A retained transcriptomic profile characterizes the CD138+ cells in the progression from smoldering to active multiple myeloma

Smoldering myeloma (SMM) is a pre-malignant monoclonal gammopathy with a 10% annual risk to progress to active multiple myeloma (MM). SMM diagnostic criteria, as well of those of others monoclonal gammopathies, have been updated by the International Myeloma Working Group (IMWG) in 2014. In particular, the previously defined “ultra high-risk” SMM (characterized by the presence of specific biomarkers associated with a ≥ 80% risk of progression to symptomatic MM within 2 years) has been included among patients with active MM. SMM is biologically heterogeneous, including a subset of patients with biological pre-malignancy and a subset with biological malignancy who have not yet developed organ damage, defined as onset of the classical CRAB criteria or Myeloma Defining Events (MDE). Thus, SMM encompassed patients with a very low rate of progression to symptomatic MM, similar to patients with monoclonal gammopathy of uncertain significance (MGUS), as well as patients who acquired organ damage and progress to active MM within the first year from diagnosis. The molecular mechanisms involved in the SMM to MM progression are still far to be fully understood. Genomic studies indicate that the genetic alterations that characterize MM patients are already present in SMM ones, who present similar mutational and copy number alteration load. However, few data are available on the transcriptional profiles of SMM patients in relationship to the progression to active MM, overall indicating minimal differential expression either in coding or non-coding RNA fraction. To date, robust data are still lacking which describe the transcriptional profiles of plasma cells (PCs) from paired samples obtained at the time of SMM and at MM onset. Herein, we compared the transcriptome of purified CD138+ PCs from paired samples of SMM patients progressed to active MM (P-SMM), aimed at describing any possible common transcriptional discrepancy that may help to understand the intra-patient disease evolution; at the same time, we investigated the transcriptional differences between P-SMM and a subset of non-progressed SMM (NP-SMM) at a minimum of 36 months. A total number of 20 SMM patients, admitted to the Hematological Unit of our Institution over the last 11 years, were considered: 12 non-progressed(NP)-SMM and 8 progressed(P)-SMM for whom paired active MM samples were available

冒烟型骨髓瘤（Smoldering Myeloma, SMM）是一种癌前单克隆丙种球蛋白病，每年有10%的概率进展为活动性多发性骨髓瘤（Multiple Myeloma, MM）。2014年，国际骨髓瘤工作组（International Myeloma Working Group, IMWG）更新了SMM及其他单克隆丙种球蛋白病的诊断标准。具体而言，此前定义的“超高危” SMM（以存在特定生物标志物为特征，这类患者在2年内进展为症状性MM的风险≥80%）已被归入活动性MM患者范畴。
SMM具有生物学异质性，既包含生物学上仍处于癌前阶段的患者亚群，也包含虽已具备生物学恶性特征但尚未出现器官损伤的患者亚群——后者的定义为符合经典CRAB标准或骨髓瘤定义事件（Myeloma Defining Events, MDE）。因此，SMM涵盖的患者群体差异极大：既有进展为症状性MM的风险极低、与意义未明单克隆丙种球蛋白病（Monoclonal Gammopathy of Uncertain Significance, MGUS）患者相似的人群，也包括确诊后1年内即出现器官损伤并进展为活动性MM的患者。
目前，SMM向MM进展的分子机制仍远未被完全阐明。基因组学研究显示，MM患者标志性的遗传改变在SMM患者中已存在，二者的突变负荷与拷贝数变异负荷相似。然而，目前关于SMM患者转录组谱与进展为活动性MM相关性的研究数据仍较为匮乏，整体而言，无论是编码RNA还是非编码RNA组分，其差异表达均较为微弱。迄今为止，仍缺乏针对SMM确诊时与MM发病时配对样本的浆细胞（Plasma Cells, PCs）转录组谱的高质量研究数据。
本研究中，我们对进展为活动性MM的SMM患者（P-SMM）确诊时与发病时的配对样本中纯化的CD138阳性浆细胞进行转录组比较，旨在明确可能有助于理解患者体内疾病进展过程的共有转录差异；同时，我们还分析了至少随访36个月仍未进展的SMM患者（NP-SMM）与P-SMM之间的转录组差异。本研究共纳入过去11年间在本机构血液科就诊的20例SMM患者：其中12例为未进展型SMM（NP-SMM），8例为进展型SMM（P-SMM），且后者均配有活动性MM的配对样本。