Monoclonal Gammopathy of Thrombotic Significance

Simple Summary It is being increasingly recognized that patients with monoclonal gammopathy (MG) who do not meet criteria for malignant disease and treatment initiation may have other manifestations that are linked to the unique properties of the monoclonal protein that are clinically significant and could provide a rationale for treatment. It has been recognized that patients with MG are at higher risk for thrombosis and a number of rare entities that include venous, arterial and micro-thrombotic events have been described. The hemostatic profile of patients with MG has not been ascertained yet and the major challenge is to identify patients with MG at high risk for thrombotic events and apply appropriate preventive measures. We propose a new umbrella term, monoclonal gammopathy of thrombotic significance, that creates a link between the M-protein and thrombotic events, posing the question of whether treatment initiation and/or long term anticoagulation is indicated for these, otherwise asymptomatic patients. The current review provides an overview of the thrombotic risk observed in patients with MG who do not otherwise require treatment. We discuss clinical and biomarker studies that highlight the heterogenous hemostatic profile observed in these patients and how knowledge has evolved over the past 20 years. Biomarker studies suggest shared biologic features between multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS), which involves both hypercoagulability and platelet activation. Hemostatic abnormalities identified in MGUS patients cannot be translated into clinical practice as they lack correlation to clinical events. The prothrombotic phenotype of MGUS patients has not been ascertained yet, but novel data on coagulation markers are promising. We also review rare conditions associated with the thrombogenic properties of the monoclonal protein that predispose to arterial, venous or microthrombotic events and demonstrate that the M-protein can be linked to clinically significant thrombotic events. Cryoglobulinemia, cryofibrinogenemia, cryo-crystaloglobulinemia and MG-related antiphospholipid syndrome are reviewed. We propose the new umbrella term "monoclonal gammopathy of thrombotic significance" (MGTS) to refer to significant, recurrent thrombotic events in patients with MGUS that provide a rationale for targeting the underlying plasma cell clone. Identifying MGUS patients at high risk for thrombotic events is currently a challenge.