The next xpac/sequel will probably revolve around the choice the nephalem have to be good or evil and how dangerous that would be to the angels and sanctuary. Some nephalem will most likely go bad and do a "zoltun kulle"-ish thing trying to become a god.
All-out war between nephalem is not unlikely from what I can tell. We've afterall fught diablo many times and different versions all the time; D1 weak Diablo, D2 stronger Diablo, D3 Prime Evil Diablo. Next Xpac we will fight the strongest being(s) of Sanctuary - the Nephalem.
It seems very obvious to me from a story perspective that this is to some degree the direction Blizzard will take.
Now that I came to think more about it we might see a nephalem trying to "fuse" with Diablo in some way possibly through the use of a new soulstone and hereby creating a super powerful nephalem infused Prime evil Diablo to wreak havoc on sanctuary. It would be a cool fight at the very least :p