Hielscher, Thomas

Abstract Accurate prediction of risk of progression from smoldering (SMM) to active multiple myeloma (MM) is paramount to individualized early therapeutic strategies with minimum risk of overtreatment. Current risk stratification models do not account for evolving biomarker trajectories. We assembled the largest cohort to date of 2,270 SMM patients from six international centers with longitudinal clinical and biological data to train and validate the PANGEA 2.0 risk models. Four evolving biomarkers were significantly associated with shorter time-to-progression: M-protein increase ≥0.2g/dL, involved:uninvolved serum free light chain ratio increase ≥20, creatinine increase >25%, and hemoglobin decrease ≥1.5g/dL. PANGEA 2.0 outperforms established models including the 20/2/20 and IMWG models by more accurately predicting progression (C-statistics=0.69–0.84), even without biomarker history (C-statistics=0.69–0.83) or recent bone marrow biopsy. PANGEA 2.0 is an easy-to-use, open-access tool (https://ghobrial.shinyapps.io/pangea_2_calculator) to improve and individualize SMM risk stratification. Validation tools are available to compare PANGEA 2.0 to established models (https://ghobrial.shinyapps.io/pangea_validation).

Abstract Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Abstract Introduction: For decades conventional skeletal survey (CSS) has been the standard imaging technique for the detection of bone impairment caused by Multiple Myeloma (MM). The development of cross-sectional imaging techniques like Whole Body Computed Tomography (WBCT) with or without Positron Emission Tomography (PET/PET-CT) and magnetic resonance imaging (MRI) led to the use of these techniques in several centers worldwide and to the implementation of their findings into the revised diagnostic criteria of MM. The aim of the current multicenter study was to compare sensitivity and prognostic significance of WBCT and CSS in patients with monoclonal plasma disorders. Methods: For the current retrospective analysis 308 patients with different stages of monoclonal plasma cell disorders from 8 centers were included. Compact discs with pseudonymized imaging data of WBCT and CSS were sent to the organizing center and uploaded to the picture archiving and communication system. In addition, questionnaires were completed by each center to collect clinical data of the patients. Image analysis was performed in consensus reading by three experienced radiologists (LAM, SD, VK) blinded to the clinical data of the patients. Osteolytic lesions in 19 pre-specified anatomic regions were characterized as "definitely present", "probably present", "probably absent" and "definitely absent". For the analysis only "definitely present" and "probably present" entries were counted as myeloma lesions. To define symptomatic or active versus smoldering myeloma based on the presence of bone lesions, findings of CSS were used to simulate the situation before the introduction of WBCT. For comparison of WBCT and CSS only those anatomic regions having valid measurements from both methods performed within 30 days without treatment in the meantime were considered. WBCT and CSS were tested for differences in detection sensitivity with the exact McNemar test. Results: Of 308 submitted datasets; 160 patients were without prior treatment and 56 of them had smoldering myeloma. Of 160 patients 80 (50%) had no osteolytic lesions on either CSS or WBCT and 33 (20.6%) showed osteolyses on both techniques. In 9 patients (5.6%) osteolyses were found on CSS but not in WBCT while 38 patients (23.8%) were positive on CT alone. Of note is that for some CT-scans, the upper extremities were not evaluable due to positioning during the examination. Odds ratio for osteolyses on WBCT compared to CSS was 4.22 (P < 0.0001). The regions where WBCT was most significantly superior in detecting osteolyses were the iliac bone, thoracic and lumbar spine as well as the ribs. CSS compared to WBCT revealed osteolyses in more patients only in the proximal extremities: for left humerus 10 (6.5%) versus 3 (1.9%), right humerus 12 (7.7%) versus 4 (2.6%), left femur 11 (7.1%) versus 7 (4.5%) and right femur 10 (6.5%) versus 8 (5.2%) respectively. Of 157 evaluable patients 63 (40.1%) showed osteoporosis (defined by radiological criteria) on both techniques while 29 (18.5%) had osteoporosis on WBCT only and 10 (6.4%) on CSS only (OR 2.90, P = 0.003). In the 56 patients with smoldering myeloma, with bone disease being defined according to the findings of CSS 12 (21.4%), were positive for osteolyses on WBCT (P = 0.0005). Conclusion: WBCT shows significantly more sites of bone destruction compared to conventional X-ray imaging particularly in skeletal regions composed primarily of trabecular bone while CSS shows more osteolyses in the appendicular skeleton - in part due to a limited field of view. More than 20% of patients with smoldering myeloma based on CSS have active disease that needs treatment based on WBCT. Therefore, WBCT is the current standard for the detection of osteolytic lesions in myeloma. The prognostic significance of WBCT and CSS findings for survival and correlation with clinical parameters will be reported at the meeting. Disclosures Hillengass: Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding; Amgen: Consultancy, Honoraria; Sanofi: Research Funding. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria. Goldschmidt:Janssen: 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, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Lentzsch:Celgene: Consultancy, Honoraria; BMS: Consultancy. Terpos:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria.