P-102: Thrombotic Significance in Plasma Cell Disorders: Do associated clonal hematopoiesis of indeterminate potential (CHIP) mutations increase the risk?

Introduction: The exact mechanisms of elevated thrombo-embolic risk in plasma cell disorders remain unclear. Whilst several factors such as therapeutic regimens, comorbid medical conditions and concurrent use of antiplatelet/anticoagulants can affect thrombotic propensity in these disease states have been reported; genomic alterations, particularly that of clonal hematopoiesis of indeterminate potential (CHIP) mutations which are somatic mutations noted to affect hematopoiesis is not well understood. Several have been linked to qualitative and quantitative platelet traits in previously described studies (Veninga et al Hematologica 2020, Vannuchhi et al, Semin Thromb Hemost 2013). We report genomic data and known thrombo-embolic events from 64 patients with plasma cell disorders within a year of their disease diagnosis or later.

Methods: In this retrospective analysis, clinical and bone marrow based genomic data (Tempus xT ® 684 gene DNA-based NGS platform) was gathered on 64 patients with a diagnosis of Monoclonal gammopathy of undetermined significance (MGUS), Multiple Myeloma (MM), Smoldering Myeloma (SM), AL amyloidosis (AMY) and Waldenstrom’s Macroglobulinemia (WM). CHIP mutations with a predilection for thrombo-embolic events (12 with increased platelet count and 4 with function) were collected as described in Veninga et al 2020. Venous thrombotic events (VTE), ischemic coronary events (ICE), and cerebrovascular accidents (CVA) within one year or after disease diagnosis were also abstracted.

Results: Twenty-two CHIP mutations were identified amongst all 64 patients. 11 being in MM, followed by WM (6), MGUS (4), SM (1), SP (0), and AMY (0). 18 of these CHIP mutations were known to increase platelet count and/or function, the most frequent ones being DNMT3A LOF (7,38.9%) and JAK2 GOF (3,16.7%). In 24 MM patients, 9 patients had a CHIP mutation which increase platelet count/function, of whom, 4 (44.4%) had a thrombo-embolic event (3 VTE and 1 ICD) whilst the frequency of thrombo-embolic events in the patients without CHIP mutations was 33.3% (5/15; 4 VTE and 1 CVA); (p 0.68, Fischer’s exact test). No thrombotic events were reported in MGUS, SM, and WM patients with identified CHIP mutations and increased platelet count/function. Of all the patients in the data set regardless of the presence of a CHIP mutation, a total of 9(14%) suffered a VTE, 3 (4.7%) CVA, and 4 (6.3%) an ICE within a year of disease diagnosis.

Conclusions: In this analysis of 64 patients, we identified a proportion of patients with CHIP mutations that affect platelet function and/or count as well as thrombo-embolic events around the time of their diagnosis or later however a clear association could not be established between them. Further studies are needed to inform of the thrombotic risk and the initiation of prophylactic anticoagulation in these disorders.