Study: Hereditary cancer mutations among people with multiple myeloma

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What is this study about?

This study looks at the role of gene mutations in people diagnosed with multiple myeloma, a type of blood cancer. Researchers wanted to find out if certain inherited mutations make people more likely to get this cancer and whether these mutations affect how people respond to treatment.

Why is this study important?

Multiple myeloma is a rare cancer that affects plasma cells, a type of white blood cell in the immune system. The risk of multiple myeloma in the average person's life is under one percent. However, some families have more than one member with multiple myeloma, which suggests inherited gene mutations may increase their risk. Research into the genetic causes of multiple myeloma has been limited.

This study is one of the first to examine which mutations might lead to multiple myeloma risk. Researchers tested 1,681 people with multiple myeloma to see if they had mutations in BRCA1, BRCA2 or other genes known to increase the risk of other cancers. They found that people with multiple myeloma were more likely to have mutations in these genes, which may suggest a small connection between these mutations and multiple myeloma. However, because this is a rare cancer, any increased risk is still very low. More research is needed to confirm this.
 

Study findings

Among 1681 people with multiple myeloma, 167 (10%) had a gene mutation associated with hereditary cancer. Researchers classified these mutations into two groups: those with high cancer risk and those with slightly increased cancer risk.

• Mutations associated with high cancer risk
  • 64 people (3.8%) had mutations in 21 different genes that cause a high or moderately increased cancer risk. The 21 genes included BRCA1, BRCA2, CHEK2, ATM, BARD1, BLM, BRIP1, CDKN2A, DDX41, MLH1, MRE11, MSH2, MSH6, PALB2, PMS2, POT1, RAD50, RAD51C, RAD51D, TP53 and XRCC2. (More information about these hereditary cancer genes can be found here.)
  • The most common gene mutations and the number of people in the study who had them were:
    • ATM (7 people)
    • BRCA1 (8 people)
    • BRCA2 (8 people)
    • CHEK2 (8 people)
  • Compared to the 1,514 people with multiple myeloma who did not have an inherited gene mutation, the 64 people with mutations in one of the 21 genes mentioned above were more likely to:
    • have experienced another cancer before being diagnosed with multiple myeloma.
      • 14% had a prior cancer, compared to slightly less than 6% of people without inherited gene mutations.  
      • Breast cancer was the most common previous cancer.
    • be diagnosed with multiple myeloma at younger ages.
      • The average age at diagnosis was 59 for those with an inherited gene mutation, compared to 62 for those without a mutation.
    • report a family history of cancer in relatives, such as parents, siblings, grandparents, aunts or uncles.
       
• Mutations associated with slightly increased cancer risk
  • 103 people (6.1%) had mutations that slightly increase cancer risk or increase risk when two mutations are present (one from each parent).
  • People in this group were diagnosed with multiple myeloma at age 66; people without gene mutations were diagnosed with multiple myeloma at age 62.  
  • Importantly, these differences were not statistically significant and may have been due to chance.

Do people with hereditary cancer mutations have an increased risk for multiple myeloma?
Researchers wanted to understand whether the hereditary cancer gene mutations among multiple myeloma study participants increased the risk of multiple myeloma. To do this, they reviewed how often people with multiple myeloma had these mutations compared to people without multiple myeloma.

Multiple myeloma is uncommon in people with a BRCA1 or BRCA2 mutation. However, compared to healthy people in the study, participants with multiple myeloma were more likely to have one of these mutations. This suggests that having a BRCA1 or BRCA2 mutation may increase the risk of multiple myeloma, but more research is needed to clarify this possibility. Even if these mutations increase the risk for multiple myeloma, the risk is very low.

This study did not look at families with BRCA1 or BRCA2 mutations who did not have multiple myeloma. For this reason, this study may overestimate the risk of multiple myeloma among people with BRCA1 or BRCA2 mutations. (Because the number of people with CHEK2 and ATM mutations who had multiple myeloma was not increased compared to healthy people, researchers concluded that these mutations did not increase the risk of multiple myeloma.)

Researchers noted one limitation of this study: the healthy group differed in several ways from participants with multiple myeloma. Ideally, the study would have included a larger group that better matched multiple myeloma participants.

Treatment differences
Knowledge of an inherited mutation may benefit people with multiple myeloma. In this study, people with multiple myeloma who had inherited mutations and were treated with the chemotherapy drug melphalan followed by a stem cell transplant remained in remission longer than those without inherited mutations. However, compared to people without inherited gene mutations, this treatment did not increase the length of time that they lived. (People with or without inherited gene mutations lived a similar length of time after treatment.)

What does this mean for me?

In this study, one in ten people with multiple myeloma had a mutation linked to hereditary cancer, 4% had a mutation in a gene associated with a high risk of other cancers, and 6% had a mutation in a gene with a slightly increased risk of other cancers. Genetic testing is not currently recommended for people with multiple myeloma.

Among participants with multiple myeloma, more people had BRCA1 and BRCA2 mutations (just under 1% of those with multiple myeloma) compared to those with multiple myeloma without these mutations (under 0.3%). These results need to be validated by additional research.

This study did not determine how much the risk of multiple myeloma increased (if at all) among people with an inherited mutation who were not diagnosed with cancer. If you have a BRCA1 or BRCA2 mutation, you may have a slightly higher risk of multiple myeloma than people without a BRCA mutation. However, this data needs to be confirmed with more rigorous testing. Multiple myeloma is not common among families with known BRCA1 or BRCA2 mutations.

No screening tests are available for multiple myeloma, and genetic testing is not currently recommended for people with multiple myeloma.

For this reason, it is important to know the signs and symptoms of multiple myeloma. These can include:

• bone pain
• nausea, constipation or loss of appetite
• mental fogginess or confusion
• tiredness
• frequent Infections
• unexpected weight loss
• weakness
• thirst and needing to urinate often

Multiple myeloma is often a slow-growing cancer. If you are diagnosed with multiple myeloma and are not experiencing symptoms, doctors may suggest watching for signs. People with multiple myeloma who need treatment have options to help manage the disease. This study suggests that treatment with high-dose melphalan followed by autologous stem cell transplant (HDM-ASCT) might benefit individuals with an inherited mutation.

Reference

Thibaud S, Subaran RL, Newman S, et al., Multiple myeloma risk and outcomes are associated with pathogenic germline variants in DNA repair genes. Blood Cancer Discov 2024;5:428–41

More information about individual hereditary cancer genes can be found here.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 4/23/25