Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect “B cell-featured” plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options.

多发性骨髓瘤（MM）的特征在于浆细胞不受控制的增殖。尽管最近有治疗进展，但由于疾病进展尚不完全了解，因此仍无法治愈。为了研究MM及其免疫环境，我们应用单细胞RNA和链接阅读全基因组测序技术，对14例患者不同疾病阶段的29个纵向样本进行了分析。在这里，我们收集了17,267个浆细胞和57,719个免疫细胞，发现了患者特异性浆细胞谱和免疫细胞表达的变化。具有相同遗传改变的患者倾向于使浆细胞和免疫细胞聚集在一起。通过整合整体基因组学和单细胞作图，我们追踪了疾病各个阶段的浆细胞亚群，并发现了三种模式：稳定性（从癌前期到诊断），和得失（从诊断到复发）。在多名患者中，我们检测到“ B细胞特征性”浆细胞亚群与B细胞紧密聚集，暗示其起源细胞。我们使用基于CyTOF的蛋白质测定法验证浆细胞亚群中AP-1复杂差异表达（JUN和FOS），对单细胞RNA和CyTOF数据的综合分析显示AP-1下游靶标（IL6和IL1B）可能导致炎症规定。我们的工作代表了对MM进展过程中肿瘤和微环境的纵向研究，并为扩大治疗选择铺平了道路。我们使用基于CyTOF的蛋白质测定法验证浆细胞亚群中AP-1复杂差异表达（JUN和FOS），对单细胞RNA和CyTOF数据的综合分析显示AP-1下游靶标（IL6和IL1B）可能导致炎症规定。我们的工作代表了对MM进展过程中肿瘤和微环境的纵向研究，并为扩大治疗选择铺平了道路。我们使用基于CyTOF的蛋白质测定法验证浆细胞亚群中AP-1复杂差异表达（JUN和FOS），对单细胞RNA和CyTOF数据的综合分析显示AP-1下游靶标（IL6和IL1B）可能导致炎症规定。我们的工作代表了对MM进展过程中肿瘤和微环境的纵向研究，并为扩大治疗选择铺平了道路。