We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR < 0.05). Gene set enrichment analysis (GSEA) showed increased expression of E2F, MYC, and glycolysis pathways and a decreased expression in TNF-NFkB and TGFbeta pathways in late compared to early stage. Single sample GSEA (ssGSEA) scores of differentially expressed pathways revealed that these changes were most evident in end-stage disease. Increased expression of several potentially targetable genes was found at late disease stages, including cancer-testis antigens, XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM.

我们调查了 29 名内部多发性骨髓瘤 (MM) 患者和 28 名来自 MMRF CoMMpass 研究的患者在治疗前后配对肿瘤样本的基因组和转录组变化。在 46/57 (82%) 的患者中发现克隆组成发生变化，单核苷酸变异 (SNV) 从中位数 67 增加到 86。RAS 基因中发现的遗传畸变患病率最高（60% 到72%）、amp1q21（18% 至 35%）和TP53（9% 到 18%）。在接受高剂量和低剂量美法仑的患者中均检测到 SBS-MM1 突变特征。早期和晚期样本之间共有 2589 个基因差异表达（FDR < 0.05）。基因集富集分析 (GSEA) 显示，与早期相比，晚期 E2F、MYC 和糖酵解途径的表达增加，而 TNF-NFkB 和 TGFbeta 途径的表达减少。差异表达途径的单样本 GSEA (ssGSEA) 评分显示，这些变化在终末期疾病中最为明显。在疾病晚期发现了几种潜在可靶向基因的表达增加，包括癌症睾丸抗原、XPO1和 ABC 运输车。我们的研究证明了在 MM 疾病进展期间支持增加增殖和代谢的途径的转录组学收敛。