After seeing a few blogs pertaining to how a sequel to Mass Effect 3 would work, I decided it was time for me to throw my two cents into the lot.
If Bioware does indeed decide to make a direct sequel, they are going to have a hell of time finding a way to write around the ending. Their repercussions are wildly different from each other and make it that much more harder to make a sequel. Let's take a look at the different options. With the endings, there's the possibility that:
A. Everyone is dead and the Reapers eventually succeeded in their extermination. Obviously, this creates a problem if they ever they want any of the current races in the game. Or they could all be back as ghosts WOOooooOOOoOOOo. Yeah, that was terrible wasn't it?
B. Shepringer and his Reaper posse are patrolling the galaxy with the liberal use of "Assuming Direct Control." This one isn't that big of an issue, considering you could just have the Reapers mysteriously disappear for some reason similar to the Warden from Dragon Age: Origins.
C. Everyone is part synthetic or something, which I guess makes it easier for people that like to rave. This is not something that can be solved by simply making everyone a bit more glowy and having a few lines referencing the fact (I assume it would have every conversation end with "Did I mention I'm also part synthetic?")
D. Everyone could have died in a fiery blaze and all synthetics have been destroyed. This one doesn't really require any elaboration.
Not only that, the sequel would need to take into account the choices that we made throughout the game. Were the quarians or geth genocide-ed or did they end up holding hands and learning the true meaning of Christmas? Do we get to see more Krogan babies, which are the most adorable things in the history of ever by the way, or are they now holed up in Tuchanka thinking Shepard is a massive dick? Hell, even the fate of the Hanar/Drell adopted homeworld is left to your choice. Then again, we wouldn't have to hear "Enkindlers" again. Then again, Blasto.
After some thought, I've come up with some possible paths Bioware could take to solve these problems.
Back to the Future.... or the More Future
I've been hearing this one a lot, they could set the game so far into the future to the point the results of these choices would be irrelevant. This one has some issues but it's better than completely nullifying player choice. My major gripe with this one however is that if it's set too far in the future it would be a completely different game. It would more than likely also require a generous amount of hand-waving in order to explain the results of certain choices without creating too many wildly different solutions.
Retcons, Retcons Everywhere AKA The DA2 Approach AKA Just F*** it
Bioware could always just create a "canon" ending for ME3 and work from there. Obviously, this would create quite a bit of fan backlash from those that liked the ending and didn't alike. Personally, I think retcons should only be used as a last resort. Only when they've exhausted every approach possible and the lore is broken enough where they can't make a sequel will I even CONSIDER forgiving them if the decide to take this route.
A Bad Case of the Sequelitis
They could always, you know, NOT make a direct sequel. There's plenty of room in the lore for a game set in a different time period so there's always that option. Also, if they need to jump hoops just so that the game could remain plausible in regard to the ending of ME3, what's the point then?
And Now for Something Completely Different
I'll be frank, I'm not a game designer nor am I writer. All I know is what I like and what I don't like, this is why I rarely mention specifics in suggestions. Bioware could always take a path wildly different from the ones I mentioned. Whether it will be the right one only time will tell.