This is my general view of things. I also think the next game should directly address the fallout of ME3 within a short time span of 50-100 years. BioWare needs to choose an ending, 90% chance it will be Destroy but with some caveats like the Geth survived, and then set the game in that universe where things have noticeably changed due to a near galactic wide extermination and all out war with a superior entity.
I don't want the game to dwell on the events of ME3, I don't need them to work overly hard to explain what happened and why, just choose the universe you want it to be in and show the results of that choice as we explore it and play the game.
There are a lot of things they need to address. Like how will the different races recover, or falter, after their near extinction. What kind of alliances and decisions will they make because of that. Play around with how easy or rather difficult it may be to repair and restore the Mass Relay System and how long periods of isolation maybe have changed some areas and portions of races. Would there be a push for new means of galactic travel outside the Mass Relays? How would it work, and more importantly what would there be to find in the vastness of space not connected by the MRS and who would be daring enough to explore those uncharted areas? Hint maybe the player?
How would having tons of dead Reapers affect the advancement of technology and science. Would that initiate another Mass Effect similar to what humans experienced after the discovery of the Prothean base on Mars? How would various races and factions within them feel about using the same technology that nearly wiped them out. Would government ban Reaper tech or heavily regulate it producing a vast blackmarket and industry for secretly acquiring, researching and developing Reaper based tech.
Put us in this galaxy and let us explore, literally and figuratively, the changes that have occurred after the events of ME3. My biggest fear is that they'll just explain away the events of ME1-3 and return things to business as usual, here's ME4 and a universe not much different from before.