Multiple myeloma (MM) is a cancer originating in the bone marrow’s plasma cells, which produce antibodies. Most cases are sporadic, occurring without a clear family history. However, scientific evidence confirms a small, recognized increase in risk for first-degree relatives—parents, siblings, or children—of an affected individual. This familial clustering suggests that shared genetic susceptibilities and environmental exposures contribute to the condition. Understanding this risk requires distinguishing between the relative increase in likelihood and the overall low absolute chance of developing this uncommon cancer.
Quantifying the Risk of Familial Multiple Myeloma
Population studies show that a first-degree relative of a patient has an approximately two- to four-fold higher relative risk of developing MM compared to the general population. Since MM is rare (lifetime risk for an average individual is 1% or less), the absolute lifetime risk for a first-degree relative remains low, typically 2% to 4%.
The risk is not distributed evenly across all family members; the strongest associations are often observed among siblings. For instance, some studies found the risk highest for daughters whose mother had the disease.
First-degree relatives also have a two- to three-fold higher risk of developing Monoclonal Gammopathy of Undetermined Significance (MGUS). MGUS is an asymptomatic condition characterized by an abnormal protein in the blood and is considered a necessary first step toward multiple myeloma.
Case reports of identical twins developing MM provide evidence of a genetic component in some families. However, these cases are rare, and concordance rates remain low. The familial increase in risk does not extend significantly to second-degree relatives, such as aunts, uncles, or cousins.
Genetic and Environmental Factors in Familial Clustering
Familial clustering is not typically linked to a single, highly penetrant gene mutation, unlike some other hereditary cancers. Instead, consensus points toward a polygenic model, where an individual inherits several small genetic variations that collectively increase susceptibility. Genome-Wide Association Studies (GWAS) have identified variants at approximately two dozen locations in the human genome that contribute to MM risk.
These small genetic changes affect biological processes, such as immune response or DNA repair, making plasma cells vulnerable to malignant transformation. Researchers are exploring specific pathways, including rare cases associated with mutations in genes like BRCA1 and BRCA2.
Shared environmental factors also play a role in the increased risk observed in families. Family members often share similar diets, locations, and occupational or household exposures that could promote disease development. Specific implicated exposures include certain pesticides, herbicides like Agent Orange, and solvents such as benzene.
The interaction between an individual’s genetic profile and these shared environmental triggers determines the final outcome. A person may inherit susceptibility genes that only become relevant if exposed to a specific inflammatory or chemical agent. This gene-environment interplay complicates the identification of a single cause for familial multiple myeloma.
Monitoring High-Risk Family Members for Precursor Conditions
The recognition of familial risk has led to monitoring high-risk individuals for precursor conditions: MGUS and Smoldering Multiple Myeloma (SMM). SMM represents a more advanced stage than MGUS, with a higher progression rate to active myeloma, especially in the first five years.
Current guidelines do not recommend routine, population-wide screening for all first-degree relatives due to the low absolute risk and lack of established MGUS treatments. Screening is considered only for individuals who have two or more first-degree relatives with MM or a related plasma cell disorder. This selective approach targets those with the greatest familial risk.
Surveillance for these high-risk family members involves periodic blood and urine tests to detect the abnormal monoclonal protein.
Standard Surveillance Tests
- Serum protein electrophoresis with immunofixation
- Serum free light chain assay
- Complete blood count
These tests track the presence and quantity of the monoclonal protein, providing an early warning sign if the condition is evolving. The rationale for this limited surveillance is to identify MGUS or SMM early, allowing for close observation. While early detection of MGUS does not change that there is no treatment for the condition itself, it allows for risk stratification and immediate action if the patient progresses to active, symptomatic multiple myeloma.