Multiple myeloma is a cancer that begins in plasma cells, a type of white blood cell found in the bone marrow. These cells are responsible for producing antibodies that help fight infections. In multiple myeloma, abnormal plasma cells multiply uncontrollably, crowding out healthy blood cells and producing dysfunctional antibodies known as M protein. Alterations in the genetic material of these plasma cells are central to the disease’s development and progression.
How Genetics Drive Multiple Myeloma
Multiple myeloma arises from acquired genetic changes, known as somatic mutations, within the plasma cells themselves. These changes occur during a person’s lifetime and are not passed down through generations. Such alterations lead to the rogue plasma cells growing and surviving beyond their normal lifespan, escaping the body’s natural controls on cell division and death.
The disease progresses through a series of genetic “hits” or changes, a process referred to as clonal evolution. An initial genetic alteration may lead to a precursor condition called monoclonal gammopathy of undetermined significance (MGUS), which can then evolve into smoldering multiple myeloma (SMM), and eventually active multiple myeloma. As the disease advances, additional genetic abnormalities accumulate, giving rise to diverse subpopulations of cancer cells, known as subclones, which can exhibit varying behaviors, including increased aggressiveness or resistance to treatment.
Common Genetic Markers in Multiple Myeloma
Specific genetic abnormalities are identified in multiple myeloma cells, playing a role in how the disease behaves. One common type of alteration is a chromosomal translocation, which involves the swapping of genetic material between two different chromosomes. For instance, translocations involving chromosome 14, particularly at the 14q32 locus, are observed in about half of all myeloma cases.
Key translocations include t(4;14), t(11;14), and t(14;16). The t(4;14) translocation, present in approximately 15-19% of patients, involves a swap between chromosome 4 and chromosome 14, leading to the dysregulation of genes like FGFR3 and MMSET. The t(11;14) translocation is the most common primary translocation, occurring in about 16-24% of patients, and results in the overexpression of cyclin D1. The t(14;16) translocation, which deregulates MAF genes, is less common, found in about 3.2% of cases.
Besides translocations, deletions, which are losses of segments of a chromosome, are common. Deletion of the short arm of chromosome 17, known as del(17p), is recognized as a high-risk feature, often involving the loss of the TP53 tumor suppressor gene. The extent of del(17p) in myeloma cells can influence its prognostic impact, with a higher percentage of affected cells indicating a poorer outlook. Another significant deletion is del(1p), a loss on the short arm of chromosome 1, which is also associated with inferior outcomes in patients.
Another abnormality is hyperdiploidy, where myeloma cells have extra copies of certain chromosomes. This condition is observed in approximately 50-55% of multiple myeloma patients and is associated with a more favorable prognosis compared to cases with specific translocations. These various genetic markers contribute to the diverse nature of multiple myeloma, influencing its progression and response to treatment.
Understanding Genetic Testing and Its Impact
Identifying genetic abnormalities in multiple myeloma cells is achieved through specialized testing, primarily performed on bone marrow samples. Fluorescence In Situ Hybridization (FISH) is a method that employs fluorescent probes to bind to specific DNA sequences on chromosomes, allowing for the detection of translocations and deletions that might be too small to see with traditional methods. FISH is particularly effective for identifying abnormalities like t(4;14), t(11;14), t(14;16), and del(17p). FISH testing is performed on CD138-selected plasma cells.
Conventional cytogenetics, also known as karyotyping, involves growing bone marrow cells in a lab and then examining their chromosomes under a microscope to detect larger structural changes or an abnormal number of chromosomes. While it can identify broad chromosomal abnormalities, its effectiveness in multiple myeloma is limited because plasma cells have a low rate of division, making them difficult to analyze. Next-generation sequencing (NGS) is an advanced technique that analyzes DNA from bone marrow or peripheral blood samples to identify a wide range of genetic variations, including single gene mutations, copy number variations, and translocations. NGS offers high sensitivity, which is particularly useful for monitoring minimal residual disease (MRD).
The information gained from these genetic tests is valuable for patient management. Specific genetic markers help predict the aggressiveness of the disease, guiding prognosis. For example, the presence of del(17p) or translocations like t(4;14) indicates a higher-risk disease, influencing treatment intensity and choice. Identifying these genetic profiles allows healthcare providers to tailor treatment strategies, leading to a more personalized approach to care and improving patient outcomes.
Multiple Myeloma and Inheritance
Multiple myeloma is not considered an inherited disease in the same way that conditions caused by a single faulty gene, such as cystic fibrosis, are passed down through families. The genetic changes that lead to multiple myeloma are acquired during a person’s lifetime within the plasma cells themselves, rather than being present at birth in all cells of the body.
While multiple myeloma is not directly inherited, studies indicate a slightly increased risk for individuals who have a close relative, such as a parent or sibling, with the condition. This suggests that a combination of inherited genetic variations might increase an individual’s susceptibility, but it does not mean they will definitively develop the disease. The overall risk of developing multiple myeloma for the general population is quite low, approximately 1 in 10,000 per year, and while having a family history might double that risk, it still remains small in absolute terms. The vast majority of multiple myeloma cases arise from spontaneous genetic changes that occur over time, influenced by other genetic and environmental factors that are not yet fully understood.