Multiple Myeloma Study Shows Widespread Genetic Heterogeneity


Key Points

  • Deep parallel sequencing of paired tumor/normal samples from over 200 patients with multiple myeloma has identified frequent mutations in several key genes known to play a role in the cancer.
  • The study results show that many of these mutations were not present in all cancer cells within a tumor and instead were often found in only a small fraction of cells, known as a subclonal population.
  • The results emphasize the need to identify the genetic diversity within a tumor when making treatment decisions.

A detailed study of tissue samples from more than 200 patients with multiple myeloma has found that an individual patient’s tumor can harbor populations of cancer cells equipped with different mutations. The result could have therapeutic ramifications for future patients, according to study investigators. The study is published in Cancer Cell.

A team of researchers from the Broad Institute of MIT and Harvard, including scientists from Dana-Farber Cancer Institute, performed parallel sequencing of paired tumor/normal samples taken from the patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. They found frequent mutations in KRAS (especially in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3.

The investigators discovered that many of these mutations were not present in all cancer cells within a tumor, but were often found only in a smaller fraction of cells known as a subclonal population. Although many promising therapies used to treat multiple myeloma target a specific genetic mutation, such as BRAF, these findings suggest that such targeted therapies may have limitations in patients whose tumors are made up of these subclonal populations.

The Need for Genomic-Based Diagnostics

To explore some of the therapeutic implications, the researchers performed follow-up laboratory experiments, looking specifically at BRAF, a gene for which several drugs exist. Previous studies have indicated that about 4% of multiple myeloma patients may have mutations in the BRAF gene, and a recent report on a single multiple myeloma patient treated with drugs targeting BRAF showed promising results. However, in the laboratory experiment the investigators found evidence that treating a tumor harboring subclonal BRAF mutations with one of these targeted drugs may kill a fraction of the cells, but also stimulate another cancer cell subpopulation to grow.

“There’s clearly potential for these drugs in some patients with multiple myeloma, but we show that there are also potential problems for others,” Jens Lohr, MD, PhD, co–first author of the study, and an Associated Scientist at the Broad Institute and a medical oncologist at Dana-Farber, said in a statement. “If a patient has a BRAF mutation in less than 100% of his cells, or if he has mutations in KRAS or NRAS at the same time, his oncologist would want to think through the potential pitfalls before giving this inhibitor.”

The study suggests that subclonal populations could be a potential reason why many patients with multiple myeloma relapse following treatment.

“These results emphasize the importance of heterogeneity analysis for treatment decisions,” concluded the researchers.

Todd R. Golub, MD, of the Broad Institute, Dana-Farber Cancer Institute, and Harvard Medical School, is the corresponding author for the Cancer Cell article.

Funding for this study was provided by the Multiple Myeloma Research Foundation and tissue samples were provided by the Multiple Myeloma Research Consortium tissue bank. Additional funding support was provided by the National Institutes of Health and a Conquer Cancer Foundation Young Investigator Award.

All the data generated through this project will be made publicly available to cancer researchers worldwide through the Multiple Myeloma Genomics Portal.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.