I don't think they'd go with the "alternate universe" route, simply because of the fact that they'd build an extremely confusing experience, where especially the more casual (read: not lore-hardened) ME fans would be alienated by having trouble to understand how and why certain plot points and lore points change due to the alternate versions of some timeline events: You need to be extremely firm in your knowledge of the lore to have a sensible picture of how the alternate universe looks. Someone earlier in this thread posted how no Reapers would mean no Rachni Wars, which would mean no Krogan uplifting, which, in turn, means no genophage as a collaboration between the Salarians and the Turians, which might have political effects on those parties, too, etc... etc... It's opening a can of worms, really.
I find it more likely that a post-ME3 game would simply settle for a less epic, more focused plot: No matter which ending happened, there will still be "Citadel space" and "Terminus systems", there'll still be thieves (like Kasumi), Justicars, police forces (like C-Sec, or the police forces on Illium), and so on, so there's plenty of place to tell stories that do not involve gigantic galactic implications, which are more likely to be heavily affected by ME3's endings. In fact, from the perspective of many "normal" people in the ME universe, life in a post-Control and post-Destroy galaxy will be pretty much indistinguishable, and even post-Synthesis won't touch on the basic workings of society. There's plenty of opportunity there, and especially if you analyze ME1 and ME2, you'll realize that many of the subplots aren't actually that epic, galaxy-shattering anyway: It's just ME3, with plots like Tuchanka and Rannoch and, of course, the resolution of the Reaper plot, that suddenly had Shepard participate in the gigantic events that change everything.
As far as sequels in the far future are concerned: Well, ME is not Star Wars, where technology and politics seem to be pretty much at a stand-still for millions of years. If they make a sequel thousands of years in the future, they could just as well make an entirely new IP coincidentally set in the same universe, but that would be nothing more than a quick nod to the ME series, rather than a continuation: In that time span, the galaxy would have changed so much that it is virtually indistinguishable from a new IP, save for the fact that it has the ME logo on the packaging.
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