Multiple myeloma develops when plasma cells in the bone marrow acquire genetic mutations that cause them to grow uncontrollably. There is no single cause. Instead, a combination of genetic changes, environmental exposures, and individual risk factors converge over years or decades to transform healthy immune cells into cancerous ones. The median age at diagnosis is 69, and most cases are preceded by a precancerous condition that may go undetected for years.
How Normal Plasma Cells Become Cancerous
Plasma cells are white blood cells that produce antibodies to fight infection. In multiple myeloma, one plasma cell accumulates enough DNA damage to begin dividing without restraint, crowding out healthy blood cells in the bone marrow and producing abnormal proteins that can damage organs.
The genetic changes behind this transformation happen in stages. The first hit often involves a chromosomal translocation, where a piece of one chromosome breaks off and attaches to another. Up to 50% of myeloma patients carry translocations involving a gene called IGH on chromosome 14. When IGH fuses with certain other genes, it acts like a switch that forces those genes into overdrive, pushing the cell toward uncontrolled growth.
After that initial event, additional mutations pile on. The signaling pathway most frequently disrupted is one that tells cells when to grow and divide. Mutations in genes called KRAS and NRAS (each found in 20 to 25% of patients) and BRAF (6 to 15%) keep this growth signal permanently turned on. Altogether, mutations affecting this single pathway appear in nearly half of all myeloma patients. Roughly 250 mutated genes have been identified in myeloma so far, about 60 of which are considered true drivers of the disease.
The Bone Marrow Environment Fuels Growth
Myeloma cells don’t survive on their own. They depend heavily on the bone marrow environment around them. Neighboring bone marrow cells release a signaling molecule called IL-6 that binds to myeloma cells and activates survival pathways inside them. This creates a feedback loop: myeloma cells stimulate the surrounding tissue, and that tissue releases signals that help myeloma cells grow and resist treatment. IL-6 also accelerates bone breakdown, which is why bone pain and fractures are hallmark symptoms of the disease.
MGUS: The Precursor Almost Everyone Has First
Nearly all cases of multiple myeloma are preceded by a condition called monoclonal gammopathy of undetermined significance, or MGUS. In MGUS, a small population of abnormal plasma cells is already present in the bone marrow, producing a detectable abnormal protein in the blood, but not yet causing symptoms or organ damage.
MGUS is surprisingly common, especially in older adults, and the vast majority of people who have it will never develop myeloma. On average, about 1% of people with MGUS progress to multiple myeloma each year. Doctors assess progression risk using blood markers measured shortly after MGUS is detected, including a subtype called light-chain MGUS that is often overlooked. When MGUS does progress, it typically moves through an intermediate stage called smoldering myeloma before becoming active disease.
Who Is Most at Risk
Several factors influence who develops multiple myeloma, though none of them guarantee it.
Age and sex. Myeloma is primarily a disease of older adults. It is more common in men than women, with an incidence rate of 9.1 per 100,000 men compared to 6.1 per 100,000 women.
Race and ethnicity. Black Americans face the highest risk of any racial or ethnic group in the United States by a wide margin. In 2019, there were an estimated 15.8 new cases per 100,000 Black Americans, compared with 6.9 per 100,000 white Americans, more than double the rate. The reasons for this disparity are not fully understood but likely involve a combination of genetic susceptibility, higher rates of MGUS, and differences in access to early detection.
Family history and inherited genes. Up to 10% of myeloma patients may carry an inherited gene variant that predisposes them to cancer. A study comparing myeloma patients to over 134,000 healthy controls found that variants in the BRCA2 gene (known for its role in breast cancer) were associated with a sevenfold increase in myeloma risk, and variants in BRCA1 with a nearly fourfold increase. These inherited variants are found in DNA repair genes, meaning the affected cells are less able to fix the kind of everyday DNA damage that accumulates over a lifetime.
Environmental and Occupational Exposures
Certain chemical and radiation exposures are linked to higher myeloma risk, though they account for a minority of cases overall.
Ionizing radiation. The International Nuclear Workers Study, which tracked hundreds of thousands of nuclear industry employees, found a positive association between cumulative radiation dose to the bone marrow and myeloma death. The workers in this study received relatively low doses (an average of 16 milligray over their careers), and the absolute risk remained small: roughly one excess death per 10,000 workers over a 35-year period. Still, the finding confirms that even low-level radiation exposure can contribute to myeloma development over time.
Chemical exposures. Workers exposed to engine exhaust face a statistically significant 34% increase in myeloma risk. Farming and agriculture are also associated with elevated risk (about 23% higher), likely because of exposure to pesticides, organic solvents, and other agricultural chemicals. Other occupational exposures that have been studied include benzene, petroleum products, rubber and plastic manufacturing, wood dust, and asbestos, though the strength of evidence varies across these categories.
Obesity and Body Weight
Carrying excess weight is one of the few modifiable risk factors for multiple myeloma. A large pooled analysis found that myeloma risk increases by about 11% for every 5-unit increase in BMI during adulthood. The connection appears even stronger when obesity begins earlier in life: people who were severely obese in young adulthood had more than double the risk of developing myeloma later compared to those with a normal BMI. The highest risk was seen in people who were overweight or obese in both young adulthood and later life, suggesting that long-term excess body weight matters more than weight at any single point.
The biological explanation likely involves chronic low-grade inflammation and changes in hormone and immune signaling that come with sustained excess body fat. These conditions create a bone marrow environment that is more hospitable to the kind of abnormal plasma cell growth that leads to MGUS and, eventually, myeloma.
Why No Single Cause Explains It
Multiple myeloma results from a chain of events that unfolds over many years. An initial genetic change creates a small clone of abnormal plasma cells. The bone marrow environment nurtures those cells. Additional mutations accumulate, some driven by inherited vulnerabilities in DNA repair, others by environmental exposures or simply by chance over decades of cell division. At some point, the balance tips from a stable, harmless condition like MGUS into active, progressive cancer. This multistep process is why myeloma has no single identifiable cause for most patients, and why it overwhelmingly appears in older adults who have had more time for these events to accumulate.