Gene Activity Patterns Identify Ultra-High-Risk Multiple Myeloma

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Micrograph of myeloma neoplasm from bone marrow biopsy
Micrograph of myeloma neoplasm bone marrow biopsy. Kappa positive insitu hybridization (ISH positive)

Patterns of unusual gene activity and gene mutations may lead to a new way to detect newly diagnosed multiple myeloma (NDMM) patients at ultra high-risk for aggressive disease progression and risk of death early in the course of their disease.

Those patients had a much poorer survival than average and are unlikely to benefit from lenalidomide maintenance monotherapy, an important drug treatment for multiple myeloma.

The prognosis for newly diagnosed multiple myeloma (NDMM) has improved with the advent of new agents, but outcome in some patients remains very poor. A partial explanation made have been found from researchers from the Institute of Cancer Research (ICR) who studied 329 patients in the Phase III Cancer Research UK Myeloma XI trial, designed to study the effectiveness of several drug treatments against newly diagnosed multiple myeloma. Their results are published in a paper in Leukemia.

They found that one quarter of the patients, 81 of 329 patients, had cancers with the SKY92 signature—a pattern of gene activity involving 92 genes linked to high-risk status. The SKY92 gene expression profiling test, also known as MM Profiler, is commercially available and used in MM clinical trials to identify patients with increased risk of disease progression.

Biomarkers including chromosomal aberrations t(4;14), t(14;16), and t(14;20) translocations, gain of 1q and deletion of 17p have been associated with adverse outcome in multiple myeloma and the occurrence of two or more such aberrations (a double-hit) is predictive of especially aggressive disease. In their analysis ICR researchers focused on identifying these high-risk chromosomal anomalies and SKY92 gene expression patterns.

The researchers found that SKY92 NNDM high-risk patients had significantly shorter progression-free survival (median 16.0 vs. 33.8 months) and overall survival (median 36.7 months vs. not reached). Those with the signature  had an up to three-fold increased risk of their cancer returning early. Those with heavily genetically mutated – so called ‘double-hit’ cancers – had a two-fold increased risk of death.

Of the 329 patients, 161 carried no chromosomal high-risk marker, but 20 (12%) were SKY92 high-risk. These patients also had shorter progression-free survival and overall survival.

About 10 percent of the patients had both the SKY92 signature and double-hit genetic features. all patients in this group progressed within 48 months from initial randomization- as opposed to much longer responses in other groups. Patients with ultra high-risk disease had an 11-fold increased risk of death compared with other patients.

The ICR researchers found that patients in this ultra high-risk group were highly unlikely to benefit from lenalidomide maintenance therapy.

Because people with ultra-high-risk myeloma need more effective treatments, the ICR researchers will test several new drug cocktails in a new OPTIMUM clinical study. The OPTIMUM study will include 470 patients to find alternative treatment options for people with high-risk myeloma.

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