Nope, no luck yet. We had to go ahead and roll out the site to production with the error continuing to occur. We got the same feedback from Sitefinity support as reported above, which was that the Multisite module must be activated, etc., but as noted in the first line of the original post that's not the case - it's neither activated nor installed.
Looking at the IIS logs, I've correlated the Windows Event with this (primary) request by a backend user in a Sitefinity designer:
That request kicks off a bunch of other requests for various designer resources like these:
There's a pause, then it looks like the user begins to edit something in the content block (or other component in a page), presumably an image or image-based link, which then kicks off these supporting designer related requests:
Which then leads to this request, which raises the exception that appears in the Windows Event log:
I'm pretty sure it doesn't impact the backend user in the designer or I would have heard from them by now. This also explains why there is no pattern to the Windows Event log entries, because they're clearly tied to some arbitrary backend design activity.
We're ignoring it for now, as is Sitefinity, apparently, because they closed our support ticket without resolving it. If anyone learns any more about it, please come back and share it with us.