@plecostomus
As someone gearing up to run Infinite Staircase (or at least a version of it), I have appreciated your questions and the kind folks here for chiming in.
It will be my first campaign and I knew I wanted to run an anthology campaign but I needed some structure to lean on and the general premise of QFTIS fit for what I wanted. But, frankly I don’t like the idea of my chaos gremlins having an infinite staircase to play with until I’m more confident as a DM.
Anyway, thanks for rewarding my lurking with good questions and ideas everyone.
Sorry, I didn't see the notification for this post! I've also graduated from reading this module out of curiosity to actually prepping it as a campaign because of the helpful responses here. It would be my first DM campaign too. And I decided to keep it single-setting.
I am still planning to let players choose between following a setting-based guide NPC, or going up to Nafas, or even alternating between the two. But if they do end up on the Staircase—the most disturbing thing I read in this book is that all the doors are unlocked. I would lock them. I tried adding a little desert travel segment to the start of Lost City and I struggled with that, so I know I am not ready for "open a door and go ANYWHERE".
Related to choosing the setting/frame: I discovered by reading Zargon's stat block that Zargon can only be truly killed by "submerging [Zargon's horn] in a cleansing waterfall on one of the Upper Planes for 101 days. While the horn is submerged in this way, Zargon doesn't re-form, and the horn slowly dissolves, sending corrupting slime downriver that permanently fouls the water for 10 miles from the place where the horn dissolved. The fouled water is unfit to drink, chokes aquatic wildlife, and withers plants."
If you have the Staircase frame, you have a way for players to access an Upper Plane. But I don't think Lost City conveys this info about Zargon, and none of the other modules explain the Upper Planes. You can modify Lost City to hint at the solution with added/modified murals, but I figure you can also use the following resources for players: the sages in When A Star Falls, Nafik in Pharaoh, Iggwilv's books in Lost Caverns of Tsojcanth, Aphelion's database in Barrier Peaks. This works even better if you are single-setting because the NPCs don't have to be omniscient of other universes to know about Zargon.
If you don't want the Staircase frame at all, think of a setting-specific solution for Zargon. I chose Dragonlance because the name sounded cool, and after 2 or 3 weeks of wiki-ing the setting I would not advise choosing Dragonlance. But if you were to go that route, maybe the players get an actual dragonlance (a type of holy artifact) at some point, and they can use it to pierce the horn and kill Zargon for real. And maybe they have to strategically choose a place to do this, because all those other effects of the surrounding area getting destroyed still happen.
I am certain my group would want to return to Zargon at the finale, so I'm trying to plan for that.
