I have areally mixed responses to Epic Destinies in 4e. Some of them are genuinely fantastic, dripping with flavor and promise, while others are more disappointing. Sometimes it's a mismatch between the flavor and the rules, sometimes it's just a concept that falls a little flat. Whatever the cause, I find them interesting to look at.
To my mind, you can spot the really good ones by their immortality blurb. A lot of the dull ones have some variant on "And then you vanish from the world" but the really exciting ones have something concrete and playable in that blurb. The War Master, for example, goes out in one, huge, impossible fight (win or lose). Eberron's Mourning Saviour exits the game and lifts the curse on the Mournlands. These are the ways stories should end and, perhaps more importantly, they feel genuinely epic.
In contrast, mechanics don't tell you much. Epic Destiny abilities tend to be pretty good, good enough to get excited about, but their scope is rarely any broader than the powers you got at first level. That is, to me, pretty jarring, but it's a symptom of my recurring friction with 4e - a disconnect between the color and the rules. And knowing that, I'm actually pretty chill about it, but it does leave me pondering ways to mix it up a little.
There's a lovely game of postmodern urban fantasy, conspiracy and general grittiness called Unknown Armies which offers some inspiration. Part of its premise is that there is an "invisible choir" composed of a set of archetypes (war, sex, the messenger, plague, greed and so on) which people can embrace to gain power. If you commit yourself fully to one of these archetypes, you can ascend and join the choir, becoming the archetype and taking that seat at the big cosmic table. But there's only one seat per archetype, so people fight pretty hard to be the one to put dibs on it.
But there's one more catch. There are only so many seats at the table (or so they say) and once they all get filled, the universe is finished. Everything gets tidily wiped clean and something new begins, something whose qualities and nature are shaped by the collection of archetypes.
So what would it do to your game if those archetypes and seats at the table corresponded to Epic Destinies? What if there could only ever be one Diamond Soul or Lorekeeper? And if all the slots are ever filled, a new universe is born (with the role of the ascended folks an open question - are they the gods of this new universe?)
Right off the bat, while you could make this incorporate every epic destiny, I don't think you'd want to. Some epic destinies (like the Mournland Purifier) already have incredibly strong stories of their own, and others (like Demigods) draw their power from the current status quo, so would not necessarily be forces of disruption. The question of "which destinies" can make for an important part of the whole structure because, in addition to the people you'd fight with for ascension, there are plenty of folks with a vested interest in THIS universe who might object to things being redone. Knowing which destinies are a threat to the universe means knowing which people to go after.
In my mind, the list of actual archetype slots ends up looking something like the major arcana of a tarot deck (or a deck of many things). Hell, there might even be an actual deck, scattered across the cosmos, desperately hidden, cards traded in secret. It's the kind of thing gods kill for.
I'm going to keep this idea in my back pocket because I think it's just about the right size. While you could make it the basis for an epic campaign, I think it becomes even more interesting as a background element of an epic campaign; one of the big truths of the universe that unfolds in play. One of those things that illustrates that Epic Destinies are not just about a few extra cool powers, they're about everything.
1- Even something moderately dull, like the Diamond Soul's "Retreat into isolation and found a new psychic order" hands the player the opportunity to create something.
2 - Someone with more UA lore than I will be aware of details I'm getting wrong, but the point here is the idea.
3 - Or rather, only one at level 30 - there may be any number on the 21-29 slope.
4- Though others might think that much that is wrong with this universe (like abberant invasions) comes from it not being "reset" properly, while others might feel they could survive a rewrite, especially if they have an ally among the archetypes. It makes for a lot of interesting axes of conflict that may have little or nothing to do with good/evil.
5 - And, randomly, if you've ever read Will Shetterly's "Cat's Have No Lord", there's a setup like this which might suggest a plot or two. Also, it includes an acknowledged Princess Bride ripoff, and is the reason I love the term "Sword Dancer".