Jodes - Yes, I use multiple devices with Calibre and you can support multiple devices in the way you are describing. For descriptive purposes let's assume you have non-drmed ebooks. You can add all the books to Calibre and they will then be available in your "library."
When you connect a device to calibre it will show you what is on that device and allow you to move content from your library onto the device or a storage card on that device. You can then repeat the process with the second reader.
A couple of considerations...
1) I'm told that you can't use both Calibre and Sony's management software with the same device... you have to use 1 or the other.
2) If your ebooks are all "DRMed" epub (you mentioned Adobe Digital Editions) then you can use Calibre to get the content to your readers, but the readers may not be able to open the content. In that case you may want to consider removing the "DRM" which is legal and illegal in various locations.