Well, Firefly fits in with the "scattered remnants of galactic society" motif. Bunch of backwater planets, colonies, moons, cut off from the rest of civilized space, turned into a sort of No Man's Land, with its inhabitants trying to eke out a living with whatever they can scrape together. With, of course, the inevitable mercenary and gangster groups moving in to establish control.
ME has already done this as minor sidequests with typically one-off characters, but always had the larger Reapers story to tell, so these had to take a backseat. But one big reason why people loved the trilogy was for those genre moments. Mass Effect wasn't just a sweeping space opera, because it pulled in a lot more than that.
And hey, the large story is done. It's time to start filling everything else out. Would anyone expect BioWare to focus a trilogy on the Mal Reynolds archetype? Not really. But there's a definite precedent for them to do exactly that.
Plus, it'd be really interesting to see what happens when the high-technology of the mass relays, Repears, biotics, or whatever, gets mashed together in an almost post-apocalyptic, outlaw's paradise.
EDIT: essentially, what I'm saying, is "Focus it DOWN, not OUT."
To put things in better perspective, I should probably mention that ME1 is my favorite game of the trilogy. I loved the fact that it drew liberally on what I consider the golden age of science fiction cinema - the late 70's to mid-80's - for inspiration, and it showed in everything from themes and visual design to the soundtrack.
One of the things that stood out for me about ME1 was that it was a rare example of a "bright future" setting in videogames. For once, the vast majority of the 'verse wasn't gritty and grimy and beaten all to shit, people and machines alike. There was an optimism there that you don't see in most games. I enjoy cyberpunk and post-apocalyptic sf stuff too, but it seems like those are the default settings for games. I get the impression developers think "bright future" settings are "boring", and don't provide enough opportunities for adventure or drama. ME 1 showed that you could set a game in a future that wasn't a run-down shambles and still keep things engaging. They seemed to gradually move away from that in the sequels, aesthetically and thematically, and it was something I was a little bummed about.
With that being the case, maybe you can see why the idea of playing as a bunch of freebooters in a post-ME3 universe that's gritty and lawless and generally gone to shit isn't as appealing a thought for me as it might be for some other fans. : /