Multiple myeloma (MM) is a cancer originating in the bone marrow, characterized by the uncontrolled proliferation of abnormal plasma cells. These specialized white blood cells produce antibodies, but when cancerous, they accumulate and interfere with normal blood cell production. The disease is fundamentally driven by genetic alterations within the plasma cells’ DNA, enabling the cells to grow and survive unchecked. Understanding these DNA changes is central to diagnosing the disease, predicting its behavior, and selecting the most effective treatment plan.
Inherited Risk Versus Acquired Mutations
The majority of cancer-driving genetic changes in multiple myeloma are somatic mutations, meaning they are acquired during a person’s lifetime and are present only in the cancerous cells, not in the inherited DNA (germline) of every cell in the body. While not strictly hereditary, a familial risk does exist, suggesting an inherited genetic predisposition.
First-degree relatives of a person with multiple myeloma have an increased risk of developing the disease, ranging from two to 5.5 times higher than the general population. This increased susceptibility is thought to be due to subtle inherited differences, or germline risk variants, in genes that make a person more vulnerable to later somatic mutations. For instance, inherited variants in DNA repair genes, such as BRCA1 and BRCA2, may contribute to a small increase in myeloma risk. However, the transition to cancer is overwhelmingly triggered by acquired, somatic DNA damage that occurs over time.
The Specific Genetic Drivers of Myeloma
Malignant plasma cells are defined by two categories of acquired genetic lesions: large-scale chromosomal rearrangements and smaller gene mutations. The earliest and most common changes are chromosomal translocations, where a piece of one chromosome breaks off and attaches to another. These translocations frequently involve the immunoglobulin heavy chain gene (IgH) locus on chromosome 14, which acts as a powerful genetic enhancer. The resulting fusion with an oncogene leads to the overexpression of proteins that drive cell growth.
Key examples include the t(11;14) translocation, which causes the overexpression of the CCND1 gene, and the t(4;14) translocation, which overexpresses FGFR3 and MMSET proteins. Another major change is aneuploidy, where the cell gains or loses entire chromosomes. Approximately half of patients exhibit hyperdiploidy (extra copies of odd-numbered chromosomes), which is generally associated with a more favorable prognosis compared to non-hyperdiploid translocations.
As the disease progresses, myeloma cells accumulate secondary mutations that accelerate their growth. The loss of a segment of chromosome 17, known as deletion 17p, is concerning because this region contains the tumor suppressor gene TP53. When TP53 is lost or mutated, the cell loses its ability to initiate programmed cell death, leading to uncontrolled proliferation. Other common secondary mutations occur in genes like NRAS and KRAS, which promote malignant cell division.
Diagnostic Testing and Risk Stratification
Identifying these specific genetic drivers requires specialized laboratory techniques performed on a bone marrow biopsy sample. Fluorescence In Situ Hybridization (FISH) is the primary method for detecting major chromosomal abnormalities, such as translocations involving chromosome 14 and deletion 17p. The FISH test uses fluorescent probes that bind to specific DNA sequences, allowing clinicians to confirm the presence of these large-scale rearrangements.
Next-Generation Sequencing (NGS) complements FISH by providing a more granular view of the myeloma genome. NGS detects smaller, individual gene mutations, like those in RAS or TP53, that are often missed by traditional FISH testing. The comprehensive genetic profile derived from these tests is used for risk stratification, predicting the likely course of the disease and its responsiveness to therapy.
The Revised International Staging System (R-ISS) integrates these cytogenetic findings with clinical markers to classify patients into standard-risk or high-risk categories. High-risk disease is defined by poor-prognostic genetic features, including deletion 17p, t(4;14), t(14;16) translocations, or abnormalities on chromosome 1 (gain of 1q or loss of 1p). High-risk patients typically require more intensive initial treatment to overcome the aggressive nature conferred by these specific genetic changes.
How Genetics Guides Treatment Selection
The genetic profile of a patient’s myeloma clone directly informs treatment intensity and drug choice. Patients with high-risk genetic features, such as t(4;14) or deletion 17p, are often treated with more aggressive regimens that combine multiple types of anti-myeloma drugs from the start. This strategy is designed to combat the tumor’s inherent resistance and higher propensity for relapse associated with these genetic markers.
Genetics guides therapy, exemplified by the use of venetoclax for patients with the t(11;14) translocation (15% to 20% of cases). The t(11;14) causes myeloma cells to become dependent on the anti-cell death protein BCL-2 for survival. Venetoclax is a BCL-2 inhibitor that targets and shuts down this protein, causing the myeloma cells to die.
Genetic testing also plays a role in monitoring the disease after treatment through Minimal Residual Disease (MRD) testing. Highly sensitive sequencing techniques detect myeloma cells at levels undetectable by standard methods, using the tumor’s unique genetic signature. Achieving MRD negativity, or the absence of detectable cancer cells, is associated with a lower risk of relapse and is a goal in modern management.