In general, doesn't like making sequels, at least not nearly as much as making original IPs. Would choose something new over making a sequel. If he's made a game for that world, he's already explored pretty much what he wanted to explore. His games are large and have multiple ways of playing them, which means he's already explored all of the ways one could play in that IP. Making sequels feels superfluous, nothing more to say or it would just be dragging thinks out.
Part of the reason he didn't want to work on Fallout 2. When Fallout 1 was finished, didn't think he was going to work on Fallout 2. Was told he'd be put on a D&D game after Fallout 1 because that would make money. Three and a half years making one game, that is a long time, and you get tired of it.
Of course, Cain has made games in other people's IPs. Wasn't expecting to ever do a South Park game, but got himself immersed in the IP, watching episodes and discussing what the team wanted to do. But these were always his first time in those IPs as video games. Explored all he wanted to explore in those worlds in the form of a videogame. Have to be very respectful IP, that was why he was happy he got to talk to Gygax. Even with it being his lowest scoring game happy how it kept the memory of Temple. Repeats his ideas for editing some stuff in a Temple remake. Has made some IPs that were fully intended to have sequels made for them. First one was Arcanum. When you start it, you are coming to a new continent to look for work, don't know anything, perfect way for player character and play to share knowing nothing, like coming out of the freeze in Outer Worlds. Bunch of stories they still wanted to tell, knows people want the gnome story continued, want to know what was happening to other dwarf clans or elf groups, how the industrial revolution continued. When he picked up the D&D license, and they told he could make any module, picked ToEE fully planning to to implement the rest of the GDQ series (Against the Giants, Queen of the Demonweb Pits.) Would have pushed for those if ToEE was a success. Outer Worlds was designed from scratch for sequels to be not only possible but desirable if it did well. Added descriptions (sometimes one line, sometimes paragraphs) of other colonies, who founded them, what the planet was like, important to be distinct from Halcyon. Earth could be a thing all of itself to explore.
Sequels are never off the table, just not his first choice, especially right after the first game. If he'd just done a game, would want to shift gears and do a different kind of game. Part of why making Arcanum 2 first person was planned. Was Excited for Bloodlines because it was his first time working with C++, first time working in World of Darkness, and first time working on a first person game.
South Park/Bloodlines/ToEE made Cain understand the difficulty of someone else's IP, have to be very respectful. Wanted to be respectful to South Park's humor, ToEE's mechanics and settings, and Bloodlines' Masquerade and modern day story. Lots to take in, Cain hopes when people making sequels they are also trying to do the same thing.
Cain dislikes hardly sequels and remakes that throw too much out, will not name certain very recent TV shows that did that and make him worry for future TV shows. Thinks they were disrespectful to the source material, they either threw too much out, or they were so desperate to add their own things to the IP that they jammed it in there, and added a very modern sensibility to something older to try and make it fit even if it didn't belong. Doesn't think you can't modernize it, but you have to be very respectful to source material. Modernize should be showing it in a better light (i.e for a game better visuals, better UI.)
People who do not respectfully making a sequel will probably end up making very bad sequels and not understand why people don't like it (The people who complain about it may not even realize why exactly they don't like it), tend to end up talking past each other.
Danger of making sequel is people have a preestablished notion, advantage of original IP is there is no pre established notion of what Cain is offering you.
Main reason he likes making original IP is that it is challenging, fun, and lets him explore things he couldn't do in previous games.
TL;DR Would make sequels, wouldn't be his first choice.