Locations such as Omega and the Citadel are iconic to the franchise, then you have the mass relay's themselves and the various organizations in the galaxy they'll be gone for good. It'll mean that the ME series is going to lose some of the aspect that helped defined the franchise.
Honestly? That's a good thing.
This is probably set far in the future, so no one you knew from before will be still around (except Reaper AI Shepard from the Control ending).
Omega without Aria is just a pale shadow, it would make me sad. The Citadel... uh... chances are it's still in orbit over Earth. And humans are the dominating species in the galaxy.
Did I mention that the setting doesn't allow proper growth anymore? Do you want to re-hash all the old stuff or do you want new stories? Because I'd rather explore new planets and encounter new species instead of dealing with Council politics, mercs going pirate or Rachni/Genophage/Morning War shenanigans again. We already did that, time for something new.