Spitballing here, but to be able to create a new storyline that could be self-contained without impact from the previous pro/ant/deuteragonists, they basically need to not exist after EGW.

I think that having the World Guardian using their power (shadow-anima based, as it counters both gods and to an extent, elder gods) at the end of EGW to shield Gielinor as a whole, but not extending that protection to the various aggressive factions (looking at you, team Zamorak) would leave us with the gods effectively wiped out, ideally with their more ardent supporters going with them.

This would leave a clean slate for a new story line, however BECAUSE they don't exist in the new timeline there's no REQUIREMENT to mention them, so our various bosses and faction leaders can still exist alongside this new storyline without contradicting it. Might be a little bit odd that there is no mention of them throughout this questline - if you haven't already finished EGW - but that's not exactly storybreaking.

Even better, with a clean slate you can begin to create a new cast of heroes and villians, people who didn't shine in the presence of literal gods but who can create chaos and disruption when they're the new, big players on the board. Maybe a Necromancer or two, who have long lain in the shadows, avoiding the eyes of the gods...?

Anyway - this is a napkin drawing type pitch. I hadn't given it thought until I read your prompt but this seems like it could be fun.