1. Is the game on high graphics settings? If you're going to multibox it, you're probably going to need to drop anti-aliasing (at the very least) in order to not lose a ton of performance during gameplay.
2. I see you have 2 monitors. Are they both powered by the same video card? From your info I am guessing they are, but if you had one monitor on each card you could very easily run into a huge FPS drop.
3. Are you using any in-game overlays? X-Fire, Mumble, Steam (doesn't support D3, but just listing some examples) overlays for example could all cause a FPS drop
4. I see in your CPU Strategy that you've tried lowering the FPS and even disabling the FPS limiter. I would try adjusting the CPU Strategy though. Since you're running 2 instances on a quad core, and your current strategy has 1 core per instance... try enabling ISBoxer's HyperThreading option (in the CPU Strategy Wizard). What this does is assign multiple CPU Cores per instance. So instead of picking core 1 for instance 1 and core 2 for instance 2, it will use cores 1,2 for instance 1 and 3,4 for instance 2. This may improve performance. Especially if HyperThreading is actually enabled for your CPU. (in which case CPU 2 in that list would be a logical/virtual core and would not be expected to run a game instance at full performance)
That's what comes to mind at the moment