Genetic Test May Help Identify Ultra High-risk Multiple Myeloma

A novel genetic test could help identify people with multiple myeloma who are at highest risk of aggressive disease and unlikely to respond to standard treatment with Revlimid (lenalidomide), a new study shows.

The study, “Predicting ultrahigh risk multiple myeloma by molecular profiling: an analysis of newly diagnosed transplant eligible myeloma XI trial patients,” was published in Leukemia.

Being able to identify those individuals with cancer that is likely to be more aggressive or unresponsive to therapies can help inform the treatment decisions of healthcare professionals. One way to do this is by looking at genetic markers in cancer cells.

For multiple myeloma, the most commonly used genetic markers of this sort are chromosomal aberrations — that is, large changes in DNA molecules. Cancers with two or more of these aberrations, termed “double-hit,” are especially likely to be aggressive.

Changes in gene expression (which genes are turned “on,” and to what extent) can also be used to predict the behavior of cancer.

In the new study, researchers assessed the utility of one such gene expression signature, SKY92, which reflects the activity of 92 genes known to have altered activity in aggressive multiple myeloma. This gene expression signature can be measured with MMprofiler, a technology produced by SkylineDx, which was not affiliated with this study.

The researchers looked at outcomes for 329 people with multiple myeloma who took part in the Myeloma XI Phase 3 clinical trial (NCT01554852). This trial evaluated the efficacy of several therapies, most notably Revlimid, in people with newly diagnosed multiple myeloma.

The MMprofiler analysis revealed that 81 of the trial participants had the SKY92 high-risk signature. These individuals lived significantly less time without disease worsening (median 16 months vs. 33.8 months) and lived a median of 36.7 months after entering the trial, while more than half of patients without this gene signature were still alive.

Additionally, individuals with the SKY92 high-risk signature derived no statistically significant benefits from treatment with Revlimid as a single agent.

The aforementioned chromosomal aberrations were also significantly predictive of less time without disease progression and lower survival rates.

The predictive power of the SKY92 signature and these chromosomal aberrations could be further increased by combining the two markers. For instance, the individuals with “double-hit” tumors who also had the SKY92 high-risk signature were at 4.5 times higher risk of cancer progression and at 11 times higher risk of death, than those with neither marker.

“Our results demonstrate the prospective prognostic validity of SKY92 profiling in the wider context as a means of identifying patients at diagnosis who have high-risk MM, and show the independent association of SKY92 and high-risk chromosomal aberrations with outcome,” the researchers wrote.

In a clinical setting, these kind of genetic tests could be employed to help guide individualized treatment plans.

“Testing for high-risk genetic features could help target myeloma treatment, focusing on the specific needs of each patient,” study co-author Martin Kaiser, MD, researcher at The Institute of Cancer Research, in London, said in a press release. “Not all patients with myeloma are the same, and we know that by better understanding their cancer’s genetic and molecular features, we can tailor their treatment much more effectively.”

“The publication by this esteemed group of researchers and clinicians is the independent confirmation that molecular biomarkers like SKY92 need to be adopted in clinical practice to avoid true fast progressing high-risk patients being missed at diagnosis,” Dharminder Chahal, CEO of SkylineDx, said in a separate press release.

The researchers intend to build off of these findings in an ongoing Phase 2 clinical trial, OPTIMUM (NCT03188172). The idea is to explore a particularly aggressive treatment — Revlimid plus Velcade (bortezomib), Darzalex (daratumumab), dexamethasone, and low-dose cyclophosphamide — in  individuals who are identified as being at the highest risk.

Results from this study, which is currently recruiting at the University of Leeds in the United Kingdom, “will provide us with more information on how to tailor treatment for patients at ultra high risk based on genetic information,” Kaiser said.

Sarah McDonald, director of research at Myeloma UK, added: “The ability to identify high-risk patients means they can receive the intensive treatment they need sooner and enables further study of this cohort to develop new treatment approaches which can improve patient survival.”