No, it's not. If two USB drives are connected, one being a E and the other an F drive, the E drive can be disconnected and then the F drive disconnected. If the F drive is then reconnected to the computer the system will map it to the first available letter, that of drive E (since drive E was disconnected).
A USB hub is a possible solution, but there is still the chance that if you disconnect the USB drive and/or the hub itself, you'll loose the mapping to it. Hubs may give you more USB ports, but it's like hooking five hoses to one spiggot and then turning the water on... only so much water can get through the spiggot and thusly you defeat the point of having that entirely. Rant deleted
But the problem with the drive letters is just coincidental in the usage of these devices. Your main issue I foresee is the program you wish to use itself will not be compatable with being launched from such a device and the fact that most consumer stick drives are too small for most games to load onto. Another difficulty might arise from the fact that a few games actually use their home directory for storage of temporary data.
We use a lot of USB stick drives for everything from portability of data to using them as keys to even access a terminal.