They could easily continue the narrative if the surviving organic races rebuilt their own mass relays, re-establishing galactic civilization (need a new antagonist though). In ME1, Vigil states that a small group of Prothean scientists contructed a small mass relay, The Conduit. Shepard succussfully uses it to teleport to the Citadel. It isn't that big a stretch to assume that the population of an entire cluster couldn't also figure it out at some point.
My bet is that a Mass Effect MMO is in the works, with ME3's multiplayer serving as testing grounds for a combat system.