If we wanna speculate here, y'know what I would have liked to have seen? Mass Effect 3 not actually ending the Reaper war, but simply beginning it, or at least beginning to turn the tide in biological life's favor. Liken Earth to the battle of Stalingrad, and then have do a whole other trilogy about the war. To me, the Reaper War sounds like something that should have taken MUCH longer than it actually did. It would have been cool to see it become a five-to-six-year conflict not unlike WWII -- truly the great war of their time. But whatever, there are probably much better things BioWare could do.
Anyway, if they are indeed moving beyond the ME3 ending, I think they need to tackle one unavoidable fact -- that humanity and the other races have all of a sudden been catapulted from being a Type II civilization to a Type III with galaxy-wide control, or will very soon become one. Fuck rebuilding relays, they've probably figured out the travel technology behind them, and might be able to straight-up build it into ships. The Protheans figured out how to, essentially, build a relay that looked small enough to fit on a large ship. Not to mention, at the time of ME1, only about two percent of the galaxy had actually been explored. Who the fuck knows what other civilizations might have remained hidden. I think with that in mind, exploration needs to be a major theme here.