Ram 6.4 with 8spd

[Cumminsfan]

It will mostly depend on where you tow. I live and tow in the PNW mostly. Up hill a lot. I very rarely get to set the cruise for more than 10-20 mile stretches. When you get in the higher elevations you lose power (3% per 1,000') so you need more pedal to the metal.
Speed maters as well. Keep it near 60 and all is good. Start pushing 70 and mpg's drop significantly.

4200 lbs dry would be around 5500 loaded. That will be a breeze for a 6.4 8 sp. IMO 3.73 gears is all thats needed.

[NevadaNick]

I towed my 8.5x20 enclosed trailer and on the wsy where i was going was fairly light, probably 5-5500 lbs and got 10.5 at mostly 80 mph. I was much heavier coming back including filling the bed of the truck and didnt go over 75 and mpg was 9.7 This was on I80 from Reno to Winnemucca and back so flat ground. I did have some wind on the way back as well