Re: Big Campaign. I kind of think they kind of need to make up some new villain if they do a part of the Realms we have recently seen. The exception would be if they do Thay, in which case they could use Szass Tam, for the movie tie in. Most of the old villains feel underpowered and they had to use a God last time (Auril) they did something in the western Realms. Pretty much all the villains other than Tam are played out long ago, so it would be good to either avoid the FR or invent a proper new threat. Maybe something in Shou if WoTC is finally brave enough to tackle non-European fantasy in a longer form.
In the Perkins/Crawford era they really loved recycling old Villains, so if they were more into Greyhawk as a setting I could see Iuz or someone making an appearance, but I think the new crew are less into looking backward. If the Vecna book didn't already try multiverse-spanning adventure, I would say they might try that.
Personally, I wouldn't hate an Eberron adventure, but that was done in the Adventuerer's League with Oracle of War.
Or maybe they really try to fuse the adventure with a new setting and do a Darksun hardcover with campaign. This was the 5E Dragonlance approach, which I felt was moderately successfull resucitating an old setting (less so), while putting a fairly good longer adventure out (more so).