Possible : yes
easy or useful : no
As a general fact : multiple drives is not recommended, it's hard to setup and can create issues. you should not try to go with that setup, and do everything on a single HDD. (or one at a time)
It depends why you want to do that, and which homebrew you want to use your drives with.
But it will depends whether the homebrew you are using lists all partition, or uses only the first it founds, has muti-hdd support or not, etc.
For example, Nintendont can use either USB Port 0 or Port 1, but will uses only ONE partition. Having multiple HDD is of no use as it will not allow you to have more games at the same time.
so, please let us know which homebrew you expect to use, and we will tell you how, and if it's really useful. *prepare an aspirin for the future guide*