Radiomics-Based Biomarkers for Risk Stratification in Newly Diagnosed Multiple Myeloma

Introduction: In myeloma, accurate risk stratification remains a challenge due to substantial biological heterogeneity and highly variable survival outcomes. Cross-sectional imaging is commonly obtained at the time of diagnosis, but imaging findings are not currently incorporated into risk stratification efforts in a standardized manner, despite their prognostic significance. Here, we investigate the use of novel image-based prognostic biomarkers obtained by automated image segmentation and radiomics feature extraction using machine learning methods.

Methods: We obtained the pre-treatment 18F-FDG PET/CT scans of 443 patients with newly diagnosed myeloma and complete demographic and cytogenetic data (seen at Mayo Clinic between 2005 and 2019). The native DICOM images were pre-processed and subjected to automated image segmentation using nnU-Net (v1.0, inference using a pre-trained hematologic malignancies model). Limitations of this automated segmentation approach include heterogeneity introduced by varying image quality, technical differences related to PET reconstruction, and potential inclusion of non-neoplastic FDG-avid lesions in segmented regions. The quality of the automated image segmentation was evaluated by comparing the radiomics features obtained from ground-truth segmentation (manual lesion segmentation) and model segmentation in a separate cohort of patients with hematologic malignancies (n=72). We selected 42 radiomics features that moderately (r≥0.30, p<0.005, n=23) or strongly (r≥0.50, p<0.001, n=19) correlated between ground-truth (manual) and model (automated) segmentation for further evaluation in myeloma patients. PyRadiomics was used to extract discrete radiomics features for clinical prediction modeling. We evaluated the prognostic significance of tumor size-, shape-, and texture-related radiomics features and compared their predictive power to established prognostic factors (International Staging System [ISS], Revised ISS [R-ISS] stage and high-risk FISH cytogenetics). The outcome of interest was overall survival and the predictive power of competing proportional hazards regression models was assessed using Harrell's C-statistic. For modeling purposes, patients without measurable tumor volume were categorized as having undetectable radiomics features (0 for all features). All radiomics features were median dichotomized for downstream modeling. Forward feature selection and testing for multicollinearity were used to remove redundant features. Select radiomics features were divided into quintiles to generate an additive radiomics risk score and associated risk strata.

Results: Median age at diagnosis of the 443 myeloma patients was 63 years (32-91) and 270 patients (62%) were men. After a median follow-up of 2.4 years (95% CI 0.1-7.4), median overall survival was 6.5 years (95% CI 5.5-NR). Most patients had detectable metabolic tumor volume (n=309, 70%) on their pre-treatment 18F-FDG PET/CT scan. Several of the 42 radiomics features were intercorrelated and two features were selected for further investigation based on their independent prognostic significance (forward feature selection). Higher maximum axial tumor diameter (HR 1.90, 95% CI 1.31-2.76, p=0.001) and a lower concentration of low gray-level values in the tumor (HR 1.73, 95% CI 1.20-2.49, p=0.004) were independently associated with overall survival in newly diagnosed myeloma. These associations were independent of age at diagnosis, sex, and R-ISS stage. We devised a simple additive risk score representing the sum of quintiles of the two radiomics features and divided the patients into three risk categories akin to the R-ISS. The predictive power of this radiomics risk score (Harrell's C=0.60) was comparable to the ISS (C=0.59) and the R-ISS (C=0.57).

Conclusions: Automated image segmentation and radiomics feature extraction from 18F-FDG PET/CT scans is feasible. This approach yields image-based biomarkers that correlate with results obtained by manual imaging segmentation. Several radiomics features such as tumor size and heterogeneity have independent prognostic significance in newly diagnosed myeloma. These novel biomarkers rival the predictive power of the currently established risk stratification methods and may be used to improve risk stratification in myeloma.

Kourelis:Novartis: Research Funding; Pfizer: Research Funding. Gertz:Astra Zeneca: Honoraria; Dava Oncology: Honoraria; Sanofi: Other: personal fees; Alexion: Honoraria; Johnson & Johnson: Other: personal fees; Abbvie: Other: personal fees for Data Safety Monitoring board ; Janssen: Other: personal fees; Prothena: Other: personal fees; Alnylym: Honoraria; Ionis/Akcea: Honoraria; Medscape: Honoraria. Fonseca:Celgene, Bristol Myers Squibb, Bayer, Amgen, Janssen, Kite, a Gilead company, Merck Sharp & Dohme, Juno Therapeutics, Takeda, AbbVie, Aduro Biotech, Sanofi, OncoTracker: Honoraria; AbbVie, Adaptive, Amgen, Apple, Bayer, BMS/Celgene, Gilead, GSK, Janssen, Kite, Karyopharm, Merck Sharp & Dohme, Juno Therapeutics, Takeda, Arduro Biotech, Oncotracker, Oncopeptides, Pharmacyclics, Pfizer, RA Capital, Regeneron, Sanofi: Consultancy; Antengene: Membership on an entity's Board of Directors or advisory committees; Patent for FISH in MM - ~$2000/year: Patents & Royalties: Patent for FISH in MM - ~$2000/year. Dasari:The Binding Site: Patents & Royalties: Intellectual Property Rights licensed to Binding Site with potential royalties. Kumar:Sanofi: Research Funding; Oncopeptides: Other: Independent review committee participation; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune/AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Roche: Research Funding; Celgene: 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; Janssen: 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.