I really do think that one of the concept art pieces was of a Prothean in battle armor and we're going to see a Prequel set in that Era.
That's honestly the only 'prequel' I'd be ok with.
I don't see Prothean battle armour, and I don't think they'd gamble on a setting totally devoid of not only humans, but a considerable chunk of the established universe that fans got attached to. Humans are that rock I think necessary to make it a mass market title, and Prothean era not only denies the game that, but also Turian, Asari, Quarian, Geth, Krogan, and every other species.
A truly blank slate would be cool, but I don't see them doing it. Not with the amount of work required, and the gamble it would be with the series.
If it's a prequel, I figure their options are pretty limited. Either:
- Very early days of human exploration, covering conflict with the Batarians. Reaper threat irrelevant.
- First contact war. Extremely limited without major retcons introducing species and conflict in more prominent roles.
Otherwise it has to be set sometime in the trilogy (While Shepard was comatose? During the ME3 war?), or they gotta go sequel.