Monoclonal Gammopathies of Undetermined Significance

Introduction

Monoclonal gammopathy of undetermined significance (MGUS) is caused due to production of abnormal proteins by the plasma cells (a type of white blood cells) in the bone marrow. MGUS is not a malignant condition or neoplastic growth. It is a noncancerous plasma cell abnormality seen in one percent of the total population. However, people with MGUS have a higher risk of developing malignant conditions with a risk percentage of one to two percent rising every year (as years advance). It is more common in males. Its prevalence is more in people more than 50 years of age. Monoclonal gammopathies remain asymptomatic in the majority of individuals. Regular clinical monitoring is needed to prevent MGUS from transforming into malignancies.

What Are Monoclonal Gammopathies of Undetermined Significance?

Production of abnormal proteins such as paraproteins or monoclonal proteins (M protein) by nonmalignant plasma cells is known as monoclonal gammopathies of undetermined significance. These abnormal proteins that are produced are antibodies (immunoglobulins) made up of heavy and light chains (amino acids), but due to their structural abnormality, they do not perform normal immunological functions (defense against infections).

MGUS differs from typical multiple myelomas in the following ways:

• Abnormal proteins are produced only from a small proportion (less than 10 percent) of plasma cells.

• No clinical evidence of organ damage that usually occurs in myelomas (cancer of plasma cells).

• Blood IgG (immunoglobulin G) paraprotein concentration is below 3 g/dL.

• Absence of other manifestations of multiple myelomas (anemia, hypercalcemia, lymphadenopathy).

Are Monoclonal Gammopathies of Undetermined Significance Considered Cancer?

MGUS are not cancers, but people with MGUS are more likely to develop malignancies of blood and bone marrow. The incidence of developing malignancies from monoclonal gammopathy of undetermined significance rises with an increase in age. The risk percentage is less than one percent in individuals below 25 years whereas it is more than five percent in people above 70 years.

MGUS is a predisposing factor for the following malignant conditions:

• Myeloma.

• Lymphoma (cancer of the white blood cells).

• Waldenstrom’s macroglobulinemia (a rare type of lymphoma).

• Chronic lymphocytic leukemia (CLL).

• Amyloidosis (light chain).

What Causes Monoclonal Gammopathies of Undetermined Significance?

The exact etiology of MGUS is unknown. Research suggests that factors that induce inflammatory response could trigger monoclonal gammopathies. Some of these factors are:

• Infection.

• Immunological disturbances (metabolic dysfunction like obesity).

• Environmental factors (nuclear radiation, carcinogen air pollutants).

• Genetic factors.

What Are the Risk Factors for Acquiring Monoclonal Gammopathies?

MGUS is a precancerous plasma cell blood disorder that predominantly progresses into multiple myeloma (MM). The rate of risk progression is one percent per year.

• Though not common, the risk percentage increases with aging.

• Though there is no evidence of any inheritance pattern, the risk of developing MGUS is increased among family members.

• MGUS is detected more frequently in men when compared to women.

• The prevalence is more in individuals of African descent.

• No dietary factors attribute to the progression of malignancies.

What Are the Types of Monoclonal Gammopathies of Undetermined Significance?

MGUS is classified depending on the immunoglobulin (M protein) or light chains present in the blood.

• Immunoglobulin M (IgM) MGUS.

• Non-immunoglobulin M (non-IgM) MGUS.

• Light chain MGUS.

Among these, individuals with IgM MGUS have a greater risk of developing cancerous disorders such as chronic lymphocytic leukemia, Waldenström macroglobulinemia, and non-Hodgkin lymphoma.

What Are the Clinical Features of MGUS?

Individuals with MGUS are predominantly asymptomatic. The presence of abnormal monoclonal proteins is only detected while doing other routine blood screening tests or while diagnosing for other disorders. Some of the clinical manifestations include:

• Peripheral neuropathy/ (numbness and tingling sensation in hands and legs).

• Increased risk for bone fractures and decreased bone density.

• Infections.

• Amyloidosis (buildup of amyloid protein in the organs).

• Hyperviscosity of blood.

• Thromboembolism.

• Lymphoma defining events.

• Reduced response to vaccination.

• Increased rate of osteoporosis.

• Anemia.

• Fatigue (lack of energy).

• Weakness.

• Pain in the bones and soft tissues.

• Increased bleeding and bruising.

• Headache and irritability.

What Are the Diagnostics Available for Monoclonal Gammopathies of Undetermined Significance?

Specific diagnosis of MGUS is done only when suspected M-protein is incidentally identified in blood and urine during routine screening procedures.

• Low levels of M-protein are detected in serum (< 3 g/dL) and urine (< 200 mg/day) samples.

• MGUS differs from neoplastic plasma cell disorders by decreased levels of M-protein.

• Baseline evaluation with a skeletal survey (conventional x-rays of the skull, long bones, spine, pelvis, and ribs) are done to assess the risk for bone fracture.

• Bone densitometry identifies osteoporotic changes.

• Bone marrow analysis shows evidence of mild plasmacytosis (presence of nucleated cells).

• Presence of monoclonal cells in the bone marrow.

• Detection of light chains and abnormal proteins in serum electrophoresis.

• Complete blood count.

• FISH (fluorescence in situ hybridization).

• Enzyme assay of LDH (lactate dehydrogenase).

• Serum-free light chain test helps to stratify MCUS patients by assessing risk where only two percent progression in 20 years and a high risk of 27 percent progression after 20 years.

• M protein of more than 3g/dL is suggestive of progression to multiple myeloma.

What Is the Management of Monoclonal Gammopathies?

Routine chemotherapies or anticancer drug administration are not recommended for MGUS. Also, many patients do not progress into malignancies hence starting anti-cancer regimes would necessarily lead to potential therapy toxicity. Symptomatic management is the preferred line of treatment.

• Intravenous bisphosphonates to treat patients with bone loss (osteoporosis).

• Nonsteroidal anti-inflammatory drugs are recommended to manage bone pain.

• The use of immunomodulators targeting monoclonal proliferation cells to cure MGUS is still under clinical trials.

• Periodic evaluation every 6 to 12 months is recommended for high-risk patients which includes complete clinical examination and laboratory screening of serum and urine proteins by electrophoresis to evaluate for disease progression.

Conclusion

Monoclonal gammopathies of undetermined significance are premalignant conditions where abnormal proteins are found circulating in the blood. Since MGUS is not a deteriorating disorder, it does not require any specific treatment intervention. However due to the risk of MGUS progressing into malignancies like myeloma is common, routine blood screening tests and regular monitoring is essential to prevent the development of neoplastic disorders. MGUS consists of a spectrum of affected individuals where some progress to malignancies and others manifest a tolerant phase. More population-based studies and sensitive laboratory techniques to detect MGUS would help to develop early prevention strategies.