MM-080: Platelet Hyperactivation in Multiple Myeloma Is Also Evident in Premalignant MGUS Patients and Persists During Treatment Initiation

Abstract

Context: Thrombotic events are a common complication in multiple myeloma (MM) and smouldering myeloma (SM) patients, and are increasingly being recognized as a feature of MGUS. Platelet hyperactivation has been implicated in this prothrombotic state but remains to be characterized in MGUS patients and MM patients initiating treatment, when thrombotic risk is greatest. Objective: To address this, we evaluated platelet activation status with an extended panel of platelet activation markers (PAC-1, P-selectin, CD63, Annexin V) and platelet responsiveness to agonists (ADP, TRAP-6) in patients and healthy controls (HC). We also assessed additional parameters; reticulated platelet levels, platelet-leucocyte aggregates (PLA), and platelet-associated immunoglobulins (PAIg). Design, Setting & Patients: MGUS (n=19) and SM (n=4) patients who lacked anticoagulant use and underlying bleeding, thrombotic, and renal disorders were recruited from outpatient clinics. Newly diagnosed MM (n=12) patients were recruited using same criteria. A subset of MM patients (n=8) provided samples two months post-initiating treatment. HC (n=16) underwent paraprotein screening to exclude MGUS status. Interventions: No interventions to routine care. MM patients received Bortezomib (Velcade), dexamethasone and Lenalidomide (Revlimid) (VRD) (n=4) or cyclophosphamide (VCD) (n=4), and aspirin thromboprophylaxis (n=5). Main outcome measures: Platelets are hyperactivated and hyporesponsive to agonists in MGUS and SM/MM patients at diagnosis and in patients undergoing treatment. Results: Median platelet activation marker levels were elevated in patients versus HC, significantly for MGUS in terms of PAC-1 (0.72 v 1.7%, p=0.024), CD63 (0.55 v 1.29%, p=0.003), Annexin V (0.47 v 1.61%, p=0.004). In MM undergoing treatment, P-selectin (1.00 v 2.46%, p=0.010), CD63 (0.48 v 1.32%, p=0.020) and Annexin V (0.54 v 1.51%, p=0.038) were significantly elevated versus HC at diagnosis and remained elevated after treatment. MGUS patients had significantly reduced P-selectin levels in response to ADP (34.85 v 10.77%, p=0.005). In MM, hyporesponsiveness was evident versus HC at diagnosis and following treatment in terms of PAC-1 (58.5 v 34.91%, p=0.009) and P-selectin (42.21 v 23.49%, p=0.028). PLA (2.38 v 5.84%, p=0.023) and reticulated platelet levels (1.82 v 24.5%, p=0.031) increased significantly in MM after treatment. PAIg were evident in subsets of MGUS and SM/MM patients. Conclusions: This study reports changes in platelet parameters at various points in MM disease progression. Further investigation of the predictive and prognostic value of platelet dysregulation in such patients is warranted. Funding: Irish Research Council (GOIPG/2017/952) & TRAP Award, College of Medicine & Health, University College Cork.