Preheat the oven to 375°F (190°C). Grease a 9x13-inch baking dish.
Cook the elbow macaroni in a large pot of salted water according to package directions, until just al dente. Drain and set aside.
In a large saucepan, melt 4 tablespoons butter over medium heat. Whisk in the flour and cook for 1–2 minutes, until lightly golden.
Slowly whisk in the whole milk and heavy cream. Cook, whisking often, until the sauce thickens, about 5–7 minutes.
Reduce the heat to low. Add sharp cheddar, smoked gouda, and pepper jack cheese a handful at a time, stirring until smooth.
Season the cheese sauce with salt, black pepper, smoked paprika, garlic powder, onion powder, and barbecue sauce.
Fold the cooked macaroni and chopped brisket into the cheese sauce until evenly coated.
Transfer the mixture to the prepared baking dish.
Mix panko breadcrumbs with 1 tablespoon melted butter, then sprinkle evenly over the mac and cheese.
Bake for 20–25 minutes, until bubbly around the edges and golden on top.
Drizzle with extra barbecue sauce before serving. Add crispy bacon on top if desired.