I actually wouldn't mind a prequel in this case. I mean if they're intent on making a more pure-bred action game then the First Contact War would seem to be the obvious choice. Or they could dare to be different and have something with no humans at all. Like say play as a Korgan or Asari over the course of a millennia; starting as a young soldier/commando in the Rachni Wars, going through the rebellions and surviving just long enough to see humans appear on the scene.
It's difficult to speculate on what a post ME3 game might be without knowing how ME3 will end. From what I gather though there's going to be a lot more variability in the end games this time around so anything set after these events will be tricky. They'd either have to pick a 'canon' ending (which would be a shame) or else set it in such a way that the larger state of the galaxy has little effect on the story.
Whatever they come up with, if it's an MMO, I won't be playing it.