ISS stage and network risk score to predict benefits of multiple myeloma treatment options.

Abstract

e20511 Background: Multiple myeloma (MM) is molecularly heterogeneous with many treatment regimens developed targeting different aspects of the disease. Multi-omics studies are now widely available, facilitating a precision medicine approach for personalized MM treatments. However, data from these studies vary with respect to treatment regimens, patient age, disease stage, and genomic alterations, thus complicating identification of treatment effects. Methods: From a Multiple Myeloma Molecular Causal Network (M3CN) model we previously described, we identified a prognostic subnetwork (prognNET) associated with survivals of newly diagnosed MM (NDMM) patients. We derived a network risk score (NRS) for each patient by inferring their molecular state with respect to prognNET, and partitioned patients into NRS low, medium, and high groups (referred as NRSL/M/H). We validated NRSL/M/H to be significantly associated with progression free survival (PFS) and overall survival (OS) in single variate and multi-variate Cox regression models including age and ISS stage in TT2,3,4 and HOVON studies. Results: To determine the impact of NRS in an independent contemporary dataset, we examined NDMM patients with RNAseq data in the MMRF-CoMMpass study. Among young patients (age < 65), ones with combined therapies (CoTs) as the first line therapy (n = 363) had better survival than ones on proteasome inhibitors (PIs) (n = 93) (p = 0.027 and 0.002 for PFS and OS). When stratified by ISS stage and NRS, there was no significant difference between CoTs and PIs except that in the stage I-NRSL group, patients on PIs had better PFS than ones on CoTs (p = 0.016). This suggests that NRS may be able to discriminate ISS stage I patients that do not need CoT. Similarly, we studied the ability of NRS to discriminate patients that benefit from autologous stem cell transplant (ASCT). In a model combining age, ISS stage, NSR, and induction treatment, ASCT was associated with better survival. When stratified young patients on CoTs by ISS stage and NRS, only the stage II-NRSM and stage III-NRSM patients benefited from ASCT in term of PFS (p = 0.01 and 0.005) and OS (p = 0.004 and 0.04). Conclusions: Stage and NRS group should be considered in personalizing treatment options for NDMM patients.