Targeted gene sequencing of bone marrow plasma cells in multiple myeloma, light-chain amyloidosis, POEMS syndrome and monoclonal gammopathy of undetermined significance

Plasma cell dyscrasias (PCDs), including multiple myeloma (MM), light-chain amyloidosis (AL), and POEMS syndrome, are malignancies of plasma cells with diverse clinical features. Although they have the same precursor stage, monoclonal gammopathy of undetermined significance (MGUS) and some mutation signatures in common, their shared mutational pathogenesis remain understudied. To comparatively analyze the mutations in PCDs, we subjected bone marrow plasma cells from patients with MM (n=163), AL (n=121), POEMS (n=67), and MGUS (n=13), using targeted gene sequencing including 370 genes. Principal component analysis revealed two major subgroups among patients with PCDs: one with heavily mutated chromatin modifying genes (namely CMGmut) and the other with a subtly higher burden of classical MM driver mutations (namely non-CMGmut). High mutational burden of RUNX1 and KMT2D was potential biomarkers to distinguish CMGmut subgroup from non-CMGmut subgroup. Patients with MM, early-stage AL, and POEMS in CMGmut subgroup were more likely to have prolonged progression-free survival than those in non-CMGmut subgroup, although those with MM and AL showed inferior responses to first-line CyBorD therapy. These results provided mechanistic insights into a patient subgroup of PCDs characterized by a high mutational burden of chromatin-modifying genes and relatively indolent clinical features, and likely to benefit from epigenetic therapy.

浆细胞疾病（Plasma cell dyscrasias, PCDs）涵盖多发性骨髓瘤（multiple myeloma, MM）、轻链型淀粉样变性（light-chain amyloidosis, AL）与POEMS综合征，均为具有多样临床表型的浆细胞恶性肿瘤。尽管此类疾病共享前驱阶段——意义未明的单克隆丙种球蛋白病（monoclonal gammopathy of undetermined significance, MGUS），且拥有部分共同的突变特征，但其共同的突变致病机制仍未得到充分研究。为对比分析PCDs的突变特征，本研究对多发性骨髓瘤患者（n=163）、轻链型淀粉样变性患者（n=121）、POEMS综合征患者（n=67）及意义未明的单克隆丙种球蛋白病患者（n=13）的骨髓浆细胞开展了包含370个基因的靶向基因测序。主成分分析显示，PCDs患者可分为两大主要亚组：一类为染色质修饰基因（chromatin modifying genes, CMGs）高频突变亚型（即CMGmut亚型），另一类为经典多发性骨髓瘤驱动突变负荷略高的非CMGmut亚型。RUNX1与KMT2D的高突变负荷可作为区分CMGmut与非CMGmut亚型的潜在生物标志物。相较于非CMGmut亚型患者，CMGmut亚型中的多发性骨髓瘤、早期轻链型淀粉样变性及POEMS综合征患者更易获得更长的无进展生存期；不过多发性骨髓瘤与轻链型淀粉样变性患者对一线CyBorD治疗的应答效果较差。本研究结果为一类以染色质修饰基因高突变负荷为特征、临床表型相对惰性的PCDs患者亚组提供了机制层面的见解，该亚组或可从表观遗传治疗中获益。