Doctor Strange in the Multiverse of Madness should be caused by the destruction of the Infinity Stones. The MCU first began subtly teasing the Multiverse in the Thor films, but it came to the fore in Avengers: Endgame, when the Avengers unwittingly created a number of branching timelines. These were (mostly) resolved when Steve Rogers traveled back in time to return the Infinity Stones, although one remaining branch will be explored in the Loki series.
But it's important to understand the MCU's Multiverse is about more than just alternate Earths. As Doctor Strange director Scott Derrickson noted in one tweet, the MCU's Multiverse is loosely inspired by Doctor Strange #21. This envisioned Earth at the center of an infinite ocean; alternate timelines were just one swim-stroke removed, but the further away you went, the more insane things become. There are pocket dimensions such as (in the comics) Asgard, or Mephisto's Hell; there are entire planes of existence that defy the laws of reality, such as the Dark Dimension or Nightmare's realm. This was briefly seen in Doctor Strange in the stunning "Magical Mystery Tour" scene, in which the Ancient One blasted Doctor Strange's psyche throughout the Multiverse. But what could cause the entire Multiverse to collapse into madness?
It's possible the damage was done when Thanos destroyed the Infinity Stones in Avengers: Endgame. The Infinity Stones appear tied to the nature of reality itself, so much so that Baron Mordo believed just using the Time Stone to adjust time around an apple risked breaking the space-time continuum. The point was made even more vocally by the Ancient One in Avengers: Endgame, when she suggested the Infinity Stones control the flow of time, and thus affect our ability to understand and interpret reality. Given all this, you would expect there to be enormous consequences from Thanos' decision to destroy them.
There is comic book precedent for the idea of reality breaking down. One prominent example was in the aftermath of 2013's Age of Ultron comic event, a story in which the Avengers used time travel to save Earth from being conquered by Ultron. Their escapades placed too much pressure on the space-time continuum, which fractured. Realities merged, portals opened between the dimensions and incredibly that was a best-case scenario. As Tony Stark noted shortly after the catastrophe, "I think we're lucky we still exist in a cohesive linear reality." That could well be the crisis faced by the Masters of the Mystic Arts in Doctor Strange 2, as they learn the fabric of reality is slowly breaking down.
This theory would also account for Scarlet Witch's role in Doctor Strange in the Multiverse of Madness. Trailers for WandaVision have already confirmed Scarlet Witch's powerset is expanding to the point where she can manipulate reality itself, and it even looks as though she has the power to reform the Mind Stone. If that is the case, then she could well be the only one able to restore the Infinity Stones and therefore end the Multiverse of Madness.
