I've not heard of any customers with custom rules in exchange on their listener accounts. Usually the inbox is where the listener is looking, however this is configurable. If you need special rules run or manual interaction prior to ISM picking up the emails then I would suggest making a folder alongside the Inbox and pointing your Inbox settings in ISM to that folder. After that's been set up, have your agents or exchange-side automation do their work and when complete drop the emails into that custom folder when they are ready for ISM to process.
There's also a lot of automation that can take place in ISM. You might look into the capabilities of the XML/XSLT listener. It can essentially parse your emails any way you need so you might be able to set up the automation there to do what you are currently handling with exchange and manual interactions.
Thanks for your advice. We will give this some thought and a try.