Prepare your smoker to about 250 degrees.
Cook pasta in boiling water according to box directions for al dente.
Drain pasta and set aside. Return pot to the stove.
Melt butter in the pot and stir in flour over medium heat. Stir it around for about 1 minute as it bubbles and comes together.
Use a whisk to stir constantly, slowly add in the whole milk. Continue stirring for 2-3 minutes until the milk begins to slightly thicken.
Add in the sour cream and continue whisking to combine.
Add the three types of cheese and continue whisking until the cheese is all melted and thoroughly combined.
Sprinkle in the salt, pepper and garlic powder and mix.
Return the cooked pasta to the pot and stir to combine.
Add the brisket to the mac and cheese and gently fold it in.
Spray a cast iron pan with non-stick cooking spray.
Carefully transfer the brisket mac and cheese to the cast iron pan.
In a separate bowl, combine the panko bread crumbs, crushed fried onions and melted butter. Sprinkle this mixture over the top of the mac and cheese.
Place the mac and cheese on a 250 degree smoker for 45 minutes to an hour.