We already know another Mass Effect is happening, but BioWare really doesn't want you calling it Mass Effect 4. Doing so would imply it has something to do with Shepard, after all.
In response to a thread on the official BioWare forums, asking whether the developer will "keep everyone happy in Me4," community manager Chris Priestly replied:
"To call the next game Mass Effect 4 or ME4 is doing it a disservice and seems to cause a lot of confusion here.
"We have already said that the Commander Shepard trilogy is over and that the next game will not feature him/her. That is the only detail you have on the game. I see people saying 'well, they'll have to pick a canon ending'. No, because the game does not have to come after. Or before. Or off to the side. Or with characters you know. Or yaddayaddayadda."
To clarify on Priestly's statement, BioWare Montreal boss Yanick Roy tried to explain that the next Mass Effect really isn't a sequel (or a prequel), though events in it could occur after Mass Effect 3. The problem with calling it "Mass Effect 4," however, is that the title would falsely imply some sort of linearity.
"Thinking of the next Mass Effect game as Mass Effect 4 would imply a certain linearity, a straight evolution of the gameplay and story of the first three games. That doesn't mean that events of the first three games and the choices you made won't get recognised, but they likely won't be what this new story will focus on.
"In other words, because the game takes place before of after the first trilogy does not mean it necessarily is a straight prequel or sequel.
"I’m not a big fan of analogies because the images you use always mean something different to different people, so they are inherently flawed. But let me use one anyway. :P
"If you had three games centred around a group of key soldiers in the US army during World War I and then decided to make a game about another group of people during the Second World War, the games could have many points in common and feel true to one another.
"You likely would have to recognise how the events of the first war influenced the ones of the second, but you would not necessarily think of it as a sequel. Again, the analogy is not great, but what I'm trying to say is that the ME universe is so rich that we are not limited to a single track when coming up with a new story."
That said, Roy did suggest that the studio will maintain the Mass Effect lore and history, likely keeping all the same races within the same galaxy -- that sort of thing. Fans "Can safely expect those in the next Mass Effect."
The upcoming Mass Effect game is being developed by BioWare Montreal, the studio behind all those sidequests in Mass Effect 2 and Mass Effect 3, plus the third game's multiplayer.