In PlayOnLinux model each software is installed in a separate environment, so it can be installed/tweaked/removed in isolation with no risk of side effects.
Agreed, bare virtual drives are becoming a bit huge with newer versions of Wine, and the integration of Gecko and wine-mono; What used to take maybe 80MB now takes over 300MB for 32bit virtual drives and over 400MB for 64bit virtual drives, as you mentionned.
If you're using Btrfs you can use copy on write clones to save disk space without sacrificing isolation; With other filesystems you may try hardlinks, but it won't be as safe.
Or you can try products like CrossOver, that give more flexibility in this regard.