There’s a lot to unpack here, and many of these are interdependent.
I think you have a couple options here. If the external HD was in its own backup job, you could use run-script-before to decide if the backup should run or not. (It could test for the presence of the external hard drive.)
But in question 2 you say that you also want files on C: in the same backup. Must it be in the same backup?
This depends on your retention policy. What do you intend to use?
They will be if dictated by your retention policy. Also, you can use the PURGE command to delete files from the backup data.
Then I would recommend setting --block-size to 1 or 2MB. This is the deduplication block size and must be set before the first backup is performed – it cannot be changed later. (See Choosing sizes in Duplicati for more info.)
Archive-class storage with most providers can cause issues with Duplicati. If you insist on using it, you probably need to set a couple options as mentioned in this post. Also you probably should use unlimited retention.
If you use unlimited retention, then your earlier concerns may be irrelevant (except the PURGE-ing of data).