Patterns of Venous Thromboembolism (VTE) Following Monoclonal Gammopathy of Undetermined Significance (MGUS) and Multiple Myeloma (MM) among 4 Million U.S. Veterans.
Authors: Landgren Ola , Fears Thomas R. , Turesson Ingemar , Bjorkholm Magnus , Kristinsson Sigurdur Y. , Gridley Gloria , Caporaso Neil E. 
Published: April 2020

Abstract
Background: VTE risk in MM patients has been reported to be 5 to 50-fold higher than the crude population incidence of 0.5 per 1000 person-years. The introduction of oral immunomodulatory drugs (e.g. thalidomide and lenalidomide) has contributed substantially to the increased risk of VTE in MM, however the precise contribution of host and drug related mechanisms remain unclear. Recently, 2 small studies reported that MGUS is associated with an elevated VTE risk suggesting that VTE might be an early marker for MM transformation in MGUS patients.
Objective: To define patterns of VTE following MGUS and MM among adult male U.S. Veterans.
Patients and Methods: The cohort was identified from review of discharge diagnoses in hospital medical records for inpatient hospitalizations at 142 nationwide U.S. Veterans Affairs (VA) hospitals between October 1, 1980 and September 30, 1996. The target population for VTE incidence calculation included all (N=4,201,697) male veterans hospitalized at least once at age 18 or older who survived one year after index hospital visit. Mean follow-up was 10 years. For estimating the risk of VTE following MGUS and MM, all MGUS and MM patients were followed until the diagnosis of a first VTE, a MM diagnosis for MGUS cases, death, or the end of the observation period, whichever came first. The estimated cumulative probability and 95% confidence intervals of developing VTE among MGUS and MM cases used Kaplan-Meier methods.
Results: We identified 22,781 VTE events in the entire VA population (crude incidence: 0.5 per 1000 person-years). Among 2424 MGUS and 6282 MM patients, 18 (1.7 per 1000 person-years) and 83 (4.2 per 1000 person-years) developed VTE, respectively. The estimated cumulative risk of developing VTE 4 years after MGUS/MM was significantly lower for patients with MGUS (0.47%; 0.15%–0.78%) versus MM (1.80%; 1.37%–2.22%). After 5 years of follow-up the relative risk of VTE following MGUS (vs. MM) increased significantly and 8 years after MGUS/MM diagnosis the cumulative VTE risk was very similar for patients with MGUS (1.91%; 0.84%–2.96%) and MM (2.23%; 1.62%–2.83%). Among MGUS patients there were 229 (9.4%) who progressed to MM; only 1 of these patients developed VTE prior MM.
Conclusions: The crude incidence of VTE among U.S. Veterans was similar to that reported in prior population-based studies. We found 4-fold and 8-fold elevated crude VTE incidence among MGUS and MM patients, respectively. MGUS patients had a low cumulative VTE risk during the first years of follow-up but over time approached that of MM. The VTE risk in MGUS patients rose significantly after 5 years of follow-up and at 8 years of follow-up the cumulative VTE risk was similar for MGUS and MM. These results suggest there are underlying gradually progressing pathogenetic mechanisms in MGUS reflected in increased hypercoagulation, e.g. increased angiogenesis, elevated IL-6 and TNF secretion, and acquired cytogenetic lesions such as (11;14) translocations. Interestingly, chromosomal translocations involving the immunoglobulin heavy-chain (IgH) locus have been proposed as early events in the development of both MGUS and MM. However, we found no evidence for VTE being associated with MM transformation in MGUS.