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Genetic Heterogeneity of Multiple Myeloma Must Be Considered in Treatment Decisions

Value-Based Care in Myeloma - Multiple Myeloma
Caroline Helwick

The most comprehensive genetic study of multiple myeloma to date reveals that the genetic landscape of this malignancy may be more complicated than previously thought. The research, published in Cancer Cell (Lohr JG, et al. 2014;25:91-101), shows that individual tumors harbor a variety of mutations, including subclonal populations, and this has strong implications for targeted therapies.

“What this new work shows us is that when we treat an individual patient with multiple myeloma, it’s possible that we’re not just looking at one disease, but at many—in the same person, there could be cancer cells with different genetic makeups,” said co–senior investigator Todd R. Golub, MD, Director, Cancer Program, Broad Institute of MIT and Harvard University, Cambridge, MA, who is also the Charles A. Dana Investigator in Human Cancer Genetics, Dana-Farber Cancer Institute, Boston, MA. “These findings indicate a need to identify the extent of genetic diversity within a tumor as we move toward precision cancer medicine and genome-based diagnostics.”

In a detailed study of samples from 203 patients, Dr Golub and colleagues evaluated a large-scale genome sequencing data set in an attempt to understand the timeline of genetic events. They identified frequent mutations in several key genes known to be important in cancer, and found that many of these key mutations were not present in all cancer cells within a tumor but in only a fraction of the cells, a subclonal population.

There were 11 recurrently mutated genes, including 5 previously identified as the most common mutations, in a 38-patient study by the same investigators. These were KRAS, NRAS, FAM46C, DIS3, and TP53; 4 other genes—BRAF, TRAF3, CYLD, and RB1—have been implicated in the pathogenesis of myeloma. In addition, several recurrently mutated and biologically relevant genes fell just below the significance threshold.

Of the 203 patients in the study—166 (82%) had mutations in 1 or more of the 11 key genes, or mutations of a gene that appeared to be a key player in the disease. The remaining 18% of the tumors lacking these obviously important mutations were likely driven by rare mutations in bona fide driver genes, the investigators suggested.

Some patients had several significant mutations in the same tumor sample. The researchers found no strong association between particular mutations and clinical features, tumor ploidy, or a history of previous treatment.

Therapeutic Implications of the Findings
“The identification of driver mutations in multiple myeloma holds great promise for personalized medicine, whereby patients with particular mutations would be treated with the appropriate targeted therapy,” the researchers reported. “However, if the mutation is present in only a fraction of the cells, one might doubt whether such targeted therapy would be clinically efficacious.”

To investigate this hypothesis and elucidate the treatment implications of their findings, the researchers focused on BRAF, a cancer gene with several known inhibitors. Previous studies indicated that approximately 4% of patients with multiple myeloma may have mutations in this gene, and anecdotally, the use of BRAF inhibitors has shown promise in patients with this mutation. In a laboratory study, however, they found evidence that treating a tumor harboring subclonal BRAF mutations with 1 of these targeted drugs may, at best, kill a fraction of the cells and, at worst, stimulate the growth of another cancer-cell subpopulation.

“There’s clearly potential for these drugs in some patients with multiple myeloma, but we show that there are also potential problems for others,” said lead investigator Jens G. Lohr, MD, PhD, Instructor in Medicine, Dana-Farber Cancer Institute. “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 the inhibitor.”

The existence of these subclonal populations may be an underlying reason for the development of resistance to BRAF inhibitors and other targeted drugs, the researchers proposed.

A Sobering Prediction
The researchers acknowledged that their findings add another layer of complexity to the hope of targeted therapy. “Perhaps the most striking finding of our study was that multiple myeloma tumors are highly heterogeneous,” they wrote. “It is…likely that our finding that multiple myeloma tumor samples contain on average at least 5 subclones underestimates the clonal diversity of the disease.”

The implications for targeted therapy will need further elucidation. “The clonal heterogeneity observed in this study offers a generally sobering view of prospects for predicting the effects of targeted therapy for cancer in general.…At a minimum, we suggest that it will not be sufficient to simply document the presence or absence of mutations in the diagnostic setting.…Effective targeted therapy will require either drug combinations targeting distinct subclones or, more likely, deployment of targeted therapies only in patients for whom the drug target is entirely clonal.”

Dr Lohr emphasized the need for clinical trials. “Matching the right drug to the right patient isn’t as easy as finding a mutation and having a drug that targets it. We have to keep this additional parameter of heterogeneity in mind.”

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Last modified: May 20, 2015
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