So we all knew that the Omega DLC was in the works the moment Aria showed up and we didn't end up retaking the place in the game. No surprise there, but it's about time. I'm surprised they didn't do this one first honestly. I wonder if they did the Leviathan DLC first in order to try to make the ending work better.
Also, we already knew they weren't done with the universe. They said that there would be games after Mass Effect 3. It's just that ME3 would finish Shepard's story. I agree that it's kind of hard to follow the whole, "Entire galactic life as we know it is doomed!" story, but it can be done. So, on to ideas!
Set the game before the Reaper invasion. Maybe during one of the many wars we always hear about. Krogan Rebellions, Rachni Wars, First Contact War. There are plenty to choose from. There just better not be a single HINT of Reapers anyway. No character going, "Hm...what is this strange machine?" because Shepard was the first person to figure them out and start really talking about them. I don't want there to be another person before her going, "Hey, look. There's this evil race of machines out there!"
Second idea is set it during the rebuilding of the galaxy. Yes, the galaxy is saved, but it's still going to be a mess. There are going to be plenty of criminals trying to exploit people, gangs roaming areas, places that need rebuilding but are too dangerous. And the Leviathans didn't exactly sound friendly.
You could also bring Shepard back. It wouldn't be hard. In destroy ending, she's still alive and the crew goes to find her. In control, all that needs to be done is build her a body like EDI's and bam! Finally, since synthesis is already magic, I'm sure they can recover her essence and bring her back that way. Fun times, although I'm sure millions of fans would be really mad if they did any of those.