Genomic Basis of Multiple Myeloma Subtypes from the MMRF CoMMpass Study

Abstract

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The MMRF CoMMpass study is a longitudinal, observational clinical study of newly diagnosed multiple myeloma patients where tumor samples are characterized using whole genome, exome, and RNA sequencing at diagnosis and progression, and clinical data is collected every three months. Analyses of the baseline cohort identified genes that are the target of recurrent gain- and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

Transcriptional signature of TP53 biallelic inactivation identifies a group of multiple myeloma patients without this genetic condition but with dismal outcome

“…On the other hand, it is noteworthy that patients with 1q gain, at the expense of 1q amplification, and 1p deletion were overrepresented in the DH‐ TP53 ‐like group. In fact, 1q gain was identified as an independent prognostic factor in the multivariable analysis, as has recently been reported in the analysis baseline cohort of the CoMMpass study 23 …”

“…In fact, 1q gain was identified as an independent prognostic factor in the multivariable analysis, as has recently been reported in the analysis baseline cohort of the CoMMpass study. 23 More importantly, the combination of DH-TP53-like group and ISS stage significantly improved prediction of outcome in MM. The median OS dropped from 59 months for patients with ISS III to 17 months for patients with ISS III that belonged to DH-TP53-like group.…”

“…A significantly greater proportion of MAX gene mutations was observed in DH‐ TP53 ‐like patients. Loss of function of MAX in MM patients has been associated with the proliferative subtype 23 . The enrichment of MAX mutations in DH‐ TP53 ‐like patients, who experience a particularly poor outcome, deserves to be investigated extensively.…”

Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence

“…The second cohort comprised 28 patients from the CoMMpass study [ 19 ], release IA13. First sample was taken at diagnosis and the second at PD (Table S1B ).…”

Multiple Myeloma With Amplification of Chr1q: Therapeutic Opportunity and Challenges

“…Patients with newly diagnosed MM have a high frequency of Amp1q by fluorescence in situ hybridization (FISH) [43%, n = 479, 43% of whom had 4 copies or more ( 34 ); 40.5%, n = 205, 22% of whom had 4 copies or more ( 35 ); 39%, n = 767 ( 36 ); 37%, n = 880, 25% of whom had 4 copies or more ( 37 ); 33%, n = 520 ( 38 )], comparative genomic hybridization (CGH) [45%, n = 51 ( 39 )], or Multiplex Ligation-dependent Probe Amplification (MLPA) [34%, n = 1,716 ( 37 )]. In a whole-exome sequencing (WES) study of 1,074 patients with newly diagnosed MM, 29% had Amp1q, and 21% of those had 4 copies or more ( 29 ); whereas, in a whole-genome sequencing (WGS) study of 871 patients, 35% had Amp1q ( 40 ). Similar prevalence estimates have been reported in patients with SMM either by FISH [45%, n = 31 ( 34 ); 41%, n = 114 ( 41 ); 30%, n = 245 ( 42 )] or next-generation sequencing (NGS) [25%, n = 77 ( 11 ); 28.5%, n = 214 ( 8 ); 24.4%, n = 90 ( 10 )].…”