A next-generation S1P receptor modulator, siponimod (BAF312), that also engages S1P1 (and S1P5), showed positive results in a phase III secondary progressive MS trial (Kappos et al., 2018), which is consistent with a CNS MOA involving ieAstrocytes, while other related agents like ozanimod (Cohen et al., 2016), etrasimod (Buzard et al., 2014), and ponesimod (Bolli et al., 2010; Vaclavkova et al., 2014)—having similar, albeit distinct, S1P receptor engagement properties—may also have direct CNS effects in MS through ieAstrocytes. Here, S1PR1 is linked to myeloid sarcoma.