P916: COEXISTENCE OF ≥2 HIGH-RISK MOLECULAR ABNORMALITIES SUPERVENES THE PROGNOSTIC VALUE OF THE REVISED INTERNATIONAL STAGING SYSTEM FOR MYELOMA: REAL-WORLD DATA ANALYSIS FROM THE GREEK MYELOMA STUDY GROUP

Abstract

Background: Revised International Staging System (R-ISS) has improved the prognostic value of ISS in multiple myeloma (MM). Recently, the Mayo Additive Staging System incorporated +1q21 to determine a 5-factor 3-tier system, providing an add-on value on R-ISS. The prognostic impact of the coexistence of ≥2 high-risk molecular abnormalities, including +1q21, compared to R-ISS, has not been validated adequately. Aims: The aim of this study was to evaluate the prognostic impact on survival of the coexistence of ≥2 high-risk molecular abnormalities, defined as Ultra High Risk (UHR) MM, in comparison with R-ISS and other established prognostic markers, in the real-world setting. Methods: We analyzed the data of 1352 consecutive newly diagnosed MM patients (M/F: 655/697, median age: 66, range: 29-87, IgG: 817, IgA: 363, light chain: 144, IgD: 9, IgM: 3, non-secretory: 16), treated between 2002-2021 and which had been tested for molecular abnormalities i.e. del17p, t(14;16), t(4;14) and +1q21 using fluorescence in situ hybridization. Patients with ≥2 high-risk features were classified as UHR. We compared the two groups for age, performance status, ISS, R-ISS, lactate dehydrogenase (LDH), albumin, hemoglobin (Hb), β2-microglobulin, estimated glomerular filtration rate (eGFR), 1st and 2nd line therapies and response rates. A Cox regression model was used to determine independent prognostic factors for overall survival (OS). Progression-free survival (PFS) and OS were plotted with Kaplan-Meier; a p<0.05 was considered as statistically significant. Results: One hundred sixteen patients (9%) were classified in the UHR group vs. 1236 (91%) in the non-UHR group; 106 patients had 2, and 10 patients had 3 molecular abnormalities. The most common combination of high-risk features was +1q21 plus t(4;14) (40%). Median age, sex, performance status, LDH and serum albumin, did not differ, whereas the UHR group had lower eGFR, higher β2-microglobulin and lower Hb (p<0.05). Early stage (ISS1/R-ISS1) was more frequent in the non-UHR group (p<0.05); 1st line treatment, including autologous transplantation (ASCT), and second line treatment were well balanced between groups (p<0.05); 66% of patients overall, received triplet/quadruplet combinations and 29% underwent ASCT upfront. Overall response rate after induction therapy was 86% and did not differ between groups (p<0.05). Complete response was lower in the UHR group (11% vs. 19%; p=0.03). After a median follow up of 49 months (95% CI: 44-54), 59% of patients were alive. Median PFS was significantly shorter for the UHR group (15.8 vs. 31.9 months, p<0.001; HR: 0.45, 95% CI: 0.36-0.58). Median OS was 28 months (95% CI:18-38) for patients in the UHR group vs. 69 months (95% CI: 61-77) for others (p<0.001). In the univariate analysis, age, anemia, eGFR, upfront ASCT, R-ISS and UHR myeloma were independent predictors for OS (p<0.05). In the multivariate analysis UHR myeloma was the strongest independent predictor for OS (p<0.001; HR: 0.42), supervening the prognostic value of R-ISS (R-ISS1 vs. R-ISS2 HR=0.58, R-ISS2 vs. R-ISS3 HR: 0.75). Additionally, UHR status singled out a distinct group within R-ISS2 patients with significantly worse OS (38 months, 95% CI: 28-48 vs. 64mo, 95% CI: 55-72) (p<0.001). Summary/Conclusion: According to our analysis of a large cohort of newly diagnosed MM patients UHR myeloma, was the strongest independent predictor for OS, supervening the prognostic value of R-ISS. Moreover, UHR status could serve as an additional prognostic marker for R-ISS2 patients, helping thus to optimize therapeutic approach of MM patients.