That makes sense, elianda. And now that you mention it, I believe there were also some protected mode games that used the real mode MIDPAK and DIGPAK drivers from The Audio Solution. DOS extenders typically pass INT 10h calls (video BIOS routines) and INT 21h calls (DOS disk access routines) on to real (or V86) mode. I guess such games used a DOS extender that also passed INT 66h calls (DIGPAK/MIDPAK routines) on to real mode in that way. Those games might therefore work with SoftMPU as well.
Someone here feel free to correct me if I'm wrong, but the only protected-mode-specific DOS audio driver model that has been open-sourced is AIL/32 (recognizable by their .DLL file extension, not to be confused with the Miles 3.0 driver model that was sold to Bink, developed further to this day, and never open-sourced).
So someone could take the sources of the MT-32 and General MIDI AIL/32 drivers and modify them to produce drivers that can drive such MIDI devices through the serial port like SoftMPU can. Basically a native driver for serial MIDI interfaces, instead of an emulator. There aren't many games that used AIL/32 drivers, though. I believe Simcity 2000 was one of them, but I'm not sure.
Also, the closed source Miles 3.0 and HMI drivers for MT-32 and General MIDI could perhaps be patched to support serial MIDI interfaces natively as well.