Multiple myeloma is not inherited in the way diseases like sickle cell anemia or cystic fibrosis are. It develops from genetic mutations that accumulate in plasma cells over a person’s lifetime, not from a single faulty gene passed down through families. That said, having a close relative with myeloma roughly doubles your risk of developing it yourself, which points to inherited genetic traits that make some people more susceptible.
Acquired Mutations Drive Myeloma
Multiple myeloma develops through a stepwise process in which plasma cells, a type of immune cell in bone marrow, accumulate genetic errors over time. These are somatic mutations, meaning they arise in individual cells during your life rather than being present in every cell from birth. The process typically begins with a precancerous condition called MGUS (monoclonal gammopathy of undetermined significance), which can eventually progress to active myeloma as additional mutations pile up.
The mutations that drive myeloma don’t follow a single predictable pattern. In sequencing studies, the most commonly mutated gene is KRAS, found in about 36% of patients, followed by NRAS at 20%, and TP53 and DIS3 each at around 16%. These mutations affect cell growth signaling, the ability to suppress tumors, and how cells process genetic instructions. Multiple mutations in the same signaling pathway can appear in a single patient, and the specific combination varies widely from person to person. This genetic diversity is one reason myeloma behaves differently in different patients and why no two cases follow exactly the same course.
In patients whose disease becomes resistant to treatment, the rate of mutations in growth-signaling pathways jumps to 72%, compared to newly diagnosed patients. This reflects the cancer’s ability to evolve under pressure, selecting for cell populations that can survive therapy.
Family Risk Is Real but Modest
A large population-based study found that first-degree relatives of myeloma patients have about 1.9 times the risk of developing the disease compared to the general population. Siblings carry the highest risk at roughly 2.3 times, while offspring and parents of patients show risks of about 1.9 and 1.8 times, respectively. For second-degree relatives overall, the increased risk was not statistically significant.
To put those numbers in perspective, myeloma affects roughly 7 out of every 100,000 people per year in the general population. Doubling that risk still leaves it an uncommon disease. A family history matters, but it’s far from a guarantee. The pattern of familial clustering suggests that what’s inherited isn’t myeloma itself but a subtle predisposition, likely involving how the immune system functions, that increases the odds of plasma cells going haywire at some point.
Inherited Susceptibility Genes
Genome-wide association studies have identified at least 17 specific locations in the DNA that are linked to a higher chance of developing myeloma. These aren’t dramatic mutations that cause disease on their own. They’re common genetic variants (called SNPs) scattered across different chromosomes, each contributing a small nudge toward increased risk. The identified regions sit near genes involved in cell growth regulation, immune function, and how cells manage their genetic material.
No single inherited variant is responsible for a large share of myeloma cases. Instead, the inherited component appears to work like a mosaic: many small genetic influences combine with environmental exposures and simple chance to determine whether someone develops the disease. This is why there’s no genetic test that can predict whether a specific person will get myeloma.
Why Certain Populations Are More Affected
People of African descent develop myeloma at roughly twice the rate of white populations, and this disparity has genetic roots. The precursor condition MGUS is also more common in people of African descent, suggesting the increased risk starts early in the disease pathway. Research into immune-related gene variants (particularly HLA alleles, which help the immune system recognize threats) has found that the specific variants linked to myeloma susceptibility differ between racial groups. An allele strongly associated with risk in white populations may have no association in Black, Asian, or Hispanic populations, and vice versa. This means the inherited genetic landscape underlying myeloma varies across ancestries, contributing to different rates of disease.
From Precursor to Active Disease
All of the genetic changes found in active myeloma are also present during the MGUS stage, which complicates the question of what triggers progression. What seems to matter is the balance between abnormal and normal plasma cells in the bone marrow. Research using gene expression scoring found that MGUS patients whose bone marrow showed a loss of normal plasma cell signatures were at higher risk of progressing to myeloma. As patients transitioned from MGUS to active disease, their risk scores consistently climbed, while scores in non-progressing patients actually decreased over time.
This means the genetics of myeloma aren’t just about which mutations are present. They’re also about how aggressively abnormal cells crowd out their healthy counterparts.
Genetic Testing After Diagnosis
Once someone is diagnosed with myeloma, genetic testing of the cancer cells becomes a critical part of treatment planning. The gold-standard test is called FISH (fluorescence in situ hybridization), which looks for specific chromosomal abnormalities in plasma cells taken from a bone marrow sample. Current guidelines recommend testing every newly diagnosed patient for several key rearrangements, including t(4;14), t(14;16), t(14;20), and t(11;14).
These chromosomal changes sort patients into risk categories. High-risk abnormalities like t(4;14), found in about 10% of patients, or deletion of part of chromosome 17, are associated with more aggressive disease and shorter responses to standard treatment. Patients with t(11;14), present in about 5% of cases, may respond particularly well to certain targeted therapies. Having two or more high-risk abnormalities at once creates a compounding effect that current treatment regimens struggle to fully overcome, even with intensive approaches.
The distinction matters practically: a patient whose myeloma carries high-risk genetics will typically receive a more aggressive initial treatment combination, and their care team will monitor more closely for signs of relapse.
Should Family Members Be Screened?
Because no single inherited gene mutation has been identified as a cause of myeloma, there’s no DNA test that can tell unaffected family members whether they’ll develop the disease. There are also no formal consensus guidelines recommending routine screening for relatives of myeloma patients.
Some researchers have proposed that families with multiple affected members (more than one first-degree relative, or one first-degree plus at least one second-degree relative) could benefit from annual blood and urine protein testing starting at age 40. In families where myeloma appeared at an unusually young age, screening could begin five years before the youngest age at diagnosis in that family. This type of screening looks for early signs of MGUS, which can then be monitored over time. These remain expert suggestions rather than official guidelines, and the decision is worth discussing with a hematologist who can weigh individual family history.