Next Generation Sequencing-based Validation of the Revised International Staging System for Multiple Myeloma: An Analysis of the MMRF CoMMpass Study

Introduction: The clinical application of the Revised International Staging System (R-ISS) for multiple myeloma may be limited by heterogeneity in clinical interphase fluorescent in situ hybridization (FISH) practices for detecting chromosomal abnormalities (CAs). Next generation sequencing (NGS)-based FISH (Seq-FISH) has demonstrated improved sensitivity and similar specificity relative to clinical FISH, and provides a standardized, single-pass method for identifying high-risk CAs. To date, calculating R-ISS stage using Seq-FISH (R-ISS-NGS) has not been validated. Patients and Methods: We identified 672 patients with sufficient data to calculate R-ISS-NGS from the Multiple Myeloma Research Foundation (MMRF) CoMMpass Study. R-ISS-NGS was calculated from original ISS stage, lactate dehydrogenase, and CAs detected by Seq-FISH. Endpoints included overall survival and progression-free survival. We conducted multivariate analyses controlling for age and gender in order to compare outcomes across stages I to III of both the original ISS and R-ISS-NGS. Results: The median follow-up was 24 months. The R-ISS-NGS resulted in significant redistribution of patients into stage II, relative to the original ISS. With respect to stage I, R-ISS-NGS stages II and III of were associated with worse progression-free survival or overall survival, more so than the staging schema of the ISS, thus validating the use of Seq-FISH in staging. Conclusion: Using CAs detected by Seq-FISH and data from the CoMMpass study, we validated the R-ISS with a large, generalizable cohort. This study validates the substitution of Seq-FISH for clinical FISH, especially in large registry studies. Additionally, use of the validated R-ISS-NGS will strengthen outcomes research generated from the CoMMpass study. The Revised International Staging System (R-ISS) better stratifies patients with newly diagnosed multiple myeloma owing to inclusion of chromosomal abnormalities detected by interphase fluorescence in situ Hybridization (FISH). The interphase FISH data in the Multiple Myeloma Research Foundation (MMRF) CoMMpass study is heterogeneous in methods and reporting, which prompted the development of Seq-FISH, next generation sequencing-based FISH. Using data from 672 patients from the MMRF CoMMpass study, we validated the R-ISS using Seq-FISH (R-ISS-NGS). The R-ISS-NGS will strengthen outcomes research from CoMMpass by allowing for improved stratification and comparability to contemporary outcomes research.