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.

Development of an Algorithm to Distinguish Smoldering Versus Symptomatic Multiple Myeloma in Claims-Based Data Sets.

Purpose: The distinction of patients with symptomatic multiple myeloma (MM) from those with smoldering MM poses a challenge for researchers who use administrative databases. Historically, researchers either have included all patients or used treatment receipt as the distinguishing factor; both methods have drawbacks. We present an algorithm for distinguishing between symptomatic and smoldering MM using ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes for the classic defining events of symptomatic MM commonly referred to as the CRAB criteria (hypercalcemia, renal impairment, anemia, and bone lesions). Patients and Methods: SEER-Medicare-linked data from 4,187 patients with MM diagnosed between 2007 and 2011 were used for this analysis. Results: Eighty-four percent had ICD-9-CM codes consistent with CRAB criteria, whereas only 57% received treatment. Overall survival of patients with symptomatic MM defined as receipt of treatment was 32.3 months versus 26.6 months for the overall population and 22.9 months for patients with symptomatic MM defined by CRAB criteria. Conceptually, removal of patients with smoldering MM should result in a reduction in overall survival; however, the cohort of patients who received treatment tended to be younger and healthier than the overall population, which could have skewed the results. Conclusion: The algorithm we present resulted in a larger and more representative sample than classification by treatment status and reduced potential bias that could result from including all patients with smoldering MM in the analysis. Although this study was performed using the SEER-Medicare database, the methodology was broad enough that the algorithm could be extended to additional claims-based data sets with relative ease.