I really like the idea of an empire in its last stage before the complete extinction of its people. Perhaps the few remaining inhabitants of the core world of a once massive interstellar empire, technologically advanced, seriously jaded regarding the universe (due to their swiftly approaching extinction) could make them extremely dangerous. After all, what do they have to lose? They're already a dying race!
Perhaps the K'relk Sodality, once a powerful empire spanning tens of light years, has fallen on hard times. The remnants of their shattered civilization - perhaps decimated in a terrible civil war - can be found throughout the quadrant on various deserted or failed colony worlds, in the form of derelict ships, or even on computer media discovered floating in space/in a subterranean chamber/in a fallen temple/etc.
The civil war saw the creation of a terrible plague that not only killed victims outright, but sterilized the survivors. Initially released on a single colony world, fleeing victims carrying the dreaded disease carried it to K'relk worlds throughout the region. Despite the efforts of their remaining scientists, the disease has mutated beyond their capacity to find a cure. The scant tens of thousands of remaining K'relk citizens are the very last of their kind, and, due to the insidious genetic infiltration of the disease, even cloning cannot create viable replacements.
Such a campaign could revolve around the collection of their civilization's records for posterity, discovering new/lost technologies, locating a lost, uninfected colony (and then having the PCs unwittingly deliver the virus to the untainted K'relk, accidentally condemning them), or even the [futile] search to discover a cure for the disease that has destroyed their civilization.
Not only is such a scenario rife with possibilities, but it is nearly completely free of elements that contradict canon Trek (if you're careful)!
This could even be played up for a future Trek game in which the few remaining K'relk were frozen in the 2150s and stored until Starfleet Medical could find a cure. In the late 2370s a cure is discovered, the aliens are thawed and cured, and they are then aided in rebuilding their civilization, perhaps as a member of the Federation!
mactavish out.