Exploring Genomic and Transcriptomic Changes Throughout Multiple Myeloma Progression

Whole-exome and RNA sequencing of early and late multiple myeloma tumor samples aimed to provide insight into disease drivers and phenotypes.

Overall survival for patients with multiple myeloma (MM) has improved in recent decades, but the disease remains incurable and is often aggressive in late stages. A study published in the journal Leukemia explored the genomic and transcriptomic changes in late tumor samples versus early samples to better understand MM progression.

The study used whole-exome sequencing and RNA sequencing to examine early and late tumor samples from 57 patients with MM. An in-house patient cohort included 29 patients with samples in the MM biobank at St. Olavs Hospital in Norway and Erasmus MC Cancer Institute in the Netherlands, while a second cohort included 28 patients from the CoMMpass study. Between samples, all patients had received a proteasome inhibitor and/or immunomodulatory drug (IMiD) at least once.

Gene set enrichment analysis (GSEA) was used to identify enriched pathways, and single-sample GSEA (ssGSEA) sorted the genes in each sample according to their expression levels in descending order. The ssGSEA score included GSEA hallmark, or core enriched, genes.

In 46 patients (82%), changes in clonal composition between early and late samples were identified. Overall, 56 patients (98%) carried mutations in at least 1 out of 80 previously identified genes that drive MM at some point in the course of their disease.

Patients receiving high-dose melphalan showed the most prominent increase in mutations (median of 36 versus 7). In both high- and low-dose melphalan patients, there was an increase in the mutational signature SBS-MM1. Single-nucleotide variants increased from a median of 67 to 86.

The most frequent MM driver in this cohort was RAS gene mutations, and 74% of patients had a KRAS or NRAS mutation during the study period.

“In 7 patients with a reduction or disappearance of a dominating clone with a RAS mutation, this was replaced by another clone with a different RAS mutation” the authors wrote. “Thus, the major clone still harbored a RAS mutation, indicating a benefit for the tumor to keep a consistently activated RAS pathway during disease progression.” RAS genes also saw the highest increase in prevalence of genetic aberrations (60% pre-treatment and 72% in later samples). Further, amp1q21 rose from 18% to 35%, and TP53 from 9% to 18%.

Overall, a total of 2589 genes were expressed differently in early versus late samples. E2F, MYC, and glycolysis pathways showed increased expression in later stages, while TNF-NFkB and TGFbeta pathways had decreased expression. Genes that may be promising targets, including cancer-testis antigens, XPO1, and ABC transporters, were increasingly expressed in later stage disease. While 75% of patients became refractory on IMiDs or proteasome inhibitors, there were few mutations identified in the IMiD pathway genes or proteasome subunits.

The proliferative index (PI) was also calculated for each tumor sample and analyzed for changes between disease stages. PI increased at later stages, with 57% showing higher PI later on, 29% showing no change, and 14% of patients showing a decrease in PI in later samples.

“A main conclusion of this study is that disease progression eventually is characterized by a transcriptomic convergence into a more proliferative phenotype supported by expression of genes that enable the tumor cells to tolerate increased cell growth and energy demand,” the authors wrote.

Reference

Misund K, Hofste Op Bruinink D, Coward E, et al. Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence. Leukemia. Published online May 28, 2022. doi:10.1038/s41375-022-01597-y