Beyond updating other lines (which, let's be honest, will happen sooner or later as long as FFG retains the license - it may not be the next year, but it'll happen for sure, maybe with OW base system like DH2, maybe they'll once again try to push something completely new, but they'll do it within the next few years), there's not that much they can do to keep a scale comparable with the existing games.
What they could do is a Xenos-centered system, either Craftworld Eldar, Dark Eldar (least likely, methinks) or Tau. I don't think they'll make that decision lightly, seeing that:
a) humanity outdoes all xenos cobbled together when it comes to popularity, which doesn't bode well for sales,
b) GW tends to be obsessive about claiming their xenos are so alien-minded as to be impossible to understand, despite them clearly being at least as understandable as any Star Trek aliens,
c) some fans are adamant about sticking to the party line when it comes to b), despite the clearly observable evidence to the contrary, which once again doesn't bode well for projected sales.
Other than that, I really don't see anything in the 40k lore that'd make a good vehicle for a roleplaying game setting.