Use PlayOnLinux as a GUI for managing different prefixes but don't use the built-in install scripts , there are GUI configs but you can also open with a button a terminal in the correct prefix and type commands there if needed.
You may still need prefixes because for game A the wine direct3d will work better but for game B you may want DXVK and if you want to mod Skyrim you will have to compile a patched wine version,
POL will also manage all versions of wine for you so it can grab the latest one if you need it or some very old one if some game/application needs that.
I read about a month ago about hat the dev of DXVK had tons of issues where small patches to fix X issue were breaking Y issue and it made no sense, so is a impossible job to be 100% compatible with all games and application bugs.