I think BioWare's rock and a hard place is that they want to abandon the baggage of the Shepard trilogy, which means trying to avoid side stories (I wouldn't be opposed to these, mind you), while also refusing to commit to a canon.
So, my assumption is Mass Effect 4 is either a sequel or set during the Shepard arc, but predominantly revolves around an exploration/first contact group that for whatever reason has found access to a new galaxy. No, it's not plausible, but I don't imagine their reasoning will be so much as going with whatever they can to ditch the Milky Way.
This group will be the "Pathfinder Initiative" as detailed by BioWare Montreal's new jumpers. ARKCON could be the new multi-species banner said group operates under (like humans operate under Alliance). Maybe post-war Reaper tech (or space magic) opens a wormhole to another galaxy that you and your crew are sent through. Maybe the reasoning is they've received a signal from said galaxy that seems like a sign of life and are reaching out for contact. Maybe they're sending a lot of Milky Way residents through to colonise this new galaxy to avoid the next game limiting its pool of familiar candidates.
But yeah, whatever the reason for going there and how they get there, I feel the next game will indeed take place in a new galaxy and almost all (if not all) familiar locations and icons from the Shepard trilogy will not make an appearance, including the Citadel.
I hated the idea at first, but that was because I didn't want to abandon a post-Shepard trilogy galaxy when I felt there was a ton of potential to continue the series there. But the more I think about it, the reality is unless BioWare is willing to commit to a canon post-trilogy state it's just not going to happen. So I hate the idea only because of BioWare's clusterfuck ending mess and how they treated their own universe moreso than the idea itself. If indeed BioWare is refusing to commit to a canon, I'd honestly rather see them take the new galaxy idea as it gives them a totally clean template to work with, rather than screw around with the Milky Way while burning resources on fruitlessly pandering to all possible Shepard trilogy game states.
If we're done with the Shepard trilogy and no canon will be established for future games, then its time to fuck it off for good.