Hi Sam
IMO SEO is not the most crucial factor for this question. Yes, you have some slight benefits by using www.mydomain.com without /en for english. On the other hand, think usability and user interaction: Users who recognise the language patterns such as /ru and /es in the URL might want to reproduce the same thing for /en.
I think those are the two points of view that should be taken into account, but both are not that central and either way is okay. Some standard CMS's might not allow the special case for one language easily and you might have to use /en in order to be consistent. But personally, I would use www.mydomain.com without /en if the majority of your audience is english. That makes the site a little little bit "flatter" with one less subfolder in the URL.
That being said, one thing I absolutely recommend: Make sure the home page is actually www.mydomain.com (and not www.mydomain.com/en). Not using the root domain means throwing away backlinks and thereby site authority, so make sure it's available whether you use /en on the rest of the site or not.