For sure, I'd be totally down with a less galaxy destroying holocaust plotline.I'd personally like them to reduce the stakes even more. We already had an existential threat with the Reapers. Refocusing things onto a smaller scale with localized conflicts would be nice. Natural Disasters, like the Dark Matter thread line they originally intended in ME1-3, is still a kind of existential threat against all life.
Andromeda dropped the ball for me with it's attempts at kind of maintaining super high stakes. Nothing kills a series more than the inability to lower stakes and keep things interesting. Always chasing the next big threat just diminishes everything and removes all sense of scale or severity to things. A natural disaster affecting like a single system could be work, but it might be a bit too abstract a central threat for a game centered around shooting things and talking to people.
Like the dark energy stuff didn't seem like it was completely destroying things, but if it turns out using that Remnant tech is what makes it grow (like using fossil fuels causes climate change) it could be interesting in that your goal is maybe to stop the Kett, Angaran, or even Milky Way species from inadvertently causing more harm to themselves and others by greedily trying to use it.
There was actually an old Star Trek TNG episode where warp drives were causing damage to space itself, but they kinda forgot about that after that episode, haha.
But it would be cool to just not to have a stupid, "evil for the sake of being evil" badguy. Like maybe just make the story about trying to resolve conflicts with other groups, or actually have the story focus on the colonization aspects of Andromeda (which were barely there in that game). Instead of using magic vault technology to make your colonies habitable, actually make alliances with neighboring aliens or just take resources and potentially make an enemy (since ME is all about choices).
The enemies you fight regularly can just be Pirates, mercenary groups, or corporations instead of an ENTIRE species that just wants to kill everyone for some dumb reason.