This queries stopforumspam.com every time a comment is submitted, and if it's a known spammer, the comment is marked as spam. If it's not a known spammer, it is not marked as spam. If something doesn't work for some reason, it's set to pending human review. It's a crazy idea, I know, but I think it's so crazy it JUST MIGHT WORK.
PLEASE NOTE, stopforumspam has a limit of 20,000 calls to its API per day. If you're getting 20,000 comments a day (god help you), don't use this plugin or they'll think you're DoSing them.