Nearly 10% of newly diagnosed multiple myeloma (NDMM) patients develop a venous thromboembolism (VTE) episode during their disease course, despite current thromboprophylaxis strategies. Changes in hypercoagulability in these patients after treatment have been analyzed using the thrombin generation (TG) assay, the results being discrepant, probably due to the use of semi-automated techniques. This study aims to assess changes in TG measured by a fully automated analyzer. This prospective and multicentric study included NDMM patients from 8 centers (December 2018-September 2023). Fully automated TG was measured at baseline and after 1 and 4 cycles of treatment with ST Genesia® analyzer. Among 100 NDMM patients, a significant decrease was observed in velocity index (after 1 cycle) and peak height (after 4 cycles) and alongside increased sensitivity to thrombomodulin (after 4 cycles), indicating a reduction in hypercoagulability post-treatment. No differences in TG were observed according to the depth of response after 4 cycles. Patients on daratumumab-containing regimens experienced a transient increase in TG after cycle 1, whereas those on proteasome inhibitors (PI)-containing regimens showed a significant reduction in peak height and velocity index after 4 cycles. The development of a VTE event was associated with increased mortality, but there was no association between VTE development and TG results at baseline. Hypercoagulability decreases with anti-myeloma treatment, especially in those receiving PI-containing regimens. These changes in TG are not related to the depth of response to treatment.