Dissertation committee:
Ευστάθιος Καστρίτης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ, Επιβλέπων
Μελέτιος Αθανάσιος Δημόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μιχαήλ Βουλγαρέλης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ευάγγελος Τέρπος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Φλώρα Ζαγουρή, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μαρία Γαβριατοπούλου, Επίκουρη Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μαριάννα Πολίτου, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Venous thromboembolism (VTE) remains one of the most common complications in patients with multiple myeloma (MΜ) and approximately 10% of patients with newly diagnosed MM (NDMM) will develop VTE during their disease course. According to an older report on the incidence of thrombosis in patients with haematological malignancies, the crude rate of deep vein thrombosis (DVT) during an 8 year follow up of more than 6000 MM patients was 8%. Most events occur within the first months following diagnosis and treatment initiation and the rates are higher in newly diagnosed compared to relapsed or refractory patients. The most frequent localization is DVT. VTE events are associated with higher morbidity and most data support an inferior overall survival in MM patients with VTE. Compared to the standard VTE risk in the population, rates are higher also in pre-symptomatic stages of the disease like monoclonal gammopathy of undetermined significance (MGUS) pointing to a possible prothrombotic role or nature of the monoclonal plasma cell.
The thrombogenicity in myeloma is multifactorial and risk factors associated with VTE occurrence in MM patients have long been distinguished in patient-related clinical risk factors, myeloma-related risk factors and finally risk linked to the type of anti-myeloma treatment administered. The treatment regimen of choice is one of the major determinants of VTE risk; the standard 1-2% VTE rates associated with conventional regimens such as melphalan and prednisone increase to about 4% with immunomodulatory drug monotherapy and up to 26% in some reports when immunomodulatory agents (IMiDs) are combined with high dose corticosteroids or multi-agent chemotherapy. The coagulation profile of the MM patient is still poorly understood. Many groups have turned their research efforts towards delineating the coagulation abnormalities that result from the crosstalk between the monoclonal plasma cell, the bone marrow microenvironment and components of coagulation.
The International Myeloma Working Group (IMWG) 2014 statement and the European Myeloma Network Guidelines in 2015 proposed a risk stratification algorithm and relevant thromboprophylaxis guidelines for MM patients who receive IMiDs. The algorithm is based on limited clinical trial data and mostly on expert opinion. The recommendation is to use low dose aspirin for Newly diagnosed MM patients on IMiDs when one or none risk factors are present and prophylactic LMWH or dose-adjusted therapeutic warfarin when 2 or more risk factors for VTE are present for a duration of 4-6 months. There are no guidelines available for MM patients who are not on IMiD containing regimens. Recent reports demonstrate that the incorporation of the above recommendations in every day clinical practice is to say the least inconsistent. The rate of residual VTE rates remains high pointing to the suboptimal value and performance of the current risk stratification tools for VTE in MM patients.
Cancer associated thrombosis (CAT) is an area of very active research efforts and considerable progress has taken place since the introduction of the Khorana risk score in 2008 for VTE risk in solid tumors. Many groups have recommended that the incorporation of biomarkers of blood hypercoagulability and endothelial cell activation can increase the sensitivity of Risk assessment models (RAMs) for VTE risk identification. A biomarker can be either generic for all malignancies or disease specific but to be useful is should be measured with tools that are readily available in non-specialized laboratories. Improved versions of the Khorana score in terms of predictive value and enhanced performance with the incorporation of coagulation markers have been introduced (Vienna CATS, Protecht score and 4TS-COMPASSE RAM). The performance of these scores in MM is poor. Two clinical scores for VTE assessment have been presented recently (IMPEDE and SAVED) but these do not include biomarkers of coagulation, and were developed retrospectively. An effective and prospectively validated Risk assessment model (RAM) is therefore needed that can capture all aspects of the pro-thrombotic environment that exists in MM patients. In addition to the need for an MM-specific RAM there is a paucity of data regarding the most appropriate, safe and effective agent for thromboprophylaxis. Data from Randomized clinical trial is needed to answer questions such as what is the right agent and for which MM patient and what amount of time? The role of Direct oral anticoagulants (DOACs) or Non-vitamin K oral anticoagulants (NOACs) is being increasingly investigated in CAT treatment and prevention.
The current thesis is part of the ongoing prospective, investigator initiated ROADMAP-MM-CAT (PROspective Risk Assessment anD bioMArkers of hypercoagulability for the identification of patients with Multiply Myeloma at risk for Cancer-Associated Thrombosis, ClinicalTrials.gov identifier NCT03405571) trial. The aim of the trial is to explore the coagulation profile (plasma and cellular hypercoagulability) of patients with plasma cell dyscrasias and in particular Multiple Myeloma (MM), Smoldering Multiple myeloma (SMM) and monoclonal gammopathy of underdetermined significance (MGUS) and to determine which MM patients are at high risk of VTE and therefore eligible for thromboprophylaxis for VTE. We also aimed to identify in NDMM patients relevant biomarkers of hypercoagulability, variables related with MM and clinical predictors of VTE risk that could be combined in a RAM for CAT in MM patients. The primary end point was the occurrence of symptomatic venous thromboembolism and secondary end-points mortality, major bleeding, disease response to treatment and progression and morbidity during follow-up.
Patients with a new diagnosis of MM, SMM and MGUS followed up in the department of Clinical Therapeutics, Plasma cell Dyscrasia Unit, General Alexandra Hospital who were >18 years of age and not on anticoagulation treatment were enrolled in the study. A clinical research form was completed and blood tests were obtained at enrollment (baseline), 3 months, 6 months and 12 months. An extensive panel of coagulation biomarkers were measured by centralization of blood samples to the core laboratory at Thrombosis Center, Service d'Hématologie Biologique, Tenon University Hospital, Paris. A total of 480 patients with a new diagnosis of MM, SMM and MGUs were enrolled in the study from June 2014 up to June 2019. Risk stratification was performed according to the IMWG guidelines and thromboprophylaxis was initiated accordingly. Data and sample analysis has been performed in a total of 144 MM patients, 80 SMM patients and 54 MGUS patients who were enrolled from June 2014 to June 2017. At 12month follow-up of 144 MM patients cumulative VTE rate was 10.4%. No events were observed in the SMM and MGUS groups. Most events occurred during the first 3 months since treatment initiation and the most common localization was Deep vein thrombosis (DVT). The VTE rate was not significantly associated with the type of treatment patient’s received (IMiD-based versus non-IMiD based) as the study was not powered to detect such differences. In addition there was no association between VTE occurrence and the type of thromboprophylaxis patients received. NDMM patients showed biological signs of cellular and plasma hypercoagulability and endothelial cell activation. Procoagulant phospholipid clotting time (Procoagulant-PPL) was shorter, P-selectin levels lower and thrombin generation attenuated overall compared to healthy subjects. Patients with SMM and MGUS also showed signs of cellular and plasma hypercoagulability with a similar but not identical profile to MM patients. Along the MGUs- SMM- MM continuum there was an increase in D-dimer levels, fibrin monomer levels and longer thrombin generation lagtime.
Among clinical parameters studied only pulmonary disease as a marker of chronic inflammation was significantly associated with VTE occurrence. Surprisingly monoclonal M-protein was inversely associated with VTE occurrence. The significance of this finding needs to be evaluated in future larger cohorts. Following 3 months of treatment most of the coagulation abnormalities detected at baseline were not reversed. The changes that were detected include a reduction in tissue factor (TF), tissue factor pathway inhibitor (TFPI), FVII and D-dimer and an increase in FV levels. Among coagulation biomarkers, longer Procoag-PPL®, lower Endogenous thrombin potential (ETP) and higher levels of Tissue factor pathway inhibitor (TFPI) were associated with VTE occurrence. Multivariate analysis showed that Procoag-PPL® and ETP were independent risk factors for VTE. A multivariate logistic regression model was developed and a score formulated. In the score 1 point was given for Procoag-PPL® ≥47, and 1 for ETP <1087 nMxmin), or 0 for Procoag-PPL® <47 sec, and ETP ≥1087 nMxmin respectively. The patients were stratified in two groups; high and intermediate/low risk group. The VTE rate was 5% in the intermediate/low risk group and 17.5% in the high risk group. The sensitivity and the specificity of the score was 71.4% and 61.8%, respectively.
Based on our data Procoag-PPL® and ETP can be prospectively incorporated into a RAM for VTE in MM in combination with clinical and disease risk factors. Such a score would optimize risk stratification of patients with MM and would allow selection of patients who are candidates for thromboprophylaxis in an efficient and safe manner. The incorporation of such a model in published guidelines by expert groups and its use in clinical trials that assess the safety and efficacy of newer anticoagulants will lead to a considerable reduction of the VTE rate in the MM population. The development of such a score is part of the ongoing ROADMAP-MM-CAT clinical trial.
