Molecular analysis of 423 cases from the MIDAS trial reveals that gene expression groups and genomic instability profiles heavily dictate minimal residual disease negativity in newly diagnosed multiple myeloma patients. While all 423 patients were screened for the MIDAS trial and included in baseline molecular characterization using whole-genome sequencing, RNA sequencing, and whole-genome enzymatic methylation sequencing, 394 of these patients were ultimately enrolled to have molecular predictors of minimal residual disease evaluated.
Genomic and Transcriptomic Profiling of the MIDAS Cohort
Baseline characteristics were generally comparable between patients with and without available multiomic data, though the multiomic subset showed a modest enrichment of higher International Staging System stages and a greater bone marrow plasma-cell burden due to the requirement for sufficient CD138-positive plasma cells for profiling. Following stringent quality controls, researchers successfully obtained 421 whole-genome sequencing profiles (with a mean depth of 46X for tumor DNA and 27X for normal DNA), 418 RNA-sequencing profiles (with a mean of 66 million read pairs per sample), and 422 whole-genome enzymatic methylation-sequencing profiles (with a mean depth of 13X), with all three data types available for 416 samples. Additionally, five normal plasma cell samples were analyzed using RNA-sequencing and whole-genome enzymatic methylation-sequencing to provide reference gene expression and DNA methylation landscapes.
Heterogeneous Responses Across Gene Expression Groups
Unsupervised classification of the samples based on gene expression profiles uncovered eight distinct molecular groups that strongly associated with genomic alterations and matched previously described transcriptomic subgroups. Driver translocations activating NSD2, MAF, MAFA, MAFB, and CCND1 defined the MS, MF, and CD expression groups, with the CD group further split into CD1 and CD2. Furthermore, researchers identified three distinct subgroups of hyperdiploid tumors designated as HP1, HP2, and HP3. Among these, HP1 exhibited a proliferative program characterized by the overexpression of CCND2 and E2F targets; HP2 expressed B cell identity genes such as PAX5, MS4A1, and VPREB3, bearing a resemblance to CD2; and HP3 overexpressed inflammatory chemokines alongside tumor necrosis factor and interferon pathway genes. Additionally, the number of structural variants also differed significantly across groups, being highest in the MF and MS groups at a median of greater than 50 structural variants and lowest in the CD1 and CD2 groups at a median of 17 structural variants.
