Thanks for the tips everybody. I don't have a CD player on me, and I also don't have a different pair of headphones to try and see if the problem goes away (I don't think plugging IEMs into the Lyr is a good idea). So there's no easy way for me to perform "diagnostics" to figure out which element is the problem. I'm going to have to put some thought into how to change the transport and source.
A brief description of what I'm using: I'm running USB out from my Vaio F (Cardas Clear USB cable), into a Audio-gd NFB11 USB (Sabre32 ES9018). From there, Audio Metallurgy GA-0 RCA IC into the Lyr (Amperex 6922) and then out to the 650s (via Zu Mobius v2). My source files are all FLAC, out of Foobar 2000. Actually, now that I think about it, I'm not using WASAPI or ASIO. Would either of those help?
Edit: If I can scrounge up some cash in the next month or so, I'll see if I can grab the dock for the Zune HD. My understanding is that the dock has a bit-perfect optical out. With Windows Lossless files on there, that might be a way to get around the USB. Although I'm sorta hoping that USB isn't the problem. If that does end up being the case though, would a Halide Bridge or some other USB-to-S/PDIF converter be an effective workaround?