The best science fiction is usually a part of a world that we can imagine existing even after the well-known stories have been told (case in point, Star Trek). The fact that Mass Effect's universe is so well-realized will be one of its strengths after the main story in the games draws to a close. I've heard complaints that it's 'too space opera' and the main species are 'too human' - in appearance and culture - to have a major, thought-provoking impact in science fiction, but frankly so few properties are willing to go the extra distance to make their worlds feel alive that Mass Effect gets props from me for being one of the properties that does. In fact, interactive media is uniquely suited to provide this kind of experience and I look forward to seeing future attempts.
I agree, though, that it probably won't carry on in the same way that iconic TV and film properties currently do. Mass Effect may be well-known by science fiction fans and people who play games, but in the end, EA/Bioware will have to care enough about what they have created to bring it into better view and understanding of the mainstream. I think this can be done, especially if they strengthen their trans-media efforts (books, comics, possible movies, and of course games) in the wake of ME3. It's all business though - the fans have to want more, and it has to be worth it for them to extend the franchise and give that universe a chance at being the most important in recent sci-fi and entertainment.