Dr Biran on the Real-World Performance of SKY92 Gene Expression Profiling for Risk Stratification in Multiple Myeloma

“[In] patients who [met] discordant definitions of high risk by IMS [criteria] and SKY92, the patients who [were classified as high risk per] SKY92, no matter whether they were standard risk or high risk by IMS, [had] adverse outcomes.”

Noa Biran, MD, medical director of Clinical Protocol Data Management and an assistant professor of medicine in the Division of Multiple Myeloma at the Hackensack Meridian Health John Theurer Cancer Center, discussed findings from the prospective PROMMIS study (NCT02911571) evaluating the real-world performance of the SKY92 gene expression profiling assay for risk stratification in multiple myeloma and its comparison with contemporary International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) risk criteria.

The PROMMIS study was designed to address a persistent challenge in multiple myeloma management: accurately identifying patients with biologically high-risk disease using tools that can meaningfully inform prognosis and treatment intensity. Traditional risk stratification relies on clinical and cytogenetic features incorporated into IMS and IMWG criteria; however, these approaches may not fully capture underlying tumor biology. SKY92, a 92-gene expression profiling assay, was evaluated as a complementary and potentially more precise method of defining high-risk disease.

A central finding of the study was a substantial discordance between risk classification by IMS criteria and SKY92. Approximately 30% of patients demonstrated discordant risk assignment, meaning they were classified as high risk by IMS criteria but standard risk by SKY92, or vice versa. This discordance highlighted that the 2 systems capture overlapping but distinct biological and clinical information.

Importantly, outcome analyses demonstrated that SKY92 risk status was independently prognostic. Patients classified as high risk by SKY92 experienced adverse outcomes regardless of their IMS-defined risk category. Whether a patient was considered standard risk or high risk by IMS criteria, SKY92 high-risk status consistently identified a subgroup with inferior clinical outcomes. In contrast, patients who were IMS high risk but SKY92 standard risk did not uniformly experience the same degree of adverse prognosis.

These findings suggest that SKY92 may provide more biologically relevant risk stratification than conventional approaches alone, according to Biran. Rather than simply refining existing classifications, SKY92 appears to identify a subset of patients with intrinsically aggressive disease biology that is not always apparent through cytogenetics or clinical staging, she stated. Biran emphasized that this independent prognostic value supports the assay’s potential role as either a complementary or, in some cases, a more informative tool than standard risk definitions.