Tales of Monkey Island was very successful in creating a new supporting cast. One of their biggest successes was integrating the old guard (Murray, LeChuck, Voodoo Lady) so well into the story. But, assuming it doesn't take ten years for a sequel, it brings up a good problem.
Winslow, Morgan and even De Singe to some extent all have legions of fans. It could be very hard to live up to everyone's expectations and include all the fan-favorite characters in the story without it feeling forced or detrimental to the plot. (See: Murray, EMI.)
Truth be told, as much as I love LeChuck, he could sit out for a game. Morgan/Voodoo Lady could be the villain(s), working to use LeChuck's corpse as some kind of voodoo ritual. De Singe probably should be "Largoed" and just stay dead considering he doesn't "believe in that voodoo stuff", Winslow could function in his same role as Tales and LeChuck could be brought back in a hypothetical Tales 3, alternating games for the character and making him less boring like Bowser of Mario fame has become.
Another problem: Elaine and Guybrush don't seem to function well as a continual, ever present married unit. Elaine spent all of CMI as statue and TMI with LeChuck or poxed. EMI's effectiveness in this regard is debatable. Will the next game (if it ever comes) shake that up? Is it possible for Elaine and Winslow to co-exist storywise?
The possible dynamics of the next game (if it ever comes) confuses me. Beyond that, it could just end there and that'd be OK too. It was a good series closer.