OBJECTIVES: To determine whether extending anti-CGRP mAb treatment beyond 3 years influences migraine course, we analyzed migraine frequency during the first month of treatment discontinuation following three 12-month treatment cycles (Ts). METHODS: This multicenter, prospective, real-world study enrolled 212 patients with high-frequency episodic migraine (HFEM) or chronic migraine (CM) who completed three consecutive Ts of subcutaneous anti-CGRP mAbs. Discontinuation periods (D1, D2, D3) were defined as the first month after T1, T2, and T3, respectively. The primary endpoint was the ≥ 50% response rate at D3 compared to D2. Secondary endpoints included changes in monthly migraine days (MMD), monthly headache days (MHD), monthly analgesic intake (MAI), numerical rating scale (NRS), Headache Impact Test-6 (HIT-6), ≥ 50% response rate at D3 versus D1 and D2, and relapse rates to CM or medication overuse. RESULTS: At D3 vs. D2, significant improvements (p <
0.001) were observed in the ≥ 50% response rate (77.8% vs. 53.8%), MMD (- 2.1 ± 1.7), MHD (- 2.9 ± 2.4), MAI (- 2.6 ± 2.4), NRS (- 0.7 ± 1.3), and HIT-6 (- 7.2 ± 5.9), with lower relapse rates to CM (2.3% vs. 18%) and medication overuse (1.3% vs. 10.1%). Compared to D1, D3 demonstrated greater benefits (p <
0.001) in MMD (- 2.6 ± 1.9), MHD (- 5.8 ± 3.3), MAI (- 4.9 ± 3.4), NRS (- 1 ± 1.6), and HIT- 6 (- 9.4 ± 7), alongside higher ≥ 50% response rates (77.8% vs. 25%) and reduced relapses to CM (2.3% vs. 67.7%) and medication overuse (1.3% vs. 34.2%). DISCUSSION: Three years of anti-CGRP mAb treatment revealed a progressive increase in the proportion of ≥ 50% responders (D1: 25%
D2: 53.8%
D3: 77.8%) and substantial reductions in migraine burden, suggesting that prolonged treatment may favorably modify migraine course.