Melt 4 tablespoons butter in a saucepan over medium heat. Whisk in the flour and cook for about 1 minute, stirring, until lightly toasty but not browned.
Slowly whisk in the warm milk. Simmer, whisking often, for 4 to 6 minutes, until the sauce coats the back of a spoon. Stir in the Dijon mustard, garlic powder, salt, and pepper.
Remove the pan from the heat. Add 2 cups cheddar and all the Monterey Jack a handful at a time, stirring until smooth. Fold in the drained pasta.
Spoon the mixture into the prepared dish and scatter the remaining 1/2 cup cheddar over it. Mix the panko with the remaining 2 tablespoons melted butter and sprinkle evenly on top.
Bake for 20 to 25 minutes, until bubbling at the edges and golden on top. Rest for 5 to 10 minutes before serving.