A Retrospective Review Assessing the Development of Myelodysplastic Syndromes in Patients with Plasma Cell Dyscrasias

Introduction

Myelodysplastic syndrome (MDS) are hematopoietic disorders defined by dysplasia of the myeloid lineage accompanied by persistent cytopenias, and recurrent cytogenetic abnormalities (MDS). Whilst therapy related myeloid disorders in patients with Multiple Myeloma have been well described, there is lack of information regarding co-occurrence of these disease states in early plasma cell disorders as well as multiple myeloma at diagnosis which may also then allude to whether there is a founder effect to the clones. Recent advances in commercial sequencing assays of genomic data have allowed for identification of relevant gene mutations in patients with hematologic malignancies, such that the presence of these gene mutations have been incorporated into classification systems. In our study, we aimed to assess the occurrence of reported MDS in patients with plasma cell disorders i.e. Monoclonal Gammopathy of unknown significance (MGUS), Smoldering myeloma (SM) and Multiple myeloma (MM) as well as relevant gene mutations that would be implicated in the pathogenesis of MDS even in those patients who do not meet the full criteria for MDS (clonal hematopoiesis of indeterminate potential; CHIP mutations).

Methods

In this retrospective review, clinical and bone marrow based genomic data (Tempus xT ® 684 gene DNA-based NGS platform) was gathered on 57 patients with a diagnosis of MGUS, SM, and/or MM. Pathogenic gene mutations that are frequently associated with MDS were reported in our patient population. Bone marrow morphologic assessments for MDS related changes were also collected at the time of genomic data abstraction. Those patients who had defined MDS were further subclassified using the World Health Organization 2022 fifth edition classification system. Those observed as having subtle MDS findings on bone marrow biopsy, but with identified CHIP mutations, not meeting criteria for MDS, were also identified.

Results

Among 57 patients with MGUS (28), SM(9), and MM(20), 2 had met criteria for defined MDS at the time of their assessment. An additional 5 had bone marrow morphologic findings concerning for MDS, but did not meet criteria to be fully defined. A total of 14 myeloid disorder related pathogenic mutations were identified in our patient population (6 in MM at disease diagnosis, 7 in MGUS, and 1 in SM). Overall, the most frequently observed recurring mutations in the cohort were that of DNMT3A (57.1%, mean VAF 4.45%), TET2 (14.3%, mean VAF 4.0%), and SF3B1 (14.3%, mean VAF 39.2%). Patients with defined MDS had recurring pathogenic mutations in genes SF3B1, ASXL1 and DNMT3A.

Discussion

In our cohort, we identified several patients with features both diagnostic and suggestive of myeloid disorders (MDS) during work up for a plasma cell disorder, in particular MGUS, SM, and/or MM prior to therapeutic intervention. Molecular work up also identified gene mutation subsets in plasma cell disorder patients that have otherwise been implicated in the pathogenesis of myeloid disorders. The identification of both morphologic and molecular abnormalities in our cohort may inform therapeutic considerations as well as vigilance for the discovery or evolution of myeloid disorders during follow-up , in particular when unexpected cytopenias or new clinical concerns emerge. We expect to design future prospective studies, based on our observations, to further inform of the risk of myeloid disorders in our plasma cell disorder patient cohorts, as well as understand its impact on therapies such as immunomodulatory agents, alkylators and/or autologous stem cell transplant.