Myeloma Genomics and Microenvironment and immune profiling

Category: Myeloma Genomics and Microenvironment and immune profiling

Bortezomib, lenalidomide, and dexamethasone reverses the inferior prognostic effect of KRAS mutation in patients with newly-diagnosed multiple myeloma

(PA-218) Bortezomib, Lenalidomide, and Dexamethasone Reverses the Inferior Prognostic Effect of KRAS Mutation in Patients with Newly-diagnosed Multiple Myeloma

Thursday, September 18, 2025

lili cheng

Beijing, China
Department of Hematology, Peking Union Medical College Hospital

Introduction: Bortezomib, lenalidomide, and dexamethasone (VRD) is a standard regimen for patients with newly diagnosed multiple myeloma (NDMM), which achieves over 90% response rate. The superior efficacy of VRd in triplet regimens is not mechanically explained. This study aims to filtrate subpopulation responding to VRd based on the data of next generation sequencing (NGS) in NDMM patients.

Methods: We analyzed clinical and NGS data from 121 NDMM patients receiving frontline VRD (June 2019–March 2024, Peking Union Medical College Hospital). Controls included 50 patients receiving bortezomib, cyclophosphamide, dexamethasone (BCD)/BD or ixazomib and dexamethasone (ID) regimens. High-risk cytogenetic abnormalities (HRCA) were defined as 1q21+, del17p, t(4;14), t(14;16). A NGS panel including 290 tumor-related genes was performed in purified plasma cells. High-risk MM (HRMM) was defined by fulfilling any of the following criteria: R-ISS stage III, soft-tissue extramedullary disease, positive circulating plasma cells, at least one HRCA (isolated 1q21 gain excluded), early relapse (progression within 2 years in transplant patinets, or < 18 months in non-transplant ones).

Results: Median follow-up: 38.8 months.Frequent mutations: KRAS (26.4%), NRAS (15.7%), TP53 (6.6%), IGLL5 (5.8%)and BRAF (3.3%). Survival analysis of patients with the aforementioned genetic alterations revealed that KRAS-mutated patients exhibited significantly longer PFS and OS than wild-type counterparts (2-year PFS 81% vs.61%; 2-year OS 97% vs.87%, p< 0.05). Univariate and multivariate analyses incorporating baseline characteristics (sex, age, M-protein type, R-ISS stage III, transplantation status, HRCA) and NGS results identified KRAS as an independent favorable factor for PFS. Among 78 HRMM patients (per defined criteria), 14 harbored KRAS mutations. Although it was not statistically significant, these mutated patients demonstrated survival advantages in both PFS (2-year PFS 64%vs.46%,p=0.144) and OS (2-year OS 93%vs.81%, p =0.193)compared to non-mutated cases.For other gene mutations, the survival differences between the two groups were not statistically significant, likely due to the limited number of cases.In contrast, among 50 patients receiving alternative first-line regimens including BCD/BD/ID, those with KRAS mutations presented significantly worse outcomes than wild-type cases (2-year PFS: 34% vs. 76%, p=0.003).

Conclusions: The prognostic value of gene mutations other than TP53 is controversial in MM patients. Although KRAS mutation is associated with inferior outcome in proteosome inhibitor-based regimens not combined with immunomodulator drugs, our findings suggest that VRD regimen may improve the response and survival in KRAS mutated NDMM patients, therefore translating into the improvement of whole population. The synergistic effect of bortezomib and lenalidomide in overcoming stimulation of RAS pathway will be further explored.