I've owned the Ultra, AFX2, AX8, and have an FM3 on the way... Through a variety of FRFR speakers such as JBL PRX612, Verve, Behringer Keyboard Amp, Equator Audio D5 studio monitors, etc..... but the absolute best quality sound I found was simply running the AFX directly into the FX Loop of a tube amp and into a cab (so turn off your CAB block).
Currently I'm running through FX Loop of my 5153 LBX2 amp into a 1x12 Creamback loaded in a Tech21 Power engine open back cab that I modified to bypass the Tech21 PE's amp so that the unit basically just acts as a passive cab. It sounds awesome - better than any FRFR/IR combination (this is just my anecdotal experience and opinion).
Before I tried this, I was convinced I was going to start using my AX8 in 4CM with the 5153. But then I tried going direct to FX loop using a 5153 100W amp emulation in the AX8 and I was blown away... I didn't want the AX8 to sound/feel better, but it did. Of course, part of this could be the 15W real amp vs. 100W emulation. But since I know the 100W is not an option for me, it proved that the emulation + FX loop combination was better than using the 5153 in 4CM. Plus it opens up the possibility of using the hundreds of other amps in the AFX.
Our world is full of confirmation bias, so since the results defied my bias, I'm convinced this was the way to go moving forward for me.