Long-term follow-up of curcumin treated MGUS/SMM patients – an updated single centre experience

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Letter to Editor
Hematology & Medical Oncology
Hematol Med Oncol, 2017 doi: 10.15761/HMO.1000125 Volume 2(2): 1-2
ISSN: 2398-8495
Long-term follow-up of curcumin treated MGUS/SMM
patients – an updated single centre experience
Terry Golombick1*, Terrence H. Diamond1, Arumugam Manoharan2 and Rajeev Ramakrishna2
1Department of Endocrinology, St George Hospital, Sydney, Australia
2Southern Sydney Haematology, University of Wollongong, NSW, Australia
Correspondence to: Terry Golombick, Department of Endocrinology, St George
Hospital, Sydney, Australia, Tel: 02 9113 2767; Mobile: 0414939655; Fax: 02 9113
3966; E-mail: terry.golombick@health.nsw.gov.au
Received: April 20, 2017; Accepted: April 27, 2017; Published: April 29, 2017
Multiple myeloma (MM) evolves through a spectrum of
disease from a premalignant stage of monoclonal gammopathy of
undetermined signicance (MGUS) (serum M-protein value of <30
g/L, bone marrow plasma cells <10%, no or small amount of M-protein
in the urine, and absence of lytic bone lesions, anemia, hypercalcemia,
or renal insuciency) to an intermediate stage of smoldering multiple
myeloma (SMM) (serum M protein level >30 g/L and/or bone marrow
plasma cells >10%, plus no anaemia, hypercalcemia, renal failure, or
lytic bone lesions) and nally presents with symptoms and signs of
end-organ damage which leads to the diagnosis of MM [1]. Studies
indicate that almost all cases of MM are preceded by the precursor state
of MGUS or SMM [2].
Patients with MGUS or SMM are not oered therapeutic options
to date and standard of care remains observation with re-evaluations
of the patient every 3-4 months. Long-term monitoring of untreated
MGUS/SMM patients has shown that the monoclonal protein can
disappear spontaneously during follow-up only in MGUS patients
with low initial concentrations of monoclonal protein (5 g/L) [3]. ere
are no reports of the monoclonal protein decreasing or disappearing
spontaneously in SMM patients.
Because symptomatic myeloma may not evolve for as long as
20 years, it is currently not possible to predict the clinical course of
MGUS or SMM. Features predicting patients at highest risk of disease
progression include the size and type of M-protein, with IgA having
a higher risk compared to IgG paraprotein, % plasma cell dyscrasia,
and abnormal serum-free light chain ratio. A number of studies have
shown that independent of the size and type of the serum M-protein, an
abnormal free lightchain (FLC) ratio increases the risk of progression
[4].
Given the uncertainty of disease progression with MGUS and
SMM, early intervention aimed at potentially slowing down or stopping
disease progression might be therapeutic. Curcuma longa (turmeric)
is a tropical plant native to southern and southeastern tropical Asia.
It is a perennial herb belonging to the ginger family. e most active
component in turmeric is curcumin [5]. Curcumin has been shown
to inhibit the proliferation of multiple myeloma cells through the
downregulation of IL-6 and NF-kB. Bharti et al. showed that curcumin
suppresses proliferation and induces apoptosis in multiple myeloma
cells through the suppression of RANKL signaling [6].
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 benet, 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.
We present here an update on the long-term follow-up of 13
MGUS/SMM patients who have been taking curcumin (at a dose
of 4 -8 grams daily) for a period of 3-9 years (Table 1). e patients
are monitored every 3-6 months with blood tests being done at each
monitoring visit. As far as we know, we are the only centre treating
MGUS/SMM patients with curcumin.
From the table, it can be seen that there are 6 MGUS and 7 SMM
patients, 11 are IgG, 1x IgA and 1x IgM. Eight have kappa disease and
5 have lambda disease. Six patients are male and 7 females and the
average age is 68 years. e median time of curcumin administration
is 5.6 years and only one patient has developed progressive disease
(patient no. 8 - cardiac amyloidosis) aer 6 years of curcumin therapy.
is patient has commenced anti-myeloma therapy. Five patients
showed a decrease in paraprotein levels, 3 increased slightly while
the rest remained stable. e bone marrow plasma cells decreased in
4 patients and increased modestly in 2 others while it remained the
same in 3. ree MGUS patients have not had bone marrow aspirates/
biopsies done. Five patients showed a decrease in hemoglobin while it
increased slightly or remained stable in the others. Whilst the involved
free light chain increased in most patients, this was accompanied by
an increase in the uninvolved free light chain in most of the patients,
leading to a decrease in ratio in 3 of the patients.
ere is currently much debate about early treatment of high
risk SMM patients, with updated IMWG diagnostic criteria for early
treatment. ese include serum free-light chains ratio >100, >60%
plasma cells and >1 focal lesion by MRI. Several trials have been initiated
to test early intervention in high-risk SMM patients. While some of the
trials have shown benet to high risk SMM patients, most of these trials
have been associated with toxic events which has included hematologic
events (neutropenia, thrombocytopenia, anemia) and nonhematologic
events (infection, rash, asthenia, constipation, diarrhoea, deep-vein
thrombosis).

Golombick T (2017) Long-term follow-up of curcumin treated MGUS/SMM patients – an updated single centre experience
Volume 2(2): 2-2
Hematol Med Oncol, 2017 doi: 10.15761/HMO.1000125
Our data suggest that curcumin administration may benet some
patients diagnosed with MGUS or SMM with little or no toxicity even
aer 9 years of therapy. Future studies should assess the role of curcumin
in both MGUS and SMM patients – prior to progression to high risk or
active myeloma – as this may lead to a delay in or may even stop disease
progression. Although one patient has progressed to amyloidosis, the
other twelve have maintained stable disease with no clear evidence of
disease progression. Patient tolerance has been good and none have
developed clinical infections. e drawback of this correspondence is
the small number of patients on long-term curcumin therapy.
Acknowledgments
anks to Caila Rothwell for assistance with data collection.
ere is no conict of interest to declare.
References
1. Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, et al. (2010) Monoclonal
gammopathy of undetermined signicance(MGUS) and smoldering (asymptomatic)
multiple myeloma: IMWG consensus perspectives risk factors for progression and
guidelines for monitoring and management. Leukemia 24: 1121-1127.
2. Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, et al. Monoclonal
gammopathy of undetermined signicance (MGUS) consistently precedes multiple
myeloma: a prospective study. Blood 113: 5412-5417.
3. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, et al. (2002) A long-
term study of prognosis in monoclonal gammopathy of undetermined signicance. N
Engl J Med 346: 564-569. [Crossref]
4. Dispenzieri A, Kyle RA, Katzmann JA, Therneau TM, Larson D, et al. (2008)
Immunoglobulin free light chain ratio is an independent risk factor for progression of
smoldering (asymptomatic) multiple myeloma. Blood 111: 785-789. [Crossref]
5. Aggarwal BB, Kumar A, Aggarwal MS, Shisodia S (2005) Curcumin derived from
turmeric curcuma longa: A spice for all seasons. Phytopharm Cancer Chemoprev pp:
349–387.
6. Bharti AC, Donato N, Singh S, Aggarwal BB (2003) Curcumin (diferuloylmethane)
down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha
kinase in human multiple myeloma cells, leading to suppression of proliferation and
induction of apoptosis. Blood 101: 1053-1062. [Crossref]
7. Golombick T, Diamond TH, Manoharan A, Ramakrishna R (2012) Monoclonal
gammopathy of undetermined signicance, smoldering multiple myeloma, and
curcumin: a randomized, double-blind placebo-controlled cross-over 4g study and an
open-label 8g extension study. Am J Hematol 87: 455-460. [Crossref]
8. Golombick T, Diamond T, Manoharan A, Ramakrishna R (2013) Long term use of
curcumin in two smoldering multiple myeloma patients. J Hematological Malignancies
3: 18-23.
Pt no. sex age Pp Curc
yrs
Bsl
Hb
(119-160g/L)
Eos Hb
(119-
160g/L)
Bsl pp
(g/L)
Eos pp
(g/L)
Bsl ic
(mg/L)
Eos ic
(mg/L)
Bsl uic
(mg/L)
Eos uic
(mg/L)
Bsl rc
(0.3-1.7)
Eos rc
(0.3-1.7)
Bsl
% pc
Eos
% pc
Bsl tp
(64-
83g/L)
Eos tp
(64-
83g/L)
1 M 71 IgGk 9 133 136 26 13.6 225 226 9.59 12.4 23.46 18.2 5 5 91 85
2 M 55 IgGk 7 109 111 28.5 16.1 97.7 1090 3.65 236 26.77 4.6 33 29 91 73
3 M 73 IgGk 5 128 134 32 37 29 31 19 11 1.53 2.82 44 25 91 94
4 M 74 IgGL 9 136 110 27 24.7 53.2 98.8 15.7 50.7 0.3 0.5 7 18 87 86
5 M 74 IgGL 3 141 111 28 28 64 83 6 10 0.09 0.12 20 11 95 86
6 F 89 IgAk 3 135 106 11.6 12 417 551 10.9 5.3 38.3 104 15 15 71 65
7 M 50 IgGL 6 144 139 29 34.6 15 41.3 6.8 8.95 0.45 0.2 10 10 101 101
8 F 77 IgGk 6 117 102 24.5 20.8 132 455 6.02 8.3 21.93 54.8 6 19 91 81
9 F 63 IgGk 5 122 128 25 19.8 54.1 114 5.82 7.2 9.3 15.8 16 15 86 83
10 F 51 IgGk 3 132 132 10 10 29 33 20 17 1.88 1.94 74 73
11 F 64 IgGL 3 134 130 11.5 11.4 10.2 9.1 1.9 6.3 0.2 0.7 80 72
12 F 66 IgMk 3 138 141 12 15.3 577 704 2 2.8 288.5 251.4 73 78
13 F 73 IgGL 3 131 11 2 17 17 61 93 4 7 0.07 0.08 7 8 79 76
Table 1. MGUS/SMM patient responses after years of curcumin therapy.Pt no: patient number; M: male; F: female; curc yrs: curcumin years; Hb: haemoglobin; Pp: paraprotein; Bsl:
baseline (at start of curcumin therapy); Eos: end of study period; ic: involved free light chain; uic: uninvolved free light chain; rc: free light chain ratio; % pc: percentage plasma cells;
tp: total protein.
Copyright: ©2017 Golombick T. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
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