BRCA variants increase risk for multiple myeloma, particularly at younger age
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Key takeaways:
- Individuals with pathogenic germline variants in BRCA1 or BRCA2 exhibited increased risk for multiple myeloma.
- High-dose melphalan and autologous stem cell transplantation improved outcomes for these patients.
Inherited variants in DNA repair genes such as BRCA1 and BRCA2 may increase risk for multiple myeloma, according to results of a retrospective study.
Patients with pathogenic germline variants exhibited increased likelihood of having a family or personal history of cancer, or of getting diagnosed at a younger age.
“Definitively, this changes care for patients with myeloma,” Kenan Onel, MD, PhD, chief of clinical genomics and director of the Center for Precision Oncology and Cancer Prevention at Roswell Park Comprehensive Cancer Center, told Healio.
‘Unique opportunity’
Prior research showed individuals with a first-degree family member with multiple myeloma have a twofold to fourfold greater risk for developing the disease or a precursor condition compared with the general population, according to study background.
Between 7% and 10% of patients with cancer have an “inherited predisposition,” Onel said.
However, no association between multiple myeloma and pathogenic germline variants (PGVs) had been established.
Onel’s interest in the subject piqued when he learned about the Multiple Myeloma Research Foundation (MMRF) CoMMpass dataset, which included genetic information from hundreds of newly diagnosed patients.
As Onel and colleagues started their investigation using the MMRF data, clinicians and researchers at the Center of Excellence for Multiple Myeloma at Mount Sinai Tisch Cancer Center began gathering genetic information on their own patients with multiple myeloma.
“It seemed like it was a unique opportunity to learn about genetics in a rare disease — a disease that is clinically very important, but one that had never really been investigated in terms of genetic predispositions,” Onel said.
Methods
The analysis included 1,681 adults (59% men; 59% white, 20.7% Black, 6% Hispanic, 4% Asian) with a median age at diagnosis of 63 years (range, 25-94).
A discovery cohort included 895 patients from the MMRF, all of whom were diagnosed between 2011 and 2015. A replication cohort that included 786 patients treated at Mount Sinai diagnosed between 2015 and 2022.
Frequency of PGV served as the primary endpoint.
Researchers broke down PGVs into three subgroups — PGV-As, PGV-Bs and PGV-Cs. They defined PGV-As as “high/moderate-penetrance variants associated with autosomal dominant cancer predisposition, characterized by their clear clinical actionability.”
Results
Approximately 10% of patients in the analysis had a PGV, with PGV prevalence of 8.6% in the discovery cohort and 11.5% in the replication cohort.
PGV-As occurred among 3.6% of patients in the discovery cohort and 4.1% of those in the replication cohort.
Researchers found variants in 20 different genes, including BRCA1, BRCA2, CHEK2, ATM, TP53 and PALB2.
Researchers concluded both BRCA1 and BRCA2 have associations with increased multiple myeloma risk, Onel said.
It is “100%” possible variants in other genes may increase multiple myeloma risk, Onel said; however, lack of data meant the study did not have sufficient power to identify those associations.
Adults with PGV-As appeared significantly more likely than non-carriers to have first- or second-degree relatives with a cancer history (discovery cohort: 81% vs. 55%; OR = 3.8; 95% CI, 1.3-10.7; replication cohort: 85% vs. 62%; OR = 3.4; 95% CI, 1.1-10.1).
A higher percentage of individuals with PGV-Bs or PGV-Cs than non-carriers had a first- or second-degree relative with a history of cancer in the discovery cohort only (66% vs. 55%; OR = 2.2; 95% CI, 1.1-4.4).
In the entire cohort, patients with PGV-As had a higher likelihood than non-carriers of having a personal cancer history at the time of their multiple myeloma diagnosis in both cohorts (14.3% vs. 5.6%; OR = 2.7; 95% CI, 1.3-5.7).
Individuals with PGV-Bs or PGV-Cs had a greater chance than non-carriers of having a personal cancer history at the time of their multiple myeloma diagnosis in the replication group only (26% vs. 9%; OR = 3.7; 95% CI, 1.9-7.1).
Overall, adults with PGV-As had been diagnosed with multiple myeloma at younger ages than noncarriers (median age at diagnosis, 59 years vs. 62 years; P = .04).
“The findings disproportionately are important for younger patients and patients with family histories of cancer,” Onel said.
An analysis of outcomes for patients who received high-dose melphalan and autologous stem cell transplantation as part of front-line therapy showed those with PGV-A achieved significantly longer PFS than those who had no variant (median, 6 years vs. 3.7 years; HR = 0.47; 95% CI, 0.26-0.84).
An analysis of patients who did not receive high-dose melphalan and autologous stem cell transplantation showed comparable PFS among those who had PGV-As and those who had no variant.
“This may help a physician personalize and develop more precise therapies for these patients,” Onel said. “In other cancers, there are some medicines like [poly(ADP)-ribose polymerase (PARP)] inhibitors that are most effective for patients who have pathogenic variants in BRCA1 and BRCA2. It may open the therapeutic armamentarium.”
‘Critically important’ for care
More research is needed to answer several other questions, Onel said.
“First, I want to know if these other genes are potentially associated with an increased risk for myeloma, [such as] PALB2 or TP53,” he said. “Can we put together other large sample sets of patients with myeloma to ask whether these other associations with these specific genes are real? Can we expand the spectrum of cancers that are associated with these other conditions?”
Onel also said he would like to see more research into the mechanism behind these associations, as well as the optimal therapies.
“How can we use this information to best treat patients?” he said. “Understanding how these genes work to defend against cancer, and what goes wrong that leads to cancer in people who have these predispositions, is critically important to figuring out how to care for them.”
For more information:
Kenan Onel, MD, PhD, can be reached at kenan.onel@roswellpark.org.
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