Terry Golombick

Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: A randomized, double‐blind placebo‐controlled cross‐over 4g study and an open‐label 8g extension study

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 Students 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. Am. J. Hematol. 87:455–460, 2012.

The Potential Role of Curcumin in Patients with Monoclonal Gammopathy of Undefined Significance—Its Effect on Paraproteinemia and the Urinary N-Telopeptide of Type I Collagen Bone Turnover Marker

Purpose: To determine the effect of curcumin on plasma cells and osteoclasts in patients with MGUS. Experimental Design: 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. Results: 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. Conclusion: 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. (Clin Cancer Res 2009;15(18):5917–22)

Prevalence of Monoclonal Gammopathy of Undetermined Significance/Myeloma in Patients with Acute Osteoporotic Vertebral Fractures

In this retrospective, cross-sectional, observational study, we determined the prevalence of MGUS/myeloma in patients presenting with acute osteoporotic vertebral fractures over 18 months. We investigated 134 consecutive patients referred to the Endocrine Department at St George Hospital with acute osteoporotic vertebral fractures between July 2005 and December 2006. We collected the following data: clinical demographics (age, sex, smoking history, alcohol intake, diagnostic diseases and medications), serum biochemistry (calcium, 25-hydroxyvitamin D, parathyroid hormone), protein electrophoresis, markers of bone resorption (urinary deoxypyridinoline, u-DPYD), spinal radiography and bone densitometry (dual-energy X-ray absorptiometry and quantitative computed tomography). All patients with a paraprotein underwent bone biopsy to determine the percentage of plasma cells in the bone marrow. Patients were grouped according to the underlying cause of their osteoporosis, i.e. primary postmenopausal, glucocorticoid-induced (prednisone therapy 1 5 mg/day for longer than 3 months), MGUS, multiple myeloma and ‘other disorders’ (see below). After giving informed consent, all patients underwent venous blood collection for biochemical studies. Serum calcium, electrolytes and liver functions were measured using standard auto-analyzer methods, serum 25-hydroxyvitamin D by radioimmunoassay (Diasorin, Stillwater, Mich., USA) and serum parathyroid hormone by an immunoradiometric assay (Nichols Institute, San CleMonoclonal gammopathy of undetermined significance (MGUS) is the most common of the monoclonal gammopathies. MGUS is typified by a serum M protein value of ! 30 g/l, fewer than 10% plasma cells in the bone marrow, no or a small amount of M protein in the urine and the absence of lytic bone lesions, anemia, hypercalcemia or renal insufficiency related to the plasma cell proliferative process [1] . In a report from the Mayo Clinic, it was found that almost 60% of patients with a monoclonal gammopathy have MGUS [1] . Multiple myeloma can be preceded by MGUS. Myeloma is a progressive neoplastic disease and is often associated with multiple osteolytic lesions, hypercalcemia, anemia, renal damage and increased susceptibility to bacterial infections. Fractures are common in myeloma as a result of lytic bone lesions, generalized bone loss and elevated bone turnover. Whilst MGUS is largely considered a benign condition, a number of studies show that patients with MGUS are at increased risk of developing fractures even before progression to myeloma [2] . Elevated bone turnover is an independent predictor of fracture risk, and a number of studies have demonstrated elevated bone resorption and/or reduced bone formation among patients with MGUS and myeloma [3, 4] . A study by Diamond et al. [5] found that in a small series of 18 MGUS patients, bone density was substantially reduced at the hip and spine compared with normal values in young persons. In a retrospective cohort study, Melton et al. [2] found that the risk of vertebral, but not peripheral, fractures is increased among MGUS patients. Received: April 10, 2008 Accepted after revision: July 7, 2008 Published online: October 14, 2008

The impact of osteoporosis (as measured by lumbar spine quantitative computed tomography) on disease activity and survival in myeloma patients: A 13-year prospective study

Myeloma is a progressive neoplastic disease characterized by plasma cell dyscrasia, progressive bone loss, and pathological fractures. We conducted a prospective, single center study on myeloma patients to determine the impact of osteoporosis on disease activity and survival. Data collected on 108 patients followed for 13 years included clinical demographics, markers of myeloma activity, skeletal radiography, and bone densitometry. There were 56 men and 52 women with mean age of 69 years. Of these, 78% presented with stage I/II disease, 11% underwent stem cell or bone marrow transplants, 78% received adjuvant intravenous bisphosphonates, and 80% died during the course of the study (median survival of 47.3 months). There were 66% with osteoporosis, 54% with fractures, and 56% with lytic bone lesions. Femoral neck dual energy X-ray absorptiometry (DXA) and lumbar spine quantitative computed tomography (QCT) were major independent predictors of patient survival. Kaplan-Meier survival estimates demonstrated that patients presenting with a lumbar spine QCT T-score ≤ -3.5, died on average 18 months earlier than those with a lumbar spine QCT T-score > -3.5. These data suggest that the severity of osteoporosis, as defined by initial BMD T-score values, significantly impact on patient survival.

The potential role of curcumin (diferuloylmethane) in plasma cell dyscrasias/paraproteinemia

Plasma cell dyscrasias, most commonly associated with paraproteinemia, are a diverse group of diseases. Monoclonal gammopathy of undefined significance (MGUS) can precede multiple myeloma, a progressive neoplastic disease. MGUS occurs in association with a variety of other diseases and currently no treatment is recommended but rather “watchful waiting”. Given that the size of the M-protein is a risk factor for disease progression, early intervention with the aim of reducing the paraprotein load would provide an innovative therapeutic tool. Preliminary results from our pilot study show a drop of between 5% and 30% serum paraprotein in patients taking curcumin compared with patients on placebo. Curcumin is a diferuloylmethane present in extracts of the rhizome of the Curcuma longa plant. As a natural product, this has exciting potential in the treatment of plasma cell dyscrasias.

The effect of a combined oral calcium and vitamin D supplement for treating mild to moderate vitamin D deficiency in postmenopausal women

Objective To evaluate the efficacy of a combined calcium and vitamin D (Ca-D3) supplement for vitamin D deficiency in a small group of postmenopausal women. Methods A prospective open label 3 month-study. Participants 23 postmenopausal women (mean age 61.2 yrs) with vitamin D deficiency were given a combined oral Ca-D3 supplement called “Osteoblast”. The supplement comprises 500 mg elemental calcium and 500 IU of cholecalciferol. The dosing regimen comprised a loading dose of 1000 IU of cholecalciferol per day for one month (two tablets) and thereafter a maintenance dose of 500 IU of cholecalciferol per day for 2 months (one tablet). Outcome measure Serum was collected for calcium, 25 hydroxyvitamin D3 (25OHD3), and PTH measurements, as well as early morning 2-hour urine calcium/creatinine excretion index (Uca/creat). Specimens were collected at baseline and after 3 months of therapy. Data are reported as mean ± 1 standard error and 95% confidence intervals. Results Data was available for the 21 subjects who completed the study. Two subjects (9%) withdrew because of gastrointestinal intolerance. There were 3 subjects with moderate (12.5–24 nmol/L) and 18 with mild (25–49 nmol/L) vitamin D deficiency. Ten subjects (48%) had secondary hyperparathyroidism. Following the oral Ca-D3 combination, serum 25OHD3 levels normalised in all subjects with 18 (86%) subjects achieving values of greater than 70 nmol/L. Serum 25OHD3 levels increased from 36 (31–41) to 91 (79–102) nmol/L (p = 0.0001), increasing by an average of 152% over the 3-month period. There was a corresponding 38% decrease in serum PTH concentrations at 3 months (5.1 + 0.6 pmol/L), compared with baseline (8.0 + 1 pmol/L) (p = 0.001). No subject developed hypercalcemia, but an elevated Uca/creat excretion index occurred in one subjects. Conclusions A combined oral Ca-D3 product (Osteoblast) is effective for treating vitamin D deficiency and is adequately tolerated.

B-Cell Disorders and Curcumin.

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.

Addition of rice bran arabinoxylan to curcumin therapy may be of benefit to patients with early-stage B-cell lymphoid malignancies (monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or stage 0/1 chronic lymphocytic leukemia): a preliminary clinical study

Hypothesis. Prior studies on patients with early B-cell lymphoid malignancies suggest that early intervention with curcumin may lead to delay in progressive disease and prolonged survival. These patients are characterized by increased susceptibility to infections. Rice bran arabinoxylan (Ribraxx) has been shown to have immunostimulatory, anti-inflammatory, and proapoptotic effects. We postulated that addition of Ribraxx to curcumin therapy may be of benefit. Study design. Monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) or stage 0/1 chronic lymphocytic leukemia (CLL) patients who had been on oral curcumin therapy for a period of 6 months or more were administered both curcumin (as Curcuforte) and Ribraxx. Methods. Ten MGUS/SMM patients and 10 patients with stage 0/1 CLL were administered 6 g of curcumin and 2 g Ribraxx daily. Blood samples were collected at baseline and at 2-month intervals for a period of 6 months, and various markers were monitored. MGUS/SMM patients included full blood count (FBC); paraprotein; free light chains/ratio; C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR); B2 microglobulin and immunological markers. Markers monitored for stage 0/1 CLL were FBC, CRP and ESR, and immunological markers. Results. Of 10 MGUS/SMM patients,5 (50%) were neutropenic at baseline, and the Curcuforte/Ribraxx combination therapy showed an increased neutrophil count, varying between 10% and 90% among 8 of the 10 (80%) MGUS/SMM patients. An additional benefit of the combination therapy was the potent effect in reducing the raised ESR in 4 (44%) of the MGUS/SMM patients. Conclusion. Addition of Ribraxx to curcumin therapy may be of benefit to patients with early-stage B-cell lymphoid malignancies.

Response to Vermorken et al ‐ curcumin and free light chains

To the editor: We thank Vermorken et al. for their interesting comments. As suggested by Hutchison and Landgren [1], the relationship between chronic inflammation and cancer is well established, although not fully understood. Measurement of inflammatory cytokines provides clinicians with a valuable tool to use across a number of clinical settings. These authors hypothesize that measuring polyclonal free light chains (FLCs) in the serum might gain new insight into the activity of the adaptive immune system potentially allowing FLC measurement to serve as a novel clinically relevant biomarker. c-reactive protein (CRP), measured as a marker of inflammation, reflects only the activity of the innate immune system. Vermoken et al. have suggested that absolute levels of FLCs rather than their ratio may be potential biomarkers of immune stimulation and inflammation [2]. Currently, only one commercial assay is available for the measurement of serum FLCs. The assay, Freelite, consists of two assays—one to measure K FLC’s and the other to measure L FLC’s. One of these measures is an assessment of monoclonal FLCs [involved FLC (iFLC)] and the other is an assessment of polyclonal FLC’s [uninvolved FLC (uiFLC)]. In our study [3], FLC was monitored as a marker of response to curcumin. Curcumin has been known for centuries in India as an anti-inflammatory agent and it is possible to speculate that the observed response to curcumin might be associated with an anti-inflammatory effect. We are, unfortunately, not in possession of data on IL-6, CRP, or erythrocyte sedimentation rate (ESR); however, we can elaborate on the findings of the uiFLC response. From Table VII (a and b—see Supporting Information on line material), it can be seen that in patients who had an abnormal ratio at baseline (Table VIIa), at both the 4g and 8g dose of curcumin, all three markers of FLC response (i.e., rFLC, dFLC, and iFLC) decreased. However, the uiFLC increased in response to curcumin at both doses with this increase reaching significance at 8g. This data is suggestive of a decrease in the number/activity of abnormal monoclonal secreting cells and a concomitant increase in the normal polyclonal secreting cells/activity. Patients with a normal ratio at baseline (Table VIIb) show a smaller response in all measured parameters (except the iFLC at 8g) at both doses. From these findings, it can perhaps be suggested that patients with an abnormal ratio at baseline may be the subgroup who could benefit from curcumin treatment.

Stabilisation of Laryngeal AL Amyloidosis with Long Term Curcumin Therapy

Multiple myeloma (MM), smoldering myeloma (SMM), and monoclonal gammopathy of undetermined significance (MGUS) represent a spectrum of plasma cell dyscrasias (PCDs). Immunoglobulin light chain amyloidosis (AL) falls within the spectrum of these diseases and has a mortality rate of more than 80% within 2 years of diagnosis. Curcumin, derived from turmeric, has been shown to have a clinical benefit in some patients with PCDs. In addition to a clinical benefit in these patients, curcumin has been found to have a strong affinity for fibrillar amyloid proteins. We thus administered curcumin to a patient with laryngeal amyloidosis and smoldering myeloma and found that the patient has shown a lack of progression of his disease for a period of five years. This is in keeping with our previous findings of clinical benefits of curcumin in patients with plasma cell dyscrasias. We recommend further evaluation of curcumin in patients with primary AL amyloidosis.