Hi Steve,
Sounds like some nice hardware. If it were me I'd keep the pedal ranks routed though the sub and then on to the mackie 450s. That way you take advantage of the mackie's built in crossover filters. They presumably went to a lot of trouble engineering a smooth tranisition from the sub to the 450s and it is not all that simple to set up the right filters in the RME to do the same job as well as Mackie has done. Plus it's easy to forget and route a pedal reed to the sub only and loose all the upper harmonics. Not to mention that you will also want to maintain any stereo "air" or spacial sense that the sample set may have captured for these voices. This is all possible with seperate outputs from the RME, but I'd keep the basic sub/speaker transition simple (daisy-chained) and save the complexity for how you handle the remaining 4 or more speakers.
But honestly, I'd probably end up trying several approaches to see what "felt right". I've recently dropped my side "reverb" speakers to give me an additional front pair for some of the lighter reed voices. At the moment I'm running three stereo pairs all in front, a percussion speaker for theater organ fun, and a sub.