LAUSR

Background: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) are myeloma precursors (MPD). A better understanding of the oncogenic/immune programs underlying progression may reveal exploitable targets for patients (pts) at high risk of progression and aid new intervention strategies. We designed a longitudinal Observational prospective Research study In monoclonal Gammopathies leadINg to myeloma (ORIGIN) to collect well-annotated, longitudinal samples (sps) for integrative genomic/transcriptomic analysis. Methods: Pts were accrued meeting MGUS/SMM IMWG definition. BM sps were partitioned into CD138-positive and -negative compartments and DNAs/RNAs extracted for bulk RNA and whole-exome sequencing (WES). Matched germline controls were included for somatic mutation and DNA copy number analysis. A number of tools and algorithms were applied, and the data were thoroughly analyzed and integrated. Results: From 12/2015-03/2022, 249 pts were accrued and 205 eligible (99 MGUS/106 SMM). Median follow up time is 33 months (6-49 months). As of 11/2022, 21 pts progressed (prog) on ORIGIN study (14% 15/106 SMM, 3% 3/99 prog to SMM from MGUS and 1% 3/205 to AL amyloidosis). To increase analytic power, genomic data of 166 SMM baseline sps from SMM pts on treatment studies were added. Altogether, genomic data of 496 sps were analyzed. Briefly, WES was performed on 170 sps from 150 pts and RNA-Seq was performed on enriched tumor/TME cells in 326 sps from 187 pts. Relative to MGUS, we observed higher mutation load in SMM and more frequent somatic mutations in known drivers of myeloma: KRAS (14% vs. 2%), NRAS (7% vs. 2%) leading to a shorter time to myeloma as well as genes recurrently mutated in other cancers: FOXO3 (7% vs 0%). We observed increased aneuploidy levels in SMM vs MGUS and in prog vs. non-prog including both gains and losses of multiple chromosomes. Transcriptome analysis of CD138+ cells revealed clearly distinct expression profiles between SMM and MGUS, and between prog and non-prog. The pathway activity of oxidative phosphorylation and MYC was significantly increased in SMM vs. MGUS and in prog vs. non-prog, suggesting their potential roles in driving progression. We noted a greater degree of heterogeneity in TME cell compositions in SMM vs MGUS sps and in prog vs. non-prog: ie, SMM and prog sps formed multiple distinct clusters exhibiting differential abundance of cytotoxic T cells, neutrophils, fibroblasts and myeloid cells. Conclusions: Together, our integrative analysis of genomic and transcriptome data in ORIGIN demonstrates extensive changes in both CD138+ cells and the immune microenvironment and co-evolution of the ecosystems during disease progression. This study is an invaluable resource and lays the molecular foundation for the community for future biomarker and target discovery. Citation Format: Minghao Dang, Chutima Kunacheewa, Hans C. Lee, Krina K. Patel, Sheeba K. Thomas, Melody Becnel, Donna M. Weber, Pei Lin, Zuzana Berkova, Mei Huang, David A. Berrios, Hima Bansal, Andrew Futreal, Cristhiam Rojas Hernandez, Vahid Afshar-Khargan, Michael Kroll, Peter Kuhn, Robert Z. Orlowski, Linghua Wang, Elisabet E. Manasanch. Integrative genomic and transcriptomic profiling of myeloma precursors in a prospective longitudinal observational study (ORIGIN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 775.