P878: HIGH MUTATIONAL BURDEN OF CHROMATIN MODIFYING GENES DEFINES A RELATIVELY INDOLENT SUBGROUP OF PLASMA CELL DYSCRASIAS

Abstract

Background: Plasma cell dyscrasias (PCDs), including multiple myeloma (MM), light chain amyloidosis (AL), POEMS syndrome, and MGUS, present different clinical features. But as malignancies of plasma cells, they potentially have common mutational patterns associated with chemotherapy and prognosis, which haven’t been elucidated. Aims: We aimed to reveal the clinically relevant subgroups of MM, AL, POEMS, and MGUS defined by mutational patterns of bone marrow plasma cells (BMPCs). Methods: We conducted targeted gene sequencing including 370 genes of BMPCs from patients with MM (n=163), AL (n=121), POEMS (n=67) and MGUS (n=13). All the subjects provided informed consent. Results: Principal component analysis of the top 100 variable genes revealed 2 major subgroups among patients with PCDs (Fig. 1a). Approximately 25% of MM, AL, POEMS and MGUS, subgroup 1 was featured by the heavily mutated genes enriched in histone modifications and chromatin organization, such as KMT2D, EP400, RUNX1, SOX9, KDM5A, NCOR2, and ARID1B. Subgroup2 showed lower total mutational burden and was featured by mutations of proto-oncogene and B cell differentiation-associated genes, such as NCOR1, APOBEC4, KRAS, TP53, FGFR3, FAM46C, and MYC (Fig. 1b). The high mutational burden of chromatin-modifying genes was exclusively observed in subgroup 1 and was comparable among MM, AL, POEMS, and MGUS (Fig. 1c). Patients in subgroup 1 showed worse responses to the first-line CyBorD for MM and AL (Fig. 1d), but better responses to the lenalidomide-based VRD for MM and Rd for POEMS. Overall, patients in subgroup 1 demonstrated longer progression-free survival (PFS), which was observed in MM, AL (Mayo12, Stage I, II), and POEMS, respectively (Fig. 1e). Image:Summary/Conclusion: These results provide mechanistic insights into a relatively indolent subgroup among patients with MM, AL, POEMS, and MGUS, which is featured by a high mutational burden of chromatin-modifying genes. This subgroup can be identified by detecting the mutations of chromatin-modifying genes in clinical management. Overall longer PFS and better response to lenalidomide-based first-line therapy can be expected.