At least according to a college course I took ~45 years ago, the most efficient cruise is what's known as a "climbing cruise". You set the power and speed for the best fuel burn (per mile) at that altitude, then leave it alone - as fuel burns off, the aircraft will slowly climb at that thrust lever setting and speed (not really constant thrust since the thrust will slowly decrease as the aircraft climbs). The trick being to pick the optimum starting altitude.
Unfortunately not very practical with ATC constraints, but the closer you can operate to a 'climbing cruise', the better.