Results of a small Australian study show that patients with the myeloma precursor diseases monoclonal gammopathy of undetermined significance and smoldering multiple myeloma experienced reduced levels of free light chains while taking curcumin.

Free light chains are proteins in the blood that are known to be linked to myeloma cell activity.

The Australian researchers also found that patients had reduced levels of bone breakdown while taking curcumin.

“A number of the patients in this study did show a free light chain response, and we suspect that curcumin should be incorporated into preventative regimens for monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma patients,” said Dr. Terry Golombick of St. George Hospital in Sydney, Australia, and lead author of the study.

The researchers also found that patients who had an abnormal free light chain ratio at the start of the clinical trial achieved more significant reductions in free light chain levels and bone breakdown than patients who had a normal free light chain ratio.

However, Dr. Golombick and his colleagues did not observe significant decreases in the level of monoclonal protein in the study participants. This finding is contrary to a previous study that showed curcumin was able to decrease monoclonal protein levels by 12 percent to 30 percent in certain MGUS patients.

According to Dr. Golombick, all patients in the study had type IgG monoclonal protein (a known risk factor for progression to multiple myeloma) and may have required a longer treatment period than the amount of time allotted in the study to demonstrate a response in their monoclonal protein levels.

Several myeloma specialists not involved with the Australian study explained to The Beacon, however, that the trial has a number of drawbacks.

One key concern is that 14 percent of the patients initially enrolled in the study experienced disease progression during the trial.  The study authors decided not to include data from these patients in their results because the patients started receiving chemotherapy after their disease progression, making it impossible to measure the independent effect of curcumin on the patients' disease.

However, by not including data from these patients, the authors may have biased their results in favor of finding that curcumin has an anti-myeloma effect.

Dr. Adam Cohen of the Fox Chase Cancer Center in Philadelphia also explained to The Beacon that “the relative changes in the free light chain measurements [of the patients in this study] are generally within the range of normal variation that we can see in clinical practice when we follow MGUS and smoldering myeloma patients over time without treatment, and would not be considered clinically significant by treating physicians.”

“While I think this is an interesting area worth exploring, it would take a larger, better-designed study to assess if there is really any benefit to curcumin in this setting,” he explained.

The Role Of Curcumin In MGUS And Smoldering Myeloma

Curcumin is the major active compound in the popular Indian spice turmeric. Preclinical and early clinical studies have shown that curcumin may possess anti-myeloma properties, as well as preventative effects for MGUS and smoldering myeloma patients (see related Beacon news).

Results of other studies have also suggested that curcumin supplementation helps reduce the likelihood of bone fractures in some MGUS patients by inhibiting the activity of bone-destroying cells. In multiple myeloma, the number and activity of bone-destroying cells are increased, making patients more prone to develop bone fractures and bone pain. An increased number of bone-destroying cells may therefore be a predictor of unfavorable disease prognosis in patients with MGUS or smoldering myeloma.

Traditionally, however, MGUS patients and smoldering myeloma patients do not experience any disease-related symptoms and do not receive any form of therapy unless their condition worsens.

The Role Of Free Light Chains In MGUS, Smoldering Myeloma, And Multiple Myeloma

Each person’s immune system has many types of plasma cells.  Each type of plasma cell produces a different type of antibody that fights infection.

People with MGUS, smoldering myeloma, or multiple myeloma overproduce a single type of plasma cell and therefore overproduce a single type of antibody, known as monoclonal protein, which then accumulates in the blood. MGUS is defined as having less than 30 g/L of monoclonal protein in the blood, while patients must have greater than 30 g/L of monoclonal protein in the blood to be diagnosed with smoldering myeloma or multiple myeloma.

Monoclonal proteins are made up of two types of smaller units called heavy chains and light chains. There are also two types of light chains, kappa light chains and lambda light chains. Plasma cells typically produce an excess of light chains, and since each type of plasma cell produces kappa or lambda light chains, people with myeloma-related conditions have an excess of either kappa or lambda light chains. These light chains build up in the blood and are called free light chains

A person’s ratio of kappa to lambda light chains can be used to help diagnose a person with a myeloma-related condition and can be used to follow the progress of their disease.

“A number of studies have shown that independent of the size and type of the monoclonal protein in the blood, an abnormal free light chain ratio increases the risk of progression to active myeloma,” explained Dr. Golombick.

“We chose to investigate the impact of curcumin on free light chains [instead of monoclonal protein levels] since free light chain analysis is now recommended [by the International Myeloma Working Group] for prognosticating plasma cell disorders [such as myeloma],” he added.

The serum free light chain assay is a blood test that allows physicians to monitor the disease status of patients with MGUS, smoldering myeloma, and other plasma cells disorders. Serum free light chain assays provide three key pieces of information.

The ratio of kappa to lambda free light chains (rFLC) has been shown in previous studies to predict the outcome of MGUS patients. Results of these studies showed that patients who had an abnormal rFLC (below 0.26 or above 1.65) had a significantly higher risk of disease progression than patients who had a normal rFLC.

Furthermore, the total number of involved free light chains (iFLC) tells how much of the excess free light chain (either lambda or kappa) produced by the abnormal plasma cells exists in the blood.

Additionally, the dFLC value is the difference between the number of free light chains produced by abnormal plasma cells and the number of free light chains produced by normal plasma cells.

Generally speaking, patients with multiple myeloma or either of the myeloma precursor diseases have abnormally high values of rFLC, iFLC, or dFLC. Often patients with MGUS or smoldering myeloma are monitored to see whether their rFLC, iFLC, and dFLC levels decrease over time, as these may be signs of a favorable prognosis.

Although serum free light chain assays provide important information regarding the status of a patient’s disease, there are other pieces of information that may also be taken into account when determining disease prognosis.

According to Dr. Cohen, the prognosis in MGUS or smoldering myeloma is based on several factors, including the size of the monoclonal protein, the percentage and type of bone marrow plasma cells, the type of the monoclonal protein, and the free light chain ratio.

“Thus, while the free light chain ratio is important, one can’t just look at it in isolation. MGUS and smoldering myeloma patients should be monitored as per the International Myeloma Working Group guidelines,” he explained.

Study Design

In the current study, Australian researchers assessed whether curcumin affected the free light chain values and bone breakdown in patients with MGUS or smoldering myeloma.

A total of 36 patients with a median age of 70 years were recruited for the study between January and September 2010. Fifty-three percent of patients had MGUS, and the remaining 47 percent had smoldering myeloma.

The patients were then randomized into two treatment groups. Fifty-six percent of patients received 4 g of curcumin daily for three months, followed by a placebo daily for the following three months. The remaining 44 percent of patients received a placebo daily for three months, followed by 4 g of curcumin daily for the following three months.

Sixty percent of patients who received curcumin first and 81 percent of patients who received the placebo first completed the planned six months of treatment.

Nine patients from each treatment group received 8 g of curcumin daily for an additional three months. The purpose of this treatment extension was to determine whether a dose of 8 g daily would provide better outcomes than a dose of 4 g daily for patients with either MGUS or smoldering myeloma.

Study Results

Patients who received curcumin during the first three months experienced reduced levels in all three free light chain values after three months (-26.1 percent rFLC, -9.1 percent iFLC, -9 percent dFLC). They experienced further reductions in their free light chain values after taking three months of daily placebo (-35.5 percent rFLC, -10.8 percent iFLC, -10.9 percent dFLC). The researchers speculated that the effects of curcumin may have lingered during these three months of placebo.

None of the changes in free light chain values for this group -- at either three months or six months -- were statistically significant.

Patients in this group also experienced a drop in the level of bone breakdown after taking curcumin for three months. However, the bone breakdown level increased after the following three months of placebo.

Patients who received the placebo first experienced increases in all three free light chain values while on the placebo (+2.4 percent rFLC, +3 percent iFLC, +3.5 percent dFLC). Although these values did not change after the following three months of 4 g daily curcumin, they decreased after taking an additional three months of 8 g daily curcumin (-36 percent rFLC, -6.7 percent iFLC, -8.5 percent dFLC).

In addition, their level of bone breakdown decreased after three months of placebo, and continued to decrease after the following three months of 4 g daily curcumin.

On average, the patients who completed the additional three months of 8 g daily curcumin following the initial six months of curcumin and placebo experienced reductions in all three free light chain values (-36.8 percent rFLC, -8.4 percent iFLC, -9.5 percent dFLC) as well as a decrease in bone breakdown.  The reduction in rFLC was statistically significant, while the changes in iFLC and dFLC were not.

The researchers found that the rFLC levels and the total protein levels at the start of the study were the most important factors influencing the rFLC response.

Based on these findings, the researchers divided the patients into two groups based on whether they had an abnormal or normal rFLC at the start of the study. Patients were classified as having abnormal rFLC if the ratio was either below 0.3 or above 1.7.

Of the patients who completed the first six months of the study, 68 percent had abnormal rFLC and the remaining 32 percent had normal rFLC at the start of the study.

The researchers found that patients who had an abnormal rFLC at the start of the study showed a decrease in rFLC, iFLC, dFLC, monoclonal protein, and bone breakdown levels after taking curcumin.  Only the decreases in rFLC and bone breakdown levels were statistically significant, however, and they did not reach statistical significance until the additional three months of 8 g daily curcumin.

Patients who had a normal rFLC  achieved minimal reductions in their free light chain ratios after taking either the 4 g dose or the 8 g dose of daily curcumin. Although they had a statistically significant decrease in iFLC (at the 8 g dose) and a small decrease in bone breakdown, they also had an increase in monoclonal protein levels.

Based on the results of their study, the Australian researchers concluded that "curcumin may benefit some but not all patients with MGUS or [smoldering multiple myeloma].  It would appear that patients with an abnormal ratio benefit most from curcumin administration and an increased effect was seen at the higher dose of 8g/day."

The researchers also noted that, in the year since their trial was completed, none of the 25 patients who completed the first six months of the trial have experienced disease progression.

Concerns About The Study

Several myeloma specialists not involved with the Australian trial told The Beacon that the study results should be interpreted with caution.

According to Dr. Ola Landgren, chief of the multiple myeloma section at the National Cancer Institute, one of the drawbacks of the study is the fact that there was no correlative science built into it. “We lack knowledge on what the mechanisms of the observed free light chain decreases are due to,” he explained.

He also pointed out that the follow-up time was short. “We don’t have a long follow-up, so we don’t know what the clinical implications of these observations are. We do not know if the observed decreases in free light chains have any impact on the risk of transformation from MGUS/smoldering myeloma to multiple myeloma,” he said. “The present study is not designed to assess that question.”

Dr. Cohen of the Fox Chase Cancer Center noted that the changes in free light chain measures observed during the study were not particularly large compared to what is normally seen by physicians tracking the progress of MGUS and smoldering myeloma patients.

Although he sees no harm in patients with MGUS or smoldering myeloma taking curcumin supplements, he said that he has "yet to see convincing evidence that [curcumin] has any long-term impact on disease progression."

Both Dr. Landgren and Dr. Cohen also noted that a substantial number of patients who initially started the Australian trial either dropped out or for other reasons were not included in the final results published by the study authors.

Over 30 percent of the patients initially enrolled in the study did not have their data included in the study's final published results.  Patients were dropped from the final data analyses because they either withdrew from the study due to side effects (6 percent), did not take their medication regularly enough (11 percent), or experienced disease progression (14 percent).

Of particular concern are the 14 percent of the patients who started the trial but experienced disease progression during the study.  These patients began chemotherapy soon after their disease progression was detected, so the study authors decided not to include the patients' free light chain and other lab results in the final data analyses reported in the study.

By excluding from the analyses the patients who clearly did not benefit from curcumin treatment, the authors may have made it more likely that their results show curcumin has activity against myeloma.

Dr. Ravi Vij, a myeloma specialist at Washington University in St. Louis, echoed the overall impressions of Drs. Landgren and Cohen in comments he provided The Beacon about the Australian study.

“This [study] is a follow-up on a trial done earlier by the same group and published in 2009. The data in the current study actually look less convincing compared to the trial published in 2009. I think it would be premature to scientifically endorse curcumin as a preventative strategy at present,” said Dr. Vij.

For more information, please see the article in the American Journal of Hematology (abstract).