Attempted to do a run with a friend in Downfall mode using Together in Spire, I just wanted state my findings in case other people were curious or in case the developers are interested in developing compatibility between the two mods.

First of all, whether a player in multiplayer is doing a "Downfall" run or a "Standard" run is dependent on the last single player run of each individual player. Hence, if one player last did a "Standard" run on single player while the other player last did a "Downfall" run, this will both carry over into the multiplayer lobby such that the two players will be playing together on the same map; however, the map will be in different modes from each other. In order to play a "Downfall" run together, all players must of last play a "Downfall" run on single player before embarking.

When actually doing a run in "Downfall" mode. Most everything works such as events and encounters. However, there are some things that are broken.

1. The Shopkeeper's health does not scale. Though the health bar does increase per player, the amount of health he has does not increase. Hence, with 2 players, he starts with 400/800 health. Also, if you leave a run, his health will desync and be set back to "400" when you return. It does resync when the player that did not leave does damage, however.

2. Gems reform when returning to a run after leaving. Thus, if you break a gem, leave the run, and then return back to the run, the gems you have broken will now be fixed and you will be able to break them again, and thus, get duplicate heart relics.

3. Broken gems are not global. Thus, each player must break their own gems individually.

4. Bosses will not be the same between players. Thus, one person can get "Watcher" while the other player gets "Defect" despite being in the same run. In fact, during my Downfall run playing as The Hermit, I actually got The Hermit for both my Act I and Act II boss while my friend got Ironclad and Defect for Act I and II respectively as the Guardian. The boss encountered in the encounter is determined by the first player to enter the boss floor. Thus, if a player enters the boss floor first and gets Hermit, Hermit will also be the boss for other players who enter.

5. The boss only functions correctly for the first player. For any other players that join afterwards, the boss will not display intentions or relics and the "Neow's Blessing" text that appears on the right will display the text for the joining player's original boss rather than the boss that is actually present. Minions within boss battles actually are functioning correctly for all players, but the boss itself will only act correctly for first player who enters. For the other players, the boss will actually do nothing each turn. Damage done directly to the boss by players is not shared. Thus, player 2's attacks will not be registered to player 1's boss. However, statuses on bosses do function correctly and are shared. Lastly, if one player kills their "boss" that boss is considered slain for all players.

Unfortunately, me and my friend were not able to complete the run, therefore, I do not know how functional Act IV is.

If I were to give any suggestions to the Downfall team in giving Downfall mode the most basic compatibility, it would be to fix the syncing issues with bosses. All other issues in Downfall mode aren't major impact, but the boss desync is a major problem as it forces each player to basically take on the fully scaled boss health pool individually, with only one player taking the full blunt of the boss's attacks.

TL;DR: It's playable, but Downfall bosses are completely broken by Together in Spire.