You are probably familiar with the concept of DC Comics of a Crisis-level event. It's not just a crossover event with tie-ins (which can be about something as mundane as an evil mayor outlawing superheroes), but a threat so big that the whole damn multiverse is in peril. Which stories from Marvel would count as a Crisis-level event?
The most obvious example is surely Secret Wars (only the 2015 one), or rather Hickman's Avengers run that led to it. And perhaps the Avengers/Justice League crossover. Any other? I don't think Spider-Verse counts, as that was a problem for the Spider-people on all universes, but not for the universes themselves.
And there's also the "Time-travel Crisis", which is not just a Back to the Future problem of a time traveler that changed history, but a whole Crisis-level disaster applied to timelines rather than alternate universes. I can think of Avengers Forever (the one by Busiek, not sure about the current one), "Beyond Good & Evil" from the X-Men animated series, and the last 2 episodes of the "What If?" animated series.