User blog comment:TheUnseelieCourt/Next Mass Effect To Be Developed By Bioware Montreal/@comment-2250460-20121112203419/@comment-213828-20121112214908

In short, the only way they could do a sequel would be to: A) Create several different styles of gameplay/storylines to fit to everyone's individual Mass Effect 3 (like Synthesis players get special Synthesis powers that Destroy and Control players don't).  That would be way too costly and take too much time.

B) Decanonize all but one of the endings and make it impossible to import an ME3 save unless you chose the "official" ending - which would piss a lot of people off.

C) Have the game take place in an entirely different galaxy that is not affected by the events of the original trilogy. This might actually work.