The spam issue sucks balls to live through, but it is a very interesting case study...
What I'm experiencing personally is sporadic posts, each from a random account set up on a random instance. One post per account/instance. Even instance level blocking is completely useless against this.
Given how many instances there are out there, poorly maintained (if maintained at all) there's almost no way to prevent this. Unless the spammer finally exhausts the supply of instances, at which case the only effective action is to suddenly create a massive blocklist of dozens of minor Masto/Misskey instances.