I think the mass effect universe is diverse and interesting enough to support more that one grand story line, if you take Sheppard's Story to be the end of the Mass Effect Universe. There is still plenty of interesting races, locations and technologies for the story to revolve around, I would personally like to see something around the Krogan/Rachnii infestation.
I also think that more than one genre could be used, like how the star wars games are first and third person shooters, RTSes, Piloting games and RPGs.