Clonal Hematopoietic Mutations in Plasma Cell Disorders: Clinical Subgroups and Shared Pathogenesis

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Plasma cell disorders (PCDs) involve abnormal plasma cell proliferation, leading to complications.
• Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are common, while primary light-chain amyloidosis (AL) and POEMS syndrome (POEMS) are rare and less understood.
• Understanding clonal hematopoietic (CH) mutations is crucial for elucidating PCD pathogenesis.

Purpose of the Study:

• To investigate the role of CH mutations and their interconnections in PCDs.
• To identify specific mutations driving disease progression and influencing clinical features.
• To explore shared genetic underpinnings across different PCD subtypes.

Main Methods:

• Sequencing of CH and myeloma driver gene mutations in bone marrow plasma cells (BMPCs) from patients with MM, AL, and POEMS.
• Analysis of mutation burden and distribution in clonal and subclonal plasma cell populations.
• Binary matrix factorization to identify mutation-associated subgroups and clinical features.

Main Results:

• Recurrent lymphoid CH mutations (FAT1, KMT2D, MGA, SYNE1) and myeloma driver mutations (ZFHX3, DIS3) were identified.
• Lymphoid CH mutations were more prevalent in MM than in AL or POEMS and associated with aging.
• Mutation patterns revealed subgroups linked to progression-free survival (PFS), age, free light chain levels, plasma cell burden, and VEGF levels.
• MGA or SYNE1 mutations consistently correlated with poor PFS across MM, AL, and POEMS.

Conclusions:

• CH mutations partially explain the shared pathogenesis of MM, AL, POEMS, and MGUS.
• Specific mutations can identify patient subgroups with distinct clinical characteristics and prognoses.
• This research enhances understanding of PCDs and aids in personalized treatment strategies.