i think the beauty of the current galaxy in 40k is it's so decrepit and on its way out. The imperium is dying. it has been dying for 10,000 years. If anything chaos needs to overtake much more of the galaxy, really put guillimans empire under strain politically from within in addition to the rise of chaos. it needs its Empire Strikes Back moment, with the death of some big name characters. not "mortarion attacks guilliman, they fight, mortarion runs away and they both live happily ever after" replace mortarion for whichever big name you want to replace him with. Abaddon? sure why not. Maybe just finally murder the emperor. instil Magnus or someone on earth, and have guilliman finally see what he needs to do, assemble a Extremum Crucis (final crusade) into the eye of terror with all the remaining sisters of silence and the eldar and have THAT as the new setting. need a big turning point? have him find Leman Russ in the warp, take on and shackle some of the chaos gods, shrink the Cicatrix Maledictum in doing so, and play the game of reclaiming earth, reshaping the imperium, and abolishing the imperial truth.
Theres so much you can do in in the current galaxy that fucking off and going to a new galaxy, you might as well play another game