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

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. To evaluate the real-world use of siponimod in Italian real world setting, focusing on discontinuation rates, possible predictors, and post-treatment management. 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. 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. High discontinuation rates, mainly due to safety, and frequent post-treatment gaps highlight the need for improved, individualized management strategies for SPMS after siponimod. Siponimod exit strategies and therapeutic gap Siponimod is a treatment for secondary progressive multiple sclerosis (SPMS), aimed at slowing disease progression. This study reviewed real-life data from six Italian MS centers, including 188 people treated with siponimod. About 40% stopped treatment after around two years, mostly due to side effects such as low white blood cells or infections. Some stopped because their MS became active again. After discontinuation, two-thirds started another therapy most often ocrelizumab or cladribine while one-third received no further treatment. No clear patient characteristics predicted who stopped therapy. These findings show that siponimod is often discontinued for safety reasons and that better strategies are needed to guide treatment choices and ensure ongoing care for people with SPMS.