Unveiling the Discrepancy in Multiple Myeloma Risk Classification between Clinical Practice and SKY92 Test and the Impact on Survival
Authors: Biran Noa , Dhakal Binod , Niesvizky Ruben , Lentzsch Suzanne , McKay John T. , Vesole David H. , Nooka Ajay K. , Paul Barry , Hari Parameswaran N. , Stork-Sloots Lisette , D'Ambrosi Silvia , Kuiper Rowan , van Vliet Martin , Siegel David S. , Usmani Saad Z , van Rhee Frits 
Published: December 2023

Introduction:Despite the advancements in therapeutic approaches for multiple myeloma (MM), which have led to improve the survival rates, a subset of high-risk patients still faces limited benefits from current treatments. Therefore, it is crucial to accurately identify specific patient groups who would benefit from tailored therapies through risk stratification. In this study, we aim to assess the risk classification of patients based on conventional risk markers currently used in clinical practices and with the gene expression profiling (GEP)-based SKY92 risk classifier (SkylineDx, San Diego). This approach could provide further insights for optimizing risk-adapted treatment compared to the standard guidelines used in clinical practice.
Methods: The PRospective Observational Multiple Myeloma Impact Study (PROMMIS; NCT02911571) trial, a prospective US multicenter study, enrolled a total of 251 newly diagnosed MM patients (NDMM). The patients underwent risk stratification using two distinct approaches. Firstly, physicians assessed their risk of progression at the time of diagnosis according to their routine practice guidelines. Then, the patients were classified into risk groups using the SKY92 molecular test. The analysis involved the processing of RNA extracted from CD138-positive plasma cells (≥80% purity), which were isolated through immunomagnetic separation. SKY92 test was carried out either at the enrolling institute or by sending samples to a central laboratory. For 221 patients, progression-free survival (PFS) and overall survival (OS) data were available, with measurements taken from date of diagnosis; the median follow-up period was 38 months. Survival analysis was performed utilizing Cox proportional hazards model.
Results: Based on conventional risk classification, 123 (49%) NDMM were classified as standard-risk and 128 (51%) patients as high-risk. However, SKY92 yielded a noticeable difference in classification, with 179 (71%) patients being categorized as standard-risk and 72 (29%) patients as high-risk. In specific 23 standard-risk and 79 high-risk (n=102, 41%) patients accordingly with clinical practice assessment were classified differently by the SKY92 test.
Standard-risk and high-risk groups identified by current clinical practice classification showed a significant difference in PFS (HR: 1.6, 95%CI 1.0-2.4, p=0.031), but not in OS (HR: 1.9, 95%CI 0.9-4.0, p=0.10). With SKY92 risk stratification, instead, a significant difference was observed between the two risk groups in both PFS (HR: 2.1, 95%CI 1.4-3.1, p&lt;0.001) and OS (HR: 3.7, 95%CI 1.8-7.6, p&lt;0.001); furthermore, the median PFS for standard-risk and high-risk patients was, respectively, 50 and 26 months. The median OS was not reached within the 60-month timeframe for both groups.
For the n=221 MM patients with survival data, we observed that most patients classified as standard-risk based on clinical practice classification were also categorized as standard-risk according to SKY92 analysis (83 out of 105, 79%). However, among those initially identified as high-risk by conventional risk classification, 71 out of 116 (61%) patients exhibit no significant difference in PFS (HR: 1.1, 95%CI 0.6-1.8, p=0.8) and OS (HR: 0.6, 95%CI 0.2-1.9, p=0.4) when compared to standard-risk patients, as determined by both risk classification methods ( Figure 1). Conversely, only 22 out of 72 (30%) patients initially identified as high-risk by SKY92 and as standard-risk by clinical practice show no significance difference for PFS (HR: 1.1, 95%CI 0.5-2.4, p=0.8) and OS (HR: 0.9, 95%CI 0.2-4.1, p=0.9) compared with standard-risk patients determined by both tests. Forty-five patients identified as HR by both risk classification methods show highly significant differences for PSF (HR: 2.9, 95%CI 1.7-4.9, p&lt;0.001) and OS (HR: 4.1, 95%CI 1.8-9.6, p&lt;0.001) compare with standard-risk group.
Conclusions: These findings based on prospective real-world clinical data, collected in a prospective US multicenter trial confirm the effectiveness of the GEP SKY92 on risk stratification both for PFS and OS. These results support the added value of integrating SKY92 into clinical practice for precise risk assessment of patients.
Figure1: PFS and OS based on the combination of the clinical risk assessment (CRA) and the SKY92 risk.