(PA-225) Development of a Cytogenetic Double-Hit Model for Survival Prediction in Multiple Myeloma

Introduction: High-risk chromosomal abnormalities (HRCAs) detected by fluorescence in situ hybridization (FISH) have a profoundly adverse impact on the prognosis for patients with multiple myeloma (MM). It is widely acknowledged that the presence of two or more HRCAs significantly increases risk, classifying these cases as double or multiple-hit MM. However, the definition of double-hit MM remains a topic of ongoing debate. In this study, we analyzed a large cohort of newly diagnosed MM (NDMM) with fluorescence in situ hybridization (FISH) examination results for HRCAs. We intended to screen out the most decisive and irreplaceable HRCAs and develop a simplified HRCA model to define double-hit MM. The analysis identified a four HRCA double-hit model after comparing various double-hit definitions in the era of novel therapies.

Methods: This study was carried out based on the MM database of the National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199), a total of 1122 NDMM patients were identified with at least one CA data and enrolled in this study. Among them, 984 patients had the required HRCAs data, including t(4;14), t(14;16), del(17p) and gain(1q). And 757 patients had complete FISH testing data, which, in addition to the aforementioned abnormalities, also included t(14;20) and del(1p), were included in the double-hit model development.

Results: When analyzing the explained variation of all HRCAs, the top four contributors to survival were gain(1q), del(17p), del(1p), and t(14;16), forming the HBDH model. The HBDH model demonstrated a concordance index of 0.59 for both PFS and OS, comparable to the NCRI model and a model incorporating all six HRCAs. The HBDH model stratified MM patients into three groups: no hit, single-hit, and double-hit, showing significant prognostic differences. Median PFS was 53.3, 32.0, and 20.6 months (P < 0.001), and median OS was 84.2, 64.2, and 40.2 months (P < 0.001) for no hit, single-hit, and double-hit MM patients, respectively. Furthermore, our results showed that the inclusion of del(13q), t(4;14), and t(11;14) did not add further prognostic value to the model. Multivariate analysis, accounting for aging, LDH abnormalities, ISS stage, and the number of HRCAs, confirmed that HBDH double-hit model can independently predict both PFS and OS.

Conclusions: Our findings suggest that double-hit MM is associated with a high risk of early progression or death. Further validation of this model in prospective studies is needed to confirm its prognostic utility and refine risk stratification for MM patients.