Genes identify ‘ultra-high risk’ multiple myeloma

A novel test could identify myeloma patients who have a lower chance of survival and unlikely to benefit from lenalidomide, British researchers have announced.

A team from the Institute of Cancer Research (ICR) in London examined the genetics of 329 patients who took part in the Myeloma XI trial. The trial looked at the effectiveness of a range of targeted drugs, including lenalidomide, for patients newly diagnosed with multiple myeloma.

The research team looked for patterns of abnormal gene activity and genetic mutations of the cancers. Their analysis identified a group at ‘ultra-high risk’, representing 10% of all patients, with an 11-fold increased risk of death.

Writing in the journal Leukemia, the researchers set out to assess the prognostic information revealed by the SKY92 gene expression signature test, as well as by high-risk chromosome alterations such as t(4;14), t(14;16), t(14;20), gain(1q), and del(17p).

Patients with the SKY92 genetic signature had a nearly three-fold increased risk of early relapse. Those with heavily mutated ‘double-hit’ form of the cancer had a two-fold increased risk of mortality.

The team then combined both these markers to attempt to predict the outcome for patients more accurately than before. This led to them to identify the ‘ultra-high risk’ group, who had both a high-risk SKY92 signature and ‘double-hit’ genetic features. All patients within this group saw their cancer progress within four years on current standard therapies, such as lenalidomide.

The researchers believe that new combinations of targeted therapies are now needed to keep their cancer at bay, and will be testing such an approach in the OPTIMUM trial.

Dr Martin Kaiser from the ICR, who led the research,  said: “Our study shows that people whose cancers have an ‘ultra-high risk’ combination of genetic features have particularly aggressive disease which doesn’t respond sufficiently to standard treatment to keep their cancer at bay.

“Testing for high-risk genetic features could help target myeloma treatment, focusing on the specific needs of each patient. 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.”

Source: Shah V, Sherborne AL, Johnson DC, Ellis S, Price A, Chowdhury F, Kendall J, Jenner MW, Drayson MT, Owen RG, Gregory WM, Morgan GJ, Davies FE, Cook G, Cairns DA, Houlston RS, Jackson G, Kaiser MF; on behalf of NCRI Haematology Clinical Studies Group (2020) “Predicting ultrahigh risk multiple myeloma by molecular profiling: an analysis of newly diagnosed transplant eligible myeloma XI trial patients”, Leukemia, doi: 10.1038/s41375-020-0750-z