The next version of my app has roughly 70K methods.
Knowing the exact implications of using Multidex (which usually means using the Multidex support library to support A
I ended up going with multidex, essentially because the roadmap of my app would have forced me to do so eventually (as I'm planning to integrate big libraries in a near future).
It's been more than a month and hundreds of thousands of installs/updates of the multidexed APK, so I can now say with decent confidence that the move to multidex did not have any significant side effect, in my specific case.
(note: the update only targetted API 11+, so I cannot speak of potential problems with Android 2.x).