Introduction: Multiple myeloma (MM) is a complex hematologic malignancy characterized by genetic instability, variable survival rates, and diverse treatment responses. SKY92 gene expression profiling (GEP) is a valuable tool in risk stratifying patients into high-risk and standard-risk groups for progression and survival. The PRospective Observational Multiple Myeloma Impact Study (PROMMIS; NCT02911571) trial, a prospective US multicenter study, was designed to validate the prognostic performance of SKY92 through real-world data.

Methods: The GEP of 251 newly diagnosed MM patients was assessed using the SKY92 assay (SkylineDx, San Diego), which involved analyzing RNA extracted from CD138-positive plasma cells (≥80% purity) isolated through immunomagnetic separation. The test was performed at the enrolling institute, or by sending the samples into a central lab. The standard method for risk stratification by R-ISS stage was integrated with SKY92 into three distinct groups: Low-Risk (LR), defined by SKY92 standard-risk (SR) combined with R-ISS I; Intermediate Risk (IR), as SKY92 SR with R-ISS II/III, or SKY92 high-risk with R-ISS I; and High-Risk as SKY92 high-risk with R-ISS II/III. Progression-free survival (PFS) and overall survival (OS) were available for 221 patients, measured from the date of diagnosis of the patients. The median follow-up at the time of analysis is 38 months. Survival analyses were performed using Cox proportional hazards model.

Results: Upon analysis, 179 patients (71.3%) were classified as SKY92 standard-risk, and 72 patients (28.7%) as SKY92 high-risk. Notably, the percentage of high-risk patients in this study was slightly higher than that observed in previous retrospective analyses (15-25%).

Furthermore, the survival analysis revealed significant differences in both PFS (HR: 2.1, 95%CI 1.4-3.1, p<0.001) and OS (HR: 3.7, 95%CI 1.8-7.6, p<0.001) between the two risk categories. The median PFS from the time of the diagnosis for SKY92 standard-risk patients was 50 months, whereas for SKY92 high-risk patients, it was 26 months. The median OS was not reached within the 60-month timeframe for both the standard- and high-risk groups.

R-ISS could be determined for 204 patients (81%), of which 29.9% (n=61) were classified as stage I, 59.3% (n=121) as stage II, and 10.8% (n=22) as stage III. We integrated R-ISS staging with SKY92 classification for these patients. The combination of these two classification systems yielded the following stratification ( Figure 1): LR n=53 (27%), IR n=96 (47%), and High-Risk n=55 (26%). Consistent with previous studies, R-ISS and SKY92 hold independent prognostic value: in particular, we found that this combined classification method identified a higher number of patients as high-risk compared to the R-ISS annotation (55 [27%] vs. 22 [11%]). The high-risk group exhibited significantly shorter OS and PFS compared to the LR group (OS: HR:18.7, 95% CI 2.5-140, p=0.004 and PFS: HR:2.6, 95% CI 1.4-4.7, p=0.002).

Conclusions: This study represents the first US-based multicenter prospective evaluation of the GEP SKY92 in a real-world clinical setting. The results obtained align with the retrospective validations of SKY92, further confirming its reliability as a prognostic marker for MM patients. In addition, we observed that the SKY92 is able to identify a higher number of high-risk patients, with significantly shorter PFS and OS, compared to the conventional R-ISS staging system.

Figure 1: PFS and OS based on SKY92+R-ISS risk classification

Biran:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; abbvie: Honoraria; Genomic testing cooperative: Divested equity in a private or publicly-traded company in the past 24 months; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Other: spouse of employee. Dhakal:Janssen, Karyopharm, GSK, Arcellx, GSK, Sanofi, Genentech, Pfizer: Consultancy, Honoraria, Speakers Bureau. Lentzsch:Janssen: Membership on an entity's Board of Directors or advisory committees; Caelum Biosciences: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: January 1, 2041; Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; Pfizer: Consultancy; Oncopeptide: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Clinical Care Options: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. McKay:BMS: Consultancy. Nooka:Aduro Biotech, Amgen, Arch Oncology, Bristol Myers Squibb, Cellectis, Genentech, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharma, Merck, Pfizer, Takeda: Honoraria, Research Funding; Adaptive Biotechnologies, Amgen, BeyondSpring, Bristol Myers Squibb, Cellectar Biosciences, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, ONK therapeutics, Pfizer, Sanofi, Secura Bio, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Paul:Janssen: Membership on an entity's Board of Directors or advisory committees. D'Ambrosi:SkylineDx: Current Employment. Kuiper:SkylineDx: Current Employment. van Vliet:SkylineDx: Current Employment. Siegel:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celularity Scientific: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Usmani:GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Moderna: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; K36 Therapeutics: Membership on an entity's Board of Directors or advisory committees; SecuraBio: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SkylineDX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; EdoPharma: Membership on an entity's Board of Directors or advisory committees; TeneoBio: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. van Rhee:Janssen Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; GlaxoSmithKline: Consultancy; Adicet Bio: Consultancy; EUSA Bio: Consultancy.

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2023
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