Regression of Intermediate-High Risk Monoclonal Gammopathy of Undetermined Significance (MGUS) With Long-term Use of Curcumin: A Case Report

Abstract

Patients with intermediate-high risk MGUS are not offered therapeutic options to date and standard of care remains observation with re-evaluations of the patient every 3 to 6 months. Given the persistent risk of progression as well as potential complications experienced by some, and anxiety experienced by most patients, early intervention with non-toxic curcumin, aimed at potentially slowing down or stopping disease progression might be therapeutic. We present here an intermediate-high risk MGUS patient who has been taking curcumin for 16 years and has shown a decrease in disease markers and an increase in uninvolved immunoglobulins, adding to the body of evidence of benefit of curcumin to MGUS patients.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant, clonal plasma cell disorder, characterized by the presence of a monoclonal (M) protein, <10% clonal plasma cells in the bone marrow, and absence of multiple myeloma (MM) or related lymphoplasmacytic malignancies (LPMs) such as immunoglobulin light-chain (AL) amyloidosis and Waldenstroms macroglobulinemia (WM). MGUS is present in 3% of the general population ≥50 years old, but only 0.3% among those ≤50 years old. The discovery of MGUS is most often incidental and made by non-hematologists. ¹

Studies indicate that almost all cases of MM are preceded by the precursor state of MGUS. ² There are 3 subtypes of MGUS, namely, immunoglobulin M (IgM) MGUS, non-IgM MGUS, and light-chain MGUS, each with distinct rate and type of progression. ¹ Patients with MGUS are not offered therapeutic options to date and standard of care remains observation with re-evaluations of the patient every 3 to 6 months. Long-term monitoring of untreated MGUS patients has shown that the monoclonal protein (paraprotein) can occasionally disappear spontaneously during follow-up, but only in MGUS patients with low initial concentrations of monoclonal protein (<5 g/L). ³

Although the risk of progression to MM or other LPMs is low (1% per year) for MGUS patients, it is still of considerable clinical importance because of its high prevalence in the general population and the persistent risk of progression. In addition, MGUS is known to be associated with peripheral neuropathy, ⁴ monoclonal immunoglobulin deposition disease ⁵ and monoclonal gammopathy-associated proliferative glomerulonephritis. ⁶ Some studies show that patients with MGUS may be at higher risk of osteoporosis and fractures and deep vein thrombosis.^7,8 Several studies have shown that psychological distress including anxiety and stress suffered by MGUS patients is no less than it is for patients with active disease. ⁹

Given the above and the uncertainty of disease progression with MGUS, 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 south-eastern tropical Asia. It is a perennial herb belonging to the ginger family. The most active component in turmeric is curcumin, a polyphenol which numerous studies have shown interacts with different cellular and molecular targets and, consequently, showing a wide range of pharmacological effects. Strong scientific evidence has emerged from clinical trials, which primarily utilized gold standard double-blind, randomized and placebo-controlled trial (D-RCT) designs, indicating that curcumin can impact various disease conditions in humans including metabolic disorders, musculoskeletal disorders, neurologic conditions, gastrointestinal diseases and cancer.^10,11 These human clinical trials have shown no dose-limited toxicity when administered at doses up to 10 g/day.

Curcumin has been shown to inhibit the proliferation and induce apoptosis of multiple myeloma cells through the downregulation of IL-6 and NF-kB. ¹² Curcumin has also been shown to inhibit osteoclastogenesis and to reduce bone turnover through the suppression of RANKL signaling. ¹³

Based on its antimyeloma cell activity, we have performed a number of clinical studies with curcumin in MGUS and SMM patients, including a randomized, double-blind, placebo-controlled cross over study in 25 MGUS and SMM patients utilizing a 4 g dose of curcumin with cross over at 3 months followed by an 8 g extension study, which demonstrated a statistically significant decrease in the free kappa to free lambda light chain ratio (rFLC, −35% and −36% for 4 and 8 g dose) and non-statistically significant reduction in involved free light chain, (iFLC, −8% and −10% for 4 and 8 g dose). ¹⁴ Statistically significant reductions in total serum and random urinary protein concentrations were also seen. Updated results from long-term follow up of 13 MGUS and SMM patients taking curcumin (4-8 g daily) for 3 to 9 years, of their own volition, showed a change in monoclonal protein (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. ¹⁵

According to the Mayo Clinic risk stratification model, ¹ an intermediate-high risk MGUS patient is defined by a monoclonal protein ≥1.5 g/dL, and an abnormal FLC ratio that is, 2 (of 3) risk factors. We report here on a male IgG kappa MGUS patient with intermediate-high risk of progression as defined by this risk stratification model. Written informed consent to publish case related data was provided by the patient.

In this model, the absolute risk of progression at 20 years is 37%. This patient was incidentally diagnosed with IgG kappa MGUS and hypogammaglobulinaemia in 2002 after a routine blood test. A bone marrow biopsy in 2003 showed 5% plasmacytosis. In 2007 at age 61, he entered our curcumin pilot study with a monoclonal protein (paraprotein) level of 26 g/L; prior to entering this study, his monoclonal protein level fluctuated in the twenties. Due to an improvement in his monoclonal protein seen at the end of the pilot study, he entered our randomized double-blind, placebo-controlled, cross-over study in 2010. His bone turnover, as measured by the urinary deoxypyridinoline (uDPYD) marker of bone resorption, was normal when he entered this study. A number of markers of active disease, including his monoclonal protein, improved by the end of this study and he thus continued to take curcumin of his own volition. Since the end of the RCT in 2010, he has been taking 2.3 g C3 complex curcumin daily (Vitacost Root2) in a divided dose and by the year 2023, has shown a 76% reduction in his monoclonal protein, an 87% reduction in his free light chain ratio, a 72% reduction in the involved (kappa) light chain and a 53% reduction in the involved immunoglobulin (IgG) (Table 1 and Figure 1).

Table 1.

Clinical Data of Male IgG Kappa Patient in 2007 (When he Entered the Clinical Trial), 2008 and 2010 (When he Completed the Clinical Trial) and his Data as Recorded in 2023.

Date	2007	2008	2010	2023
Monoclonal protein (<0.1 g/L)	26			6.3
rFLC (0.3-1.7)			23.46	3.1
Kappa light chain (3.3-19.4 mg/L)			225	63
Lambda light chain (5.71-26.3 mg/L)			9.59	20.3
IgG (6.2-14.4 g/L)		33.3		15.8
IgA (0.6-3.96 g/L)		0.48		1.19
IgM (0.48-3.04 g/L)		0.12		0.25
uDPYD/creatinine (2.3-5.4 nmol/mmol)			5.5	7.1

Figure 1.

Decreases seen in monoclonal protein (normal range < 0.1 g/L), free light chain ratio (normal range 0.3-1.7) and involved IgG immunoglobulin (normal range 6.2-14.4 g/L) from 2007 to 2023.

In addition, he has shown a 147% and 108% increase in the uninvolved immunoglobulins that is, IgA and IgM respectively (Table 1 and Figure 2). His uninvolved lambda light chain has shown a 128% increase (Table 1).

Figure 2.

Increases seen in uninvolved immunoglobulins (IgA and IgM) seen from 2008 to 2023.

There has been no significant change in his bone resorption as measured by the uDPYD excretion rate expressed as nmol/mmol urinary creatinine (Table 1).

In summary, after 16 years of curcumin therapy, multiple markers of active disease including his monoclonal protein, involved kappa light chain, uninvolved lambda light chain, free light chain ratio, involved IgG and uninvolved IgA and IgM, have improved. Although this patient is being monitored at regular intervals due to his intermediate-high risk of progression, for simplicity, we have provided annual values.

Future Curcumin Research in MGUS and Smoldering Myeloma (SMM) Patients

Humans have used curcumin-containing turmeric (Curcuma longa L.) medicinally for thousands of years, due to its anti-inflammatory and anti-cancer properties. It is now well known that dysbiosis in the human intestinal microbiome has been linked to the pathogenesis of many chronic diseases including the pathogenesis of multiple myeloma. ¹⁶ Curcumin supplementation has been shown to shift the ratio between beneficial and harmful bacteria in the gut microbiota community in favor of beneficial butyrate-producing bacteria strains, such as Bifidobacteria and Lactobacilli, and reduce the abundance of the pathogenic ones. It has been suggested that these changes may drive its anti-inflammatory or anti-cancer properties. ¹⁷ Two randomized clinical trials are currently underway investigating curcumin supplementation on the gut microbiota in plasma cell disorders. The NUTRIVENTION-2 trial will evaluate 2-week microbiome changes in SMM patients on a curcumin supplement arm, while the NUTRIVENTION-3 trial will evaluate microbiome changes in 12 weeks in MGUS/SMM patients on both curcumin and algae omega-3 supplements. ¹⁸

Conclusion

Although curcumin therapy may not show a response in all patients with MGUS, this patient has shown a remarkable improvement in his markers of disease progression over the years. Additionally, his uninvolved immunoglobulins (ie IgA and IgM) and uninvolved lambda light chain have increased. A decrease in his rFLC was accompanied by an increase in the uninvolved free light chain. This may explain the reduction in the ratio, that is, an increase in the clone secreting the normal free light chain or a decrease in the clone secreting the abnormal free light chain. This case study adds to the body of evidence that curcumin administration may benefit some patients diagnosed with MGUS with little or no toxicity even after 16 years of therapy.