I prefer a simple structure. In my case that is
[format]/[author]/[series]/[nr - book title]
or
[format]/[author]/[book title]
Calibre just doesn't do what I want. First of all, I want to sort author by last name. Calibre refuses to do that simply because I have [Lastname, Firstname] in my metadata. The second author gets a new line.
About multiple authors: I put them in a folder of the primary author. Which is most often the author I know best
My current formats are [source], epub, mobi and pdf. Where source is the unzipped version of epub.
ISBN's I couldn't care about, and neither genre. I only care about the author and within that the series.