Genetic Test Identifies Ultra-High-Risk Myeloma Patients

Liam Davenport

April 13, 2020

A new test can identify patients with multiple myeloma (MM) who have a high-risk genetic profile as well as multiple chromosomal abnormalities. In this subgroup of patients with ultra-high-risk MM, disease progression is increased, survival is very poor, and it is unlikely that patients will respond to a commonly used maintenance therapy, British researchers report.

The research was published online in Leukemia on March 11.

"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," commented lead author Martin Kaiser, MD, PhD, team leader in myeloma molecular therapy at the Institute of Cancer Research (ICR), London.

Patients with "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," he added in a statement.

The research team used a doubled-pronged approach to identify patients at increased risk.

Numerous chromosomal abnormalities, such as aberrations, translocations, gains, and deletions, are known to be associated with adverse outcomes in MM, and having two or more of those, known as a "double hit," is predictive of aggressive disease, they explain.

Separately, various gene expression profiles (GEPs) have been linked to MM outcomes with the SKY92 MMprofiler (SkylineDx), which measures the activity of 92 cancer genes and has been validated as a prognostic test.

In examining the combined predictive value of both of these approaches, the research team used data on almost 329 patients with newly diagnosed MM.

They found that patients with a high-risk SKY92 signature alone had a threefold increased risk for progression in comparison with those who did not have the signature, and their risk for death was more than doubled.

Moreover, patients who had both a SKY92 high-risk signature and a chromosomal double hit had a more than fourfold increased risk for progression and an 11-fold increased risk for death compared with those who had no risk markers.

Commenting on the research, Paul Workman, PhD, chief executive of the ICR, said this study "shows how it is possible to use genetic information to divide patients with bone marrow cancer into different disease subtypes and to plan treatment accordingly."

Sarah McDonald, director of research at Myeloma UK, commented that "myeloma isn't a 'one-size-fits-all' cancer, and treatment needs to become more personalized."

Consequently, the "innovative research undertaken by the ICR team is a huge step forward," she 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," she said.

Study Details

For their study, the researchers used data from the Meyloma XI trial, which compared thalidomide and lenalidomide combination therapies in the treatment of MM.

They included data on 329 patients newly diagnosed with MM who received intensive therapy and were assessed for chromosomal abnormalities and GEP risk status. The majority of patients (59.9%) were male, and 24.6% were older than 65 years at randomization.

Eighty one (24.6%) patients were found to have a SKY92 high-risk tumor signature.

In this group of 81 patients, in comparison with other patients, progression-free survival (PFS) was significantly shorter, at 16.0 months vs 33.8 months (hazard ratio [HR] on multivariate analysis, 2.14; P < .00001), and overall survival was significantly shorter, at 36.7 months vs not reached (HR, 2.72; P < .00001).

Moreover, the team found that patients with the SKY92 high-risk profile did not derive any statistically significant benefit from being treated with lenalidomide single-agent maintenance therapy.

Among the 161 patients with no high-risk chromosomal abnormalities, 20 (12%) had a high-risk disease profile on SKY92. This was associated with significantly shorter PFS (HR, 3.18; P < .0001) and overall survival (HR, 2.42; P = .04).

As expected, the presence of double-hit chromosomal abnormalities was predictive of both PFS and overall survival. The researchers divided the patients into four risk groups:

  • double hit and SKY92 high-risk signature (9.7%);

  • double hit or SKY92 high-risk signature (23.4%);

  • a single chromosomal high-risk marker (24.0%); and

  • no risk marker (42.9%).

For those who had a single risk marker, overall survival was reduced compared to people with no risk marker (HR, 1.88; P = .03).

In comparison to those who had no risk marker, for those with a double hit or a SKY92 signature, PFS was shorter (HR, 2.34; P < .0001), and overall survival was reduced (HR, 3.8; P < .0001).

For patients who had both a chromosomal double hit and a SKY92 high-risk profile, there was an even greater reduction in PFS in comparison with those with no risk marker (HR, 4.50; P < .0001), and there was a marked reduction in overall survival (HR, 10.98; P < .0001).

Treatment with lenalidomide single-agent maintenance therapy extended PFS in individuals with no risk markers and those with a single high-risk marker, but it did not benefit those in the SKY92 and/or double-hit groups.

Moreover, the team found that all patients with both a double-hit chromosomal profile and a high-risk status on SKY92 experienced disease progression within 48 months of initial randomization. The predicted overall survival at that time was 12.5%.

"Our results demonstrate that patients with double-hit or GEP high-risk status are unlikely to benefit from current treatment approaches, including single agent lenalidomide maintenance therapy," the researchers comment.

"In such patients, intensified ongoing therapy with combination agents may be beneficial," they add.

The next step will be for the researchers to combine the results from their study with those of the ongoing OPTIMUM trial. This "will provide us with more information on how to tailor treatment for patients at ultra–high risk based on genetic information," Kaiser commented.

The study was funded by Myeloma UK and the National Institute of Health Biomedical Research Center at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research. Further support was provided by Cancer Research UK and the Jacquelin Forbes-Nixon Fellowship. Kaiser has relationships with Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, and Celgene. Other authors also report relationships with pharmaceutical companies.

Leukemia. Published March 11, 2020. Full text

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