Positioning siponimod and the post-treatment gap: the unmet needs of SPMS patients in Italian real-world practice

Background: Siponimod, a selective sphingosine-1-phosphate receptor modulator was approved for patients with Secondary progressive Multiple Sclerosis (SPMS) with ongoing disease activity. However, its real-world positioning and management after discontinuation remain challenging. Objectives: To evaluate the real-world use of siponimod in Italian real world setting, focusing on discontinuation rates, possible predictors, and post-treatment management. Methods: A retrospective, multicenter study on patients treated with siponimod across six Italian MS centers. Demographics, prior disease modifying therapy (DMTs), reasons for discontinuation, adverse events, and subsequent therapies were collected. Statistical analyses included propensity-adjusted Cox model. Results: A total cohort of 188 patients (63.8% female, median age 52 years) was enrolled, out of them 76(40.4%) discontinued siponimod, with a median treatment duration of 26 months. The main reason for discontinuation was safety concerns (72.4%), particularly persistent lymphopenia (43.6%) and recurrent infections (27.3%). Disease activity accounted for 27.6% of discontinuations. No significant demographic or clinical predictors of discontinuation were identified. After discontinuation, 49 patients (64%) started a new DMT, most commonly ocrelizumab ( n  = 22) or cladribine ( n  = 15), while 25 (32.9%) received no further therapy. Conclusion: High discontinuation rates, mainly due to safety, and frequent post-treatment gaps highlight the need for improved, individualized management strategies for SPMS after siponimod.