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Background: Multiple myeloma is a hematologic malignancy which confers a high venous thromboembolic risk. This risk is linked to patient-related factors, disease-specific mechanisms, and antimyeloma therapy, especially immunomodulatory drugs. Some studies have suggested that the thrombin generation assay may be a predictive marker of thrombosis. This study aimed to assess the hypercoagulable state in patients with multiple myeloma at diagnosis and after myeloma therapy., Methods: Thirty-one patients with multiple myeloma were included in a prospective study and were compared with 31 matched controls with age and gender. Thrombin generation assay was performed in patients at diagnosis prior to treatment initiation and at the end of myeloma therapy, and in controls. Parameters of lag time, peak thrombin concentration, time to peak, endogenous thrombin potential, and velocity index were analyzed., Results: Median age of patients at diagnosis was 58 years (11 men and 20 women). Twenty-three patients (74%) were classified as high vascular risk and received thromboprophylaxis. No thromboembolic events have been reported during follow-up, except a symptomatic pulmonary embolism in one patient which occurred at diagnosis. At baseline, patients with myeloma had significantly elevated velocity index as compared to controls (178 vs 128 nmol/L/min; P = .013). High-risk patients showed an elevation of plasma thrombin generation as compared to low-risk patients (endogenous thrombin potential = 1244 vs 1052 nmol/L/min; P = .043). Myeloma therapy did not significantly change the thrombin generation parameters., Conclusion: Thrombin generation appears to be higher in patients with myeloma compared with controls, especially in high-risk patients, and does not change significantly after treatment completion., (© 2019 John Wiley & Sons Ltd.)