I believe Bioware has already confirmed that ME3 will not be the last game to take place in the Mass Effect universe and that ME3 was the conclusion of Shephard's story but not the Mass Effect Universe. So my question is how would they even go about making another game set in the ME universe when that universe at least as we know it has been effectively destroyed. All the endings contain the destruction of the Relays which is the backbone of Galactic Civilization. Not to mention the corny synthesis ending which as you might recall utilizes space magic to make all the species half robot. Insert facepalm here. Potentially, the Quarians and the Geth could both be wiped out and the Krogan can be facing almost certain extinction. To even make a new game work would probably necessitate retconning a lot of ME3 content especially the ending.