I've used it with several different amps. Marshalls and Mesas. The limiting factor here isn't the amp. It's the HD500. Two things:
1. There's a signal drop at the FX Loop send of -2 dB. You have to find ways to compensate for that, and there are multiple approaches depending on how you configure the POD. I'm not a fan of any of them. The loop should allow for unity gain in and out. It doesn't.
2. To do 4CM "right", you might find yourself running out of effects slots on the 500. Depending on how noisy your amp is at high gain, you might want two noise gates: one after the guitar and one after the amp. You'll probably want an EQ block and reverb, especially if your amp's reverb comes before it's effects loop. No idea why Mesa does that, but it's annoying. Add in an overdrive, wah, and volume pedal and that's 7 blocks taken up right off the bat (don't forget the FX Loop takes a block). So what do you have left? Delay? Might be enough for some, but it's still pretty sparse.
3. I can't count, obviously, but the third thing actually has to do with your amp. Make sure you have a serial effects loop on the amp. PURE serial loop, not a parallel loop with the mix control set 100% wet. You will still get bleed of the dry signal and it can set up some phasing issues.
The HD500 can work, but it takes a lot more work and patience than some other units.
It doesn't seem lighter by much.DT-25 Head or Combo. I see a few on eBay for under $700. I'd prefer the head, It's lighter, lol.