I'd like to start by saying that I really like the idea of multiple protagonists. If it is done right, it could really help all aspects of a GTA game feel fresh, inventive and approachable. What I mean is that each character would have to be varied enough in their surroundings and backstory.
Gameplay should be unique to the different characters. Let's go with a hypothetical situation and say that Tommy and CJ were both characters in this game (please don't let this actually be true, it would be awful). Tommy could buy property and control the city, while CJ could run the ghetto through turf-based combat. Each seperate story has to be diverse enough in what you can do to make you actually want to play as someone else. A character like Carl Johnson would never deal drugs, which meant that awesome drug selling mini-game in Chinatown Wars would never have made sense in San Andreas - so add a character to this game that it does work for.
GTA IV's main problem was that Niko's story got stale - fast. The only place that really made sense for him was Hove Beach, and those missions were only used as an introduction to gameplay mechanics and thus none of them were that good. This is opposed to the Lost and Damned and Ballad of Gay Tony, which both had 30 or so missions based in almost entirely different aspects of the criminal underworld - thus, different and more uniquely succinct stories developed. The simple reason these stories were better than IV's was because they were short and to the point.
What I would truly hate is for Rockstar to make each characters story interweave throughout the entire game. To pull a Heavy Rain and play as one character one mission and then cut to someone else would make for an absolutely horrible playing experience in this type of game. Each story has to play out separately and independent of the others, and I would argue that they should all be in different timelines. I don't necessarily mean they occur years or decades apart, but make one story begin as another one ends - this has to be done in order for the player to feel as if the game is progressing between each character.
Multiple-playable characters would have to be done with a careful dynamic - each character still has to be strong enough for the player to want to be them (No Jack Marstons allowed). I don't know how it would work at the end of the game, especially with cutting out elements of gameplay for each character. If you are stuck with only one character at the end it would be quite unfortunate to only be limited to that characters exclusive traits and abilities.
Multiple characters would mean that all elements of gameplay from previous games would fit succinctly into this one game, in an epic fashion.