomatic plasma cell disorder which has an overall risk of progression to multiple myeloma of 10% per year. The cornerstone of managing SMM is a “watch and wait” strategy. Curcumin has been shown to improve disease status in some patients with MGUS and SMM and has been added to the mainstream treatment of myeloma patients. We report here for the first time on long term use of oral curcumin in 2 SMM patients. Patients: Two male Caucasian patients over the age of 40 presented to their general practitioners with fatigue/shoulder pain. Blood tests revealed paraproteinemia and a diagnosis of SMM was made based on IMWG guidelines. Both were entered into a 9 month clinical trial of oral curcumin in patients with plasma cell dyscrasias. Thereafter, they elected to continue on the same regimen of oral curcumin, for a period of 2 years. Results/Discussion: Both patients showed continued improvement in a number of markers of disease activity including serum free light chains, paraprotein and % plasma cells in the bone marrow. These results suggest that patients with smoldering myeloma may benefit from daily ingestion of curcumin and long term use does not result in toxicity.
www.sciedu.ca/jhm Journal of Hematological Malignancies, 2013, Vol. 3, No.1
ISSN 1925-4024 E-ISSN 1925-4032
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CASE REPORT
Long term use of curcumin in two smoldering multiple
myeloma patients
Terry Golombick1, Terrence H. Diamond1, Arumugam Manoharan2, Rajeev Ramakrishna2
1. Department of Endocrinology, St George Hospital, Sydney, Australia. 2. Southern Sydney Haematology, University of
Wollongong, NSW, Australia.
Correspondence: Terry Golombick. Address: Prichard Wing, St George Hospital, Kogarah, NSW, Australia, 2217. Email:
terry.golombick@sesiahs.health.nsw.gov.au
Received: November 13, 2012 Accepted: January 24, 2013 Online Published: February 18, 2013
DOI: 10.5430/jhm.v3n1p18 URL: http://dx.doi.org/10.5430/jhm.v3n1p18
Abstract
Introduction: Smoldering Multiple Myeloma (SMM) is an asymptomatic plasma cell disorder which has an overall risk
of progression to multiple myeloma of 10% per year. The cornerstone of managing SMM is a “watch and wait” strategy.
Curcumin has been shown to improve disease status in some patients with MGUS and SMM and has been added to the
mainstream treatment of myeloma patients. We report here for the first time on long term use of oral curcumin in 2 SMM
patients.
Patients: Two male Caucasian patients over the age of 40 presented to their general practitioners with fatigue/shoulder
pain. Blood tests revealed paraproteinemia and a diagnosis of SMM was made based on IMWG guidelines. Both were
entered into a 9 month clinical trial of oral curcumin in patients with plasma cell dyscrasias. Thereafter, they elected to
continue on the same regimen of oral curcumin, for a period of 2 years.
Results/Discussion: Both patients showed continued improvement in a number of markers of disease activity including
serum free light chains, paraprotein and % plasma cells in the bone marrow. These results suggest that patients with
smoldering myeloma may benefit from daily ingestion of curcumin and long term use does not result in toxicity.
Key words
Smoldering Multiple Myeloma, Monoclonal Gammopathy of Undetermined Significance, Curcumin
1 Introduction
Smoldering Multiple Myeloma (SMM) is an asymptomatic plasma cell disorder which has an overall risk of progression to
multiple myeloma of 10% per year for the first 5 years. This diminishes gradually thereafter. SMM is a more advanced
pre-malignant condition than monoclonal gammopathy of undetermined significance (MGUS).The cornerstone of
managing SMM is a “watch and wait” strategy [1]. Although it is currently not possible to predict the clinical course of
SMM, features predicting patients at highest risk include the size and type of M-protein, with IgA having a higher risk
compared to IgG paraprotein, % plasma cell dyscrasia, and an abnormal serum-free light chain ratio.
www.sciedu.ca/jhm Journal of Hematological Malignancies, 2013, Vol. 3, No. 1
Published by Sciedu Press 19
Given the uncertainty of disease progression with SMM, early intervention aimed at reducing the abnormal protein load,
the abnormal serum-free light chain ratio and the % plasma cell load would be of benefit to the patient. It would be
essential that this preventative approach does not itself increase the risk of progression or result in toxicity. Curcuma longa
(turmeric) is a perennial herb belonging to the ginger family. The most active component in turmeric is curcumin [2]. Based
on its demonstrated anti-myeloma cell activity, both in vitro and in vivo [3, 4], we have carried out both a 6 month pilot
study [5] and a 6 month randomised, double-blind placebo-controlled cross-over 4g study and a 3 month open-label 8g
extension study [6] and shown that oral curcumin can, in a select group of MGUS and SMM patients, decrease free light
chains (rFLC, dFLC and iFLC), paraprotein and bone resorption. Here, we present a report of two patients with SMM who
were recruited into our second study [6] and who elected to continue on the same regimen of oral curcumin daily after the
study.
2 Case presentations
Patient 1: A 47 year old male presented to his GP in 2010 with a 3 month history of fatigue. Routine blood tests showed an
IgG kappa paraprotein of 29.7g/L, 33% plasma cells in the bone marrow and a free light chain ratio (rFLC) of 26.77 (K =
97.7 mg/L; L = 3.65 mg/L). Renal function and calcium levels were normal.
Patient 2: A 66 year old male whose disease was diagnosed in 2010 because of an unusual acromio-clavicular septic
arthritis. Blood tests revealed an IgG lambda paraprotein of 31.7g/L, 7% plasma cells in the bone marrow and rFLC of 0.3
(K = 15.7 mg/L; L = 53.2 mg/L). Renal function and calcium levels were normal.
Table 1. Clinical data of patients 1 and 2 at baseline, 9 months and at 2 years of curcumin therapy
Variable 1. Baseline 1. 9 months 1. 2 years 2.Baseline 2. 9 months 2. 2 years
age (years) 47 48 49 66 67 68
% plasma cells 33 15 7 2
Paraprotein (g/L) 29.7 26.6 24.4 31.7 27.7 23.6
Free light chain ratio (0.3-1.7) 26.77 14.37 4.5 0.3 0.22 0.4
dFLC (mg/L) 94.1 137.7 125.4 37.5 37.9 46
iFLC (mg/L) 97.7 148 161 53.2 48.6 71.6
uiFLC 3.65 10.3 35.6 15.7 10.7 25.6
Globulin (22-38 g/L) 47 40 39 53 48 51
Gamma globulin (7-16g/L) 32.8 28.3 26.4 34.8 31.8 28.2
Ig G (6.2-14.4g/L) 44.25 38.8 39.47 49.03 41.62 44.12
Ig M (0.48-3.04g/L) 0.23 0.23 0.2 0.62 0.45 0.5
Ig A (0.6-3.96g/L) 0.12 0.12 0.12 1.15 1.36 1.55
CD3 T cell (%) 81 72 63 76 75 76
CD4 T helper cell (%) 48 41 30 40 44 47
CD8 cytotoxic T cell (%) 29 26 26 29 27 31
Total protein (64-83g/L) 95 84 84 92 86 84
25-OH Vitamin D (nmol/L) 153 158
Based on the IMWG classification system, these two patients were diagnosed with SMM. They were entered into our 6
month randomised, double-blind placebo-controlled cross-over 4g study and 3 month open-label 8g extension study of
oral curcumin. After 9 months of curcumin therapy, both patients demonstrated an improvement in paraprotein, rFLC,
iFLC, uiFLC, total protein, as well as decreases in their elevated IgG, globulin and gamma globulin levels (see Table 1).
Based on their overall clinical improvement, they elected to continue with curcumin therapy after completion of the
clinical trial on a maintenance dose of 6g/day. Follow up blood tests and a bone marrow biopsy were performed after 2
years of curcumin therapy in order to determine whether the curcumin had altered the disease progression.
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To further determine the effect of curcumin on immune function, we re-looked at and analysed the data from our previous
randomised study [6]. Eighteen (of 25) patients completed the 9 month study (ie 6 months of 4g and 3 months of 8g
curcumin). All 18 patients had IgG plasma cell dyscrasias. Analysis of surface leucocyte antigen characterisation and
immunoglobulin level data from baseline till 9 months showed that in 18 patients there was no mean change in percentage
distribution of CD3 T cells, CD4 T helper cells and CD8 cytotoxic T cells (see Table 2) over 9 months of curcumin
therapy. There was no change in IgA, however, there was a decrease in IgM (P=0.04) from baseline till 9 months (see
Table 2).
3 Discussion
We describe the effects of 2-years of curcumin therapy on two SMM patients, one of these (ie patient 1) at high risk of
transformation to multiple myeloma. Both these patients showed a continued improvement in several markers of their
disease activity and in particular, a decrease in % plasma cells in the bone marrow. These data are in accordance with our
previous findings [5, 6]. Although myeloma is a “patchy” disease, the bone histopathology failed to demonstrate progression
of the disease, but suggested an improvement in the plasma cell infiltrate.
The mechanism(s) by which curcumin slows down the disease activity in plasma cell dyscrasias is unclear. Previous
studies have identified down-regulation of interleukin-6 (a growth factor for myeloma and also an inflammatory cytokine)
and suppression of receptor activator of nuclear factor kappa-B ligand (RANKL) signaling as two possibilities [2-4, 8]. In
their recent review [9], Vermorken et al have attributed the beneficial effect of curcumin to its potential anti-inflammatory
action. They also expressed concerns about the possible immunosuppressive effects of curcumin and its effects on cellular
immunity. Our experience to date does not substantiate these concerns. A detailed analysis of immune function in 18
patients who had previously been studied and treated with curcumin for 9 months (see Table 2) did not show significant
changes in the number of T-cell (CD3, CD4 and CD8) subsets. These findings can now be extended to 2 years as shown in
Patients 1 and 2. Neither of these patients had any clinical events attributable to immunosuppression (infections,
progression to myeloma or development of a second malignancy). Furthermore, neither patient displayed any side-effects
from long term, high dose curcumin therapy and neither has developed skeletal events that require bisphosphanate therapy.
Our results are encouraging, but the exact role and place of curcumin for patients with monoclonal gammopathies and
SMM will need to be determined by large scale, multi-centre studies.
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[6] Golombick T, Diamond T, Manoharan A, Ramakrishna R. Monoclonal Gammopathy of Undetermined Significance (MGUS),
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[9] Vermorken AJM, Zhu J, Van de Ven WJM, Andres E. Curcumin for monoclonal gammopathies. What can we hope for, what
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... Statistically significant reductions in total serum and random urinary protein concentrations were also seen [45]. Updated results from long-term follow up of 13 MGUS/SMM patients taking curcumin (4-8 g daily) for 3-9 years showed a change in paraproteins (decrease in 5, slight increase in 3 and rest stable), bone marrow plasma cells (decrease in 4, increase in 2 and rest stable) and reduction in free light chain ratio in 3 patients [46,47]. Although these preliminary studies suggest a possible long-term benefit for a small subset of patients, additional larger and more mechanism focused studies are needed to define appropriate recommendations for plasma cell disorder patients. ...
... Curcumin [45][46][47] • Short-term (3 months) curcumin therapy (4-8 g doses) was associated with was associated with reduction in free kappa light chain to free lambda light chain ratio, total serum protein, and random urinary protein concentrations (associated markers with MM progression risk) • Long term (3-9 years) curcumin therapy (4-8 g doses) was associated with change in paraprotein levels, bone marrow % plasma cells, and reduction in free light chain ratio • Research suggests that curcumin supplementation might have association with microbiome changes and may provide anti-inflammatory and anti-cancer properties Vitamin D [56][57][58][59][60][61][62][63] • Vitamin D deficiency (<20 ng/ml) or insufficiency (21-29 ng/ml) is present in up to 75% of MM patients. Deficiency or insufficiency is associated with increased inflammation, higher ISS stage at diagnosis, neuropathy, and negative impact on myeloma activity, bone turnover, and bone mineral density • In the transplant setting, Vitamin D deficiency or insufficiency was associated with inferior progression free survival and overall survival Vitamin A [10] • Vitamin A through food sources was associated with reduced MM risk Vitamin C [9,67] • Vitamin C intake or Vitamin C-rich food intake is associated with reduced overall cancer risk ...
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... Previous studies carried out in our clinics have demonstrated that oral administration of curcumin, even at high doses (up to 8 g daily), is well tolerated and can decrease the paraprotein load, free light chains, bone turnover, and % plasma cell dyscrasia in a selected group of patients with multiple myeloma precursor disease that is monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). [20][21][22][23] The multitude of published studies, including an in vitro study carried out in our laboratory, 16 suggest that curcumin can potentiate not only the cytotoxic effect of multiple agents used in the treatment of MM, but also enhance the chemo-sensitizing effects of these agents. The implications arising from these observations may be of important clinical benefit: i) curcumin studies can be designed to assess the additive antimyeloma effects of curcumin to the current treatment protocols and ii) curcumin may be used as an alternative to corticosteroids in such protocols. ...
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Curcumin, when used in a combination regimen in multiple myeloma patients, has comparable progression‐free survival without the adverse effects of steroid‐based combination therapies that is curcumin may be a viable alternative to corticosteroids in combination with an immunomodulatory drug or proteasome inhibitor. Curcumin, when used in a combination regimen in multiple myeloma patients, has comparable progression‐free survival without the adverse effects of steroid‐based combination therapies that is curcumin may be a viable alternative to corticosteroids in combination with an immunomodulatory drug or proteasome inhibitor.
... Curcumin is a yellow colored substance isolated from the plant Curcuma longa (Zingiberaceae). Efficacy of curcumin was evaluated in 29 patients with multiple myeloma and lowering level activated of NF-κB was reported in all participants 4 . The word Arsenic originated from Middle East and literally means "yellow gold". ...
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Curcumin has been shown to inhibit the activation of nuclear factor-κB (NF-κB), which is closely linked to chemo-resistance, in multiple myeloma cells. Malignant cells of this kind typically develop progressive multidrug resistance. Our aim was to investigate new possibilities for overcoming this resistance by suppressing cell signaling pathways. MTT-dye reduction assay was used to evaluate the cytotoxic activity of degrasyn, curcumin and Arsenic (ATO) on U-266, RPMI-8226 cell lines. Carfilzomib served as reference drug. Western blot analysis was performed. In RPMI-8226 cells evident activation of caspase 3 by ATO was seen. PARP cleavage was detected after degrasyn treatment. Curcumin led to PARP degradation as well. Caspase 9 was found to be activated by ATO, degrasyn and Carfilzomib. LC3b (autophagy hallmark) level was increased after exposure to ATO, curcumin and degrasyn. In U-266 cells significant LC3b increase was recorded after carfilzomib treatment. Procaspase 9 was cleaved after curcumin usage. Degrasyn activated procaspase 3. Elisa test was performed. All substances showed inhibition of NF-κB p65 fraction in both U-266 and RPMI-8226 cell lines. Proteomic analysis was performed with Curcumin and Arsenic in U-266 cell line. Significant up regulation of pro-apoptotic proteins was seen, evident down regulation of anti-apoptotic pathways was visible as well. Taken together our data showed that all studied compounds induced different forms of cell death. Despite both cell lines RPMI-8226 and U-266 originate from patients with multiple myeloma they substantially differ in their pattern of induced cell death, which could be explained by the essential heterogeneity of this specific NHL malignancy.
... Based on its antimyeloma cell activity, we have performed a number of studies with curcumin in MGUS/SMM patients, including a randomised, double-blind placebo-controlled cross-over study, published in the American Journal of Hematology [7] where we showed that treatment of MGUS/SMM patients with curcumin resulted in an improvement in markers of disease progression (i.e., free light-chain ratio (rFLC), paraprotein levels, percentage plasma cells) in some patients [8]. A number of patients who participated in our studies and who showed a benefit, have continued to take curcumin over a number of years, of their own volition, even though the studies in which they were participating are complete. ...
... Recent clinical studies have demonstrated that oral administration of curcumin, even at high doses, is well tolerated and can decrease the paraprotein load, free light chains, bone turnover and % plasma cell infiltrate into the bone marrow in some patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) [12][13][14][15] . ...
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Background: Curcumin, the active component of the Curcuma longa plant, has been shown to potentiate the effect of the immunomodulatory drugs (IMiDs) thalidomide and Bortezomib against human myeloma cell lines and a nude mice model. Its effect on the other IMid, lenalidomide, has not been evaluated. This study aims to investigate the mechanism of action of curcumin and its potential ability to positively interact with lenalidomide. Method: we designed an in-vitro study to investigate the cytotoxic and chemo-sensitising effects of curcumin alone and in combination with lenalidomide on the human myeloma H929 cell line. Results: Incubation of H929 cells with curcumin (30M) or lenalidomide (2.5 mM) for 3 days resulted in 26.35% (±1.06) and 30.81%(±2.98) apoptotic cells respectively. When 30 M curcumin was combined with 2.5 mM lenalidomide, 50.4% (±3.37) apoptotic cells were detected by flow cytometry and the increase was significant compared to either curcumin alone or lenalidomide alone (anova p = 0.0026). Furthermore, gene analysis studies show that curcumin enhances the cytotoxic effect of lenalidomide via suppression of the cereblon and multi-drug resistant genes. Conclusion: Curcumin exerts a cytotoxic effect additive to that of lenalidomide on H929 myeloma cells, and it also enhances the chemo-sensitizing effects of this agent.
... We administered curcumin as Meriva, a standardized mixture of natural curcuminoids and lecithin in a 1:2 ratio [12] [13], to 21 individuals with stage 0/1 CLL to determine 1) its effect on ALC, and 2) whether any observed effect could be mediated by the numbers of CD4, CD8 and NK cells. Our previous data has demonstrated the safety and efficacy of this compound in MGUS/SMM patients [14]- [17]. Meriva was chosen for this study based on its increased absorption and bioavailability. ...
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Clinical studies with patients with early hematological malignancies (ie, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or stage 0/1 chronic lymphocytic leukemia) suggest that early intervention with curcumin, derived from the spice turmeric, may lead to prolonged survival and delay in progressive disease in some of these patients.
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To determine the effect of curcumin on plasma cells and osteoclasts in patients with MGUS. Twenty-six patients with MGUS were recruited into the study and administered 4 grams/day oral curcumin. Blood and urine samples were collected at specified visits after initiating therapy. Full blood count, B2 microglobulin, serum paraprotein, and immunoglobulin electrophoresis (IEPG and EPG) were determined for all patients at each visit. Serum calcium, 25 hydroxyvitamin D3, and bone-specific alkaline phosphatase were determined at baseline only. Urine, as a morning second-void sample, was collected at each visit for urinary N-telopeptide of type I collagen. Our results show that oral curcumin is able to decrease paraprotein load in a select group (i.e., those having a paraprotein level of >20 g/L) of patients with MGUS. Fifty percent (5 of 10) of these patients had a 12% to 30% reduction in their paraprotein levels, while on curcumin therapy. In addition, 27% of patients on curcumin had a >25% decrease in urinary N-telopeptide of type I collagen. Due to the possible progression of MGUS to multiple myeloma, the potential role of curcumin as a therapeutic intervention for MGUS patients warrants further investigation.
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Curcumin (diferuloylmethane), a pigment derived from turmeric, has anti-oxidant and anti-inflammatory activities. Accumulating evidence points to a biochemical link between increased oxidative stress and reduced bone density. Osteoclast formation was evaluated in co-cultures of bone marrow stromal cells (BMSC) and whole bone marrow cells (BMC). Expression of receptor activator of nuclear factor-kappaB ligand (RANKL) was analyzed at the mRNA and protein levels. Exposure to curcumin led to dose-dependent suppression of osteoclastogenesis in the coculture system, and to reduced expression of RANKL in IL-1alpha-stimulated BMSCs. Addition of RANKL abolished the inhibition of osteoclastogenesis by curcumin, whereas the addition of prostaglandin E2(PGE2) did not. The decreased osteoclastogenesis induced by curcumin may reduce bone loss and be of potential benefit in preventing and/or attenuating osteoporosis.
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Because of the central role of the transcription factor nuclear factor-kappaB (NF-kappaB) in cell survival and proliferation in human multiple myeloma (MM), we explored the possibility of using it as a target for MM treatment by using curcumin (diferuloylmethane), an agent known to have very little or no toxicity in humans. We found that NF-kappaB was constitutively active in all human MM cell lines examined and that curcumin, a chemopreventive agent, down-regulated NF-kappaB in all cell lines as indicated by electrophoretic mobility gel shift assay and prevented the nuclear retention of p65 as shown by immunocytochemistry. All MM cell lines showed consitutively active IkappaB kinase (IKK) and IkappaBalpha phosphorylation. Curcumin suppressed the constitutive IkappaBalpha phosphorylation through the inhibition of IKK activity. Curcumin also down-regulated the expression of NF-kappaB-regulated gene products, including IkappaBalpha, Bcl-2, Bcl-x(L), cyclin D1, and interleukin-6. This led to the suppression of proliferation and arrest of cells at the G(1)/S phase of the cell cycle. Suppression of NF-kappaB complex by IKKgamma/NF-kappaB essential modulator-binding domain peptide also suppressed the proliferation of MM cells. Curcumin also activated caspase-7 and caspase-9 and induced polyadenosine-5'-diphosphate-ribose polymerase (PARP) cleavage. Curcumin-induced down-regulation of NF-kappaB, a factor that has been implicated in chemoresistance, also induced chemosensitivity to vincristine and melphalan. Overall, our results indicate that curcumin down-regulates NF-kappaB in human MM cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of MM patients with this pharmacologically safe agent.
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Although the role of NF-kB and STAT3 pathways in proliferation/metastasis of various tumor cells is well established, no agent has been described which could downregulate the activation of these transcription factors in cancer patients (pts). Curcumin has been shown to potently suppress the activation of these transcription factors in cultured cells. Based on these observations, we initiated a clinical trial of curcumin alone (administered orally at 2, 4, 6, 8, or 12 grams/day in 2 divided doses) or in combination with Bioperine (10 mg in 2 divided doses) for 12 weeks in multiple myeloma (MM) pts. The objectives of this study were to evaluate the clinical safety and biologic effects in MM pts who had asymptomatic, relapsed/refractory, or plateau phase disease. Blood was collected for PK/PD and PBMCs were examined (baseline and during treatment) for evaluating the effect of treatment on expression of NF-kB (p65), COX-2 and phospho-STAT3 as surrogate biomarkers. NF-kB activation status was also measured by electrophoretic mobility shift assay. At least 6 pts are enrolled at each dose level; 3 on the curcumin arm and 3 on the curcumin + bioperine arm. Pts with at least stable disease were allowed to continue treatment up to one year. Treatment with curcumin and bioperine has been well tolerated, with no significant adverse events. At the 12 grams dose level, 2 of the 5 pts had difficulty swallowing the large number of capsules. Of the 29 evaluable pts treated so far, no objective responses have been seen. Twelve pts continued treatment for more than 12 weeks and 5 (1 patient at 4 grams, 2 pts at 6 grams, and 2 pts at 8 grams dose levels) completed one year of treatment with stable disease. With few exceptions, little if any free drug was found in the plasma. Total curcumin levels (mostly conjugated drug) were dependent on both dose and the duration of administration. PBMCs from 28 MM pts examined showed constitutively active NF-kB (mean ± STD, 74.2% ± 14.0 positive cells), COX2 (66% ± 15.4), and STAT3 (52.8% ± 19.2). Oral administration of curcumin significantly downregulated the constitutive activation of NF-kB (at 3 months a median reduction of 77%, p<0.0001) and STAT3 (69%, p<0.001), and suppressed COX2 (66%, p<0.0001) expression in most of the pts at each of the monthly time points. Conclusions: This is the first report to indicate that curcumin, a highly safe agent, is bioavailable and can downregulate NF-kB, STAT3 and COX2 in MM pts. These findings suggest a potential therapeutic role for curcumin that can be further investigated either alone or as a modulator of chemo-resistance in combination with other active agents.
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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 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.
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Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) represent useful models for studying multiple myeloma precursor disease, and for developing early intervention strategies. Administering a 4g dose of curcumin, we performed a randomised, double-blind placebo-controlled cross-over study, followed by an open-label extension study using an 8g dose to assess the effect of curcumin on FLC response and bone turnover in patients with MGUS and SMM. 36 patients (19 MGUS and 17 SMM) were randomised into two groups: one received 4g curcumin and the other 4g placebo, crossing over at 3 months. At completion of the 4g arm, all patients were given the option of entering an open-label, 8g dose extension study. Blood and urine samples were collected at specified intervals for specific marker analyses. Group values are expressed as mean ± 1 SD. Data from different time intervals within groups were compared using Student's paired t-test. 25 patients completed the 4g cross-over study and 18 the 8g extension study. Curcumin therapy decreased the free light-chain ratio (rFLC), reduced the difference between clonal and nonclonal light-chain (dFLC) and involved free light-chain (iFLC). uDPYD, a marker of bone resorption, decreased in the curcumin arm and increased on the placebo arm. Serum creatinine levels tended to diminish on curcumin therapy. These findings suggest that curcumin might have the potential to slow the disease process in patients with MGUS and SMM.
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Monoclonal gammopathy of undetermined significance (MGUS) is defined as a serum M protein level of less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of end-organ damage. The prevalence of MGUS is 3.2% in the white population but is approximately twice that high in the black population. MGUS may progress to multiple myeloma, AL amyloidosis, Waldenström macroglobulinemia, or lymphoma. The risk of progression is approximately 1% per year, but the risk continues even after more than 25 years of observation. Risk factors for progression include the size of the serum M protein, the type of serum M protein, the number of plasma cells in the bone marrow, and the serum free light chain ratio. Smoldering (asymptomatic) multiple myeloma (SMM) is characterized by the presence of an M protein level of 3 g/dL or higher and/or 10% or more monoclonal plasma cells in the bone marrow but no evidence of end-organ damage. The overall risk of progression to a malignant condition is 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% to 2% per year for the following 10 years. Patients with both MGUS and SMM must be followed up for their lifetime.
Curcumin for monoclonal gammopathies. What can we hope for, what should we fear? Critical Reviews in Oncology
  • Ajm Vermorken
  • J Zhu
  • Wjm Van De Ven
  • E Andres
Vermorken AJM, Zhu J, Van de Ven WJM, Andres E. Curcumin for monoclonal gammopathies. What can we hope for, what should we fear? Critical Reviews in Oncology/Hematology. 2012. http://dx.doi.org/10.1016/j.critrevonc.2012.04.005