Understanding Multiple Myeloma: An Overview of Causes and Risk Factors

Is Multiple Myeloma Hereditary?

Multiple myeloma is not usually a hereditary condition, but there is some indication that genetics might be involved. Although most instances are sporadic, research indicates that people with a close relative (parent or sibling) who has had multiple myeloma or a similar plasma cell disorder (such as monoclonal gammopathy of undetermined significance, or MGUS) might have a slightly increased risk of developing the disease. Nevertheless, the overall hereditary risk is low.

Genetic mechanisms that could play a role include immune system regulation and DNA repair variation, but no inherited gene mutation has been discovered as a direct etiology. Environmental and lifestyle exposures, including ionizing radiation, specific chemicals (e.g., benzene), and chronic inflammation, are thought to play a larger role in the development of multiple myeloma than inherited characteristics.

What Causes Multiple Myeloma Cancer?

Multiple myeloma results from uncontrolled proliferation of abnormal plasma cells in the bone marrow. The multiple myeloma causes are still not clear, but a combination of factors precipitates its development:

1. Genetic Mutations

Alteration in the plasma cell DNA may result in unlimited cell growth. Some of the frequent genetic anomalies in multiple myeloma involve mutations in MYC, TP53, and RAS genes and chromosomal translocations t(14q32) involving chromosomes 14q32 (IgH gene rearrangement).

2. Environmental & Occupational Exposure

Radiation and some chemicals such as benzene, pesticides, and Agent Orange have been associated with an elevated risk. Individuals who work in agriculture, oil refining, or petrochemical industries are said to be at a greater risk.

3. Chronic Immune Stimulation & Infections

Conditions that lead to prolonged immune stimulation, such as chronic infection or autoimmune diseases, have been associated with an elevated risk of plasma cell disorders.

4. Monoclonal Gammopathy of Undetermined Significance (MGUS)

MGUS is a pre-malignant condition where the abnormal plasma cells secrete M proteins (monoclonal proteins) but do not make the person ill. Approximately 1% of individuals with MGUS develop multiple myeloma yearly.

5. Age & Gender

Most frequent in individuals older than 60 years; infrequent before the age of 40. Males have a very slightly greater risk than females.

6. Family History & Race

Risk is slightly elevated with a first-degree relative having multiple myeloma. African Americans have almost double the risk than Caucasians.

7. Obesity & Diet

Excess body weight is associated with increased risk of myeloma. Certain research indicates that chronic inflammation due to obesity is believed to cause the disease.

Multiple Myeloma Etiology

Multiple myeloma develops from the unrestrained growth of neoplastic plasma cells in the bone marrow, resulting in overproduction of aberrant monoclonal (M) proteins. The definite reason is not yet clear, but multiple myeloma etiology is thought to be polyfactorial with respect to genetics, environment, and immunity.

1. Genetic Factors

Numerous genetic abnormalities have been implicated in the pathogenesis of multiple myeloma:

Chromosomal translocations:

• t(11;14), t(4;14), t(14;16), t(14;20) – involve the IgH gene (chromosome 14q32), resulting in oncogene activation.

Gene mutations:

• Mutations in MYC, TP53, RAS (KRAS/NRAS), FGFR3, and BRAF are common in plasma cell malignancy.

Chromosome deletions & duplications:

• 17p deletion (del17p) is seen with aggressive disease and adverse prognosis. Gain of chromosome 1q (1q+) is associated with treatment resistance.

2. Precursor Conditions (Plasma Cell Dyscrasias)

• Multiple myeloma frequently arises from preceding asymptomatic conditions: Monoclonal Gammopathy of Undetermined Significance (MGUS) A harmless condition where atypical plasma cells secrete monoclonal proteins.
• 1% of MGUS develop multiple myeloma per annum.
• Smoldering Multiple Myeloma (SMM)
• A more advanced precursor stage with a higher risk of disease progression (10% per year).

3. Environmental & Occupational Factors

Environmental exposure to some triggers is related to higher risk:

• Exposure to radiation (e.g., survivors of the atomic bomb, radiation treatment)
• Exposure to chemicals (e.g., benzene, herbicides, pesticides, Agent Orange)
• Petroleum products and industrial chemicals

4. Immune Dysregulation & Chronic Inflammation

• Chronic antigenic stimulation (due to infection or autoimmune disorder) can be stimulatory to plasma cell transformation.
• Dysregulated cytokine function (IL-6, IL-1β, TNF-α) is responsible for myeloma cell survival.

5. Demographic & Lifestyle Risk Factors

• Age: The majority are in older individuals (>60 years of age).
• Sex: A slightly increased risk in men over women.
• Race: African Americans have approximately double the risk compared to Caucasians.
• Obesity: Increased inflammation and insulin resistance may be implicated in plasma cell proliferation.

6. Bone Marrow Microenvironment

• Bone marrow niche establishes a survival niche in the form of a protective microenvironment for myeloma cells.
• Interaction of stromal cells, osteoclasts, and cytokines (such as IL-6, VEGF, RANKL) facilitate tumor progression and bone resorption.
• Multiple myeloma is a multistep disease involving genetic mutations, precursor disease (MGUS/SMM), environmental exposures, immune dysregulation, and bone marrow microenvironmental interactions. There is not a single cause but all of these factors in concert that propel plasma cell malignancy.

Multiple Myeloma Risk Factors

Multiple myeloma is a multifactorial condition, i.e., its etiology is determined by a combination of genetic, environmental, and lifestyle factors. The following are the major multiple myeloma risk factors linked to the disease:

1. Age

• The strongest risk factor.
• Most of the cases present in individuals above 60 years, with the median age at diagnosis being 69 years.
• Uncommon before the age of 40.

2. Gender

• Men have a slightly increased risk compared to women.
• Cause is not known but possibly due to hormonal fluctuations or occupational exposures.

3. Race & Ethnicity

• African Americans have a doubled risk of having multiple myeloma when compared to Caucasians.
• There is less occurrence of the disease in the Hispanic and Asian populations.

4. Family History & Genetic Predisposition

• First-degree relative (parent, sibling) with multiple myeloma doubles the risk 2-4 fold.
• There may be inherited genetic alterations related to immune function and plasma cell growth.
• Multiple myeloma is not very hereditary, however, and most are sporadic.

5. Precursor Plasma Cell Disorders

• Monoclonal Gammopathy of Undetermined Significance (MGUS)
• Noncancerous disease where aberrant plasma cells produce monoclonal (M) proteins.
• MGUS progresses to multiple myeloma in 1% of patients each year.
• Smoldering Multiple Myeloma (SMM)
• More advanced precursor condition with a 10% per year chance of progressing to multiple myeloma.

6. Environmental & Occupational Exposures

Radiation exposure:

• Atomic bomb survivors and those with high radiation exposures are at increased risk.

Chemical exposure:

• Benzene, pesticides, herbicides, Agent Orange, petroleum products
• Industry workers, farmers, and oil refinery employees may be at increased risk.

7. Chronic Immune Activation & Inflammation

• Autoimmune disease (e.g., rheumatoid arthritis, lupus, Sjögren's syndrome)
• Chronic infections (e.g., HIV, hepatitis, Epstein-Barr virus)
• Continued activation of the immune system may cause plasma cell abnormalities.

8. Obesity & Metabolic Factors

• Obesity is associated with an increased risk of 20-30%.
• Excess body fat may induce chronic inflammation and insulin resistance, which could promote increased myeloma cell proliferation.

9. Diet & Lifestyle Factors

• Dietary high in fat and low in fruits/vegetables may contribute to risk, but evidence is scarce.
• Smoking has been incriminated as increasing risk in some studies.
• Drinking alcohol does not have a clear link with risk for multiple myeloma.

10. Viral & Bacterial Infections

• HIV and Epstein-Barr virus (EBV) might increase the risk of plasma cell disorders.
• Helicobacter pylori (ulcer-causing bacteria) have been suggested as a possible risk factor, although more research needs to be conducted.