Is there a secret or guide to this. I keep putting in runes and getting something that has nothing in common with what I put in. Is it totally random?

I'm pretty sure it's completely random.

Quoting from the 'Runes FAQ':

it fails 99% of the time. giving you useless runes.

the interesting thing is that if you are VERY lucky, you can get a quintessence from two regular runes. Let's hope you get a good quintessence.

also, always use the cheaper runes to combine to do this

lol that really sucks for people with all fighter toons that get mana and ap **** from it.