Lots of threads on this if you do a search.

October is the best time of year for a New England driving tour, in my view. Fly to Boston then drive up through the White Mountains into some of the more rural parts of New England, then head south to Newport / Cape Cod then back up to Boston. This is a 10-14 day holiday, though.

The only snag with this plan is that Boston is not very far, so its a slight waste of an Amex voucher, and I wouldn't bother with First for such a short flight - Club would do. (Although, with 500k miles, whats another 50k between friends?!) For a long weekend Boston is not a bad choice - if you can pad it out to 5 days then you could drive out of the city for a couple of nights to go leaf peeping.

Ideally, with that many miles, you should think about First to Asia. Availability is dreadful on most routes, but you should find Shanghai and Tokyo OK. From a purely flight perspective, Tokyo is (or at least was last year when I did it) a 747 and Shanghai is a 777 - and First is a lot better on a 747 if you believe this board. A week in Japan - Tokyo and Kyoto - is very, very interesting I promise you.

For a long weekend with a good flight, South Africa is the obvious choice because of the minimal time difference. Not sure how good availability is for October, though, but 4 days in Cape Town would be good.