I don't really see them 'pulling a Nier' as you put it.
At most... I'd say they might pull a Legacy of Kain.
Let me explain...
In the original game, Blood Omen 1, back when they thought it was the only game they were going to make out of this, they gave the player one of two choices... Either A) sacrifice themselves to restore the world's balance, or B) Refuse the sacrifice and doom the world to an eternity of decay.
Ending B. turned out to be the canon ending... and they, arguably, retconned A so that it would have actually resulted in a far worse state of things than B. (don't worry, they fully justify it within the context of the series... did I mention that this is a series about time travel and vampires? And... proper vampires, by the way, not the Twilight imitation brand)
Point is, the Legacy of Kain series was a rare series in which the first game's 'bad ending' was canon, and they rolled with its consequences and spent the rest of the series having the two main characters at first trying to prevent it from happening (they quickly give up on that), and later trying to fix or at least mitigate the damage that ending B entailed. (Did I mention that Simon Templeman and the late Tony Jay are in this series?)
So, basically, what I see happening is that Bioware will pick one of ME3's endings as cannon and go with that, and explore its consequences. This approach would be much more manageable from a writer's perspective.
Either that... or they'll pull an Invisible War (the often maligned sequel to Deus Ex), which sort of had all of the original's endings happening at the same time... at least partially in each case. Not saying this approach won't work, but as Invisible War proved... its tricky to get it right without pissing off a lot of fans.
Ideally though?
I'd like to see a game that either takes place in the universe's far future or far past.
As in... either A) playing as the relatively distant inheritors of the universe... or a previous race that fell to the Reapers, like the Protheans or one even older that we haven't met yet.
EDIT:
Actually, THE IDEAL situation is if Bioware handed their universe over to someone else... like say... Obsidian, who have repeatedly proven they can write much deeper, more interesting stories than Bioware can. Bioware may good with dialogue... but when it comes to writing... Obsidian's better at everything else involved in telling a story.