I think an approach like the GTA IV trilogy would work out quite well if they did it right. Two or three protagonists which you can switch between each with their own intertwining story. I think it'd certainly be tough to pull off but I think Rockstar could manage it, it'd also allow them to experiment with ideas that many gamers might not yet be open to in terms of a protagonist.
Personally I'd rather it be one sole protagonist throughout the entire game as I prefer to get to know a character for the duration and I'd rather it be a system where we can shape their look and style to a degree and go through that empire building system. This is just me though and if I'm being honest I think regardless of the approach Rockstar would make it interesting.