Inherited Changes in BRCA Genes Linked to Increased Risk of Multiple Myeloma

• Pathogenic germline variants in BRCA1 and BRCA2 linked to early-onset disease
• About 10% of multiple myeloma patients carry variant in hereditary cancer gene
• Study and Spotlight commentary appear in Blood Cancer Discovery

BUFFALO, N.Y. - A significant number of multiple myeloma patients may have an inherited but previously unrecognized risk of developing the disease - a type of blood cancer that affects plasma cells. That's the finding of a genetic study that is the first to definitively associate multiple myeloma risk with inherited differences in the BRCA1 and BRCA2 genes. The study also suggests that genetic testing for young or newly diagnosed patients could help clinicians identify the most promising treatment option for those patients.

Led by 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, the study was published Sept. 16 by Blood Cancer Discovery, a journal of the American Association for Cancer Research (AACR).

BRCA genes are responsible for repairing DNA and preventing tumors from forming. Mutations in those genes can allow cells to grow out of control, raising the risk of breast, ovarian, prostate and pancreatic cancers, among others. The study found that, compared with healthy subjects, multiple myeloma patients were more likely to have pathogenic germline variants (PGVs) - inherited changes that can increase cancer risk - in the BRCA1 and BRCA2 genes.

While multiple myeloma affects mostly older adults - 95% are over 50 - Dr. Onel and his colleagues discovered that patients whose BRCA genes contained PGVs, which dramatically increase cancer risk, were more likely to be diagnosed at a younger age and to have a personal or family history of cancer.

The team also found that patients with PGVs were more likely to benefit from therapy that included the alkylating chemotherapy melphalan (brand name Alkeran) along with autologous stem cell transplant, the only curative multiple myeloma treatment. The study authors conclude that genetic testing should be considered for young or newly diagnosed patients who have a personal or family cancer history, to guide treatment decisions and gauge family members' cancer risk.

"Increasingly we're seeing that cancer predisposition matters when it comes to cancer treatment," says Dr. Onel. "This expands the therapeutic options we have for these patients."

He notes that multiple myeloma is a rare disease, so he and his colleagues were fortunate to have access to the two largest multiple myeloma datasets in the world. They provided data for a total of 1,681 patients - 895 in the CoMMpass℠ Study of the Multiple Myeloma Research Foundation (MMRF) and replication data from another 786 at Tisch Cancer Institute at Mount Sinai in New York City that were used to verify findings from the CoMMpass data. The data included information about patients' tumors, treatments and post-treatment outcomes.

"The study highlights yet again how important genetics is to both the diagnosis and treatment of cancer," says Dr. Onel.

Also key to this effort were first author Santiago Thibaud, MD, and co-senior author Samir Parekh, MD, from the Icahn School of Medicine at Mount Sinai, New York City, and collaborators from the Mount Sinai's Tisch Cancer Institute. Blood Cancer Discovery also published today an In the Spotlight commentary from Brian Walker, PhD, of the Indiana University School of Medicine.

The first of its kind in the nation, Roswell Park's new Department of Clinical Genomics focuses on diagnosing and caring for patients whose genetics or family history increase their risk of cancer.

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From the world's first chemotherapy research to the PSA prostate cancer biomarker, Roswell Park Comprehensive Cancer Center generates innovations that shape how cancer is detected, treated and prevented worldwide. Driven to eliminate cancer's grip on humanity, the Roswell Park team of 4,000 makes compassionate, patient-centered cancer care and services accessible across New York State and beyond. Founded in 1898, Roswell Park was among the first three cancer centers nationwide to become a National Cancer Institute-designated comprehensive cancer center and is the only one to hold this designation in Upstate New York. To learn more about Roswell Park Comprehensive Cancer Center and the Roswell Park Care Network, visit www.roswellpark.org, call 1-800-ROSWELL (1-800-767-9355) or email [email protected].