I heard awhile ago that it was going to be a trilogy. But then again that source also told me that all three games would involve the same main character, and clearly that is not the case.
As far as the Medici family goes, I would definatly bet that they are involved in the plot somehow. I think they are based in Florence if memory serves, but they were very important to the whole of Europe.
When I first learned that the game would be set in 15th century Italy the first thing that came to mind was Borgia.
But apparently the set year is 1476 which means that the Borgia family will probably not be mentioned.
That also means that Machiavelli probably wont be involved either, bummer.
They have confirmed that Leonardo da Vinci will be a contactable character.