Validation of the high-risk consensus genomic staging system in the era of bispecific antibodies: Role of NGS and cytogenetic reclassification

Abstract

Abstract Introduction:The International Myeloma Working Group (IMWG) and International Myeloma Society (IMS) recently proposed a consensus high-risk genomic classification for multiple myeloma integrating next-generation sequencing (NGS) and updated cytogenetic definitions. Although this system has improved risk stratification, its prognostic value in patients treated with bispecific antibodies remains unclear, as their mechanism differs significantly from that of conventional therapies on which the classification was originally based. Aim:To evaluate the prognostic value of the IMWG-IMS high-risk genomic classification in multiple myeloma patients treated with bispecific antibodies. Methods:A retrospective cohort study was conducted including patients treated with bispecific antibodies at a single center between 2020 and 2025. Fluorescence In Situ Hybridization (FISH) was performed to assess cytogenetic alterations, and NGS was employed to detect TP53 mutations on sorted CD138+ plasma cells from all patients prior to bispecific therapy.High-risk status according to the new classification was defined by: (1) del(17p) with a clonal fraction cutoff >20% and/or TP53 mutation; (2) an IgH translocation including t(4;14), t(14;16), or t(14;20) in combination with 1q gain and/or del(1p32); (3) monoallelic del(1p32) combined with 1q gain or biallelic del(1p32). Classic high-risk cytogenetic alterations included t(14;16), t(4;14), or del(17p).Statistical analyses were performed using SPSS®: Chi-square tests, Kaplan–Meier survival estimates with log-rank comparisons, and Cox proportional hazards regression models. Results: We analyzed 99 patients with multiple myeloma, the majority of whom had relapsed or refractory disease. The median age at treatment initiation was 61 years (IQR 55–68), and 56.1% were male.Bispecific antibodies administered included teclistamab (27.6%), linvoseltamab (22.4%), talquetamab (21.4%), etentamig (14.3%), and elranatamab (12.2%).The most frequent high-risk cytogenetic alteration was 1q gain (38.8%), followed by del(17p) (21.4%), monoallelic del(1p32) (14.3%), t(4;14) (11.2%), and t(14;16) (3.1%). TP53 mutations were identified in 16.1% of patients. Based on these data, 30.6% were classified as high-risk using the classic criteria and 36.7% according to the revised IMWG-IMS classification. 3.1% of patients were reclassified from high to standard risk, and 9.1% from standard to high risk under the updated system (p < 0.001).At a median follow-up of 19 months (IQR 13–29), the estimated 3-year OS was 56.6% [95% CI: 42.5–70.7], and the 3-year PFS was 46.4% [95% CI: 34.0–58.8]. The median progression-free survival (PFS) was 21 months [95% CI: 10–31].According to the new IMWG-IMS genomic classification, high-risk patients had significantly lower 3-year PFS compared to standard-risk patients: 28.4% [95% CI: 12.0–44.8] versus 63.1% [95% CI: 52.1–74.1] respectively (p = 0.025). In addition, the risk of progression was higher in high-risk patients (HR 1.9, 95% CI: 1.05–3.44; p = 0.033). Furthermore, high-risk patients had a numerically higher hazard of death compared to standard-risk patients (HR 1.829, 95% CI: 0.923–3.625; p = 0.083), with 3-year OS of 41.0% [95% CI: 19.4–62.6] versus 69.1% [95% CI: 55.3–82.9], respectively (p = 0.076).Conversely, the estimated 3-year PFS according to the classic cytogenetic classification was 38.5% [95% CI: 18.3–58.7] in the high-risk group versus 55.2% [95% CI: 42.5–67.9] in the standard-risk group (p = 0.318). The risk of progression was similar in high-risk group vs standard-risk group (HR 1.35, 95% CI: 0.73–2.5; p = 0.34). High-risk status based on the classic cytogenetic classification was associated with similar survival compared to the standard-risk group in univariable analysis (HR 1.318, 95% CI: 0.648–2.680; p = 0.445). Specifically, the 3-year OS was 54.1% [95% CI: 33.8–74.4] in the high-risk group and 58.0% [95% CI: 41.9–74.1] in the standard-risk group (p = 0.439). Conclusion:The revised IMWG-IMS high-risk genomic classification improved risk stratification over classic criteria in a large cohort of patients treated with bispecific antibodies. Even among heavily pretreated high-risk patients, the updated classification more accurately identified those with poorer outcomes. These findings support incorporating next-generation sequencing and refined cytogenetic definitions for prognostic assessment and treatment decisions in this patient population.