As of now, the FAR 121.161 reads
no certificate holder may operate two-engine or
three-engine airplanes (except a three-engine turbine powered airplane)
over a route that contains a point farther than 1 hour flying time (in
still air at normal cruising speed with one engine inoperative) from an
adequate airport.
So, 3 engine piston props were forbidden from long flights (But the wording of rule suggests that turbine-powered turboprops with 3 engines are allowed long flights... the only turboprop trimotor is Trislander, and does it have range for 2 hours?).
No language forbids 6 engine piston powered planes, but though B-36 was mass produced and XC-99 flew, Convair 37 did not enter service.
Now, Boeing 377 was not required to survive 2 engines out of 4. There was a famous incident where a 377 did lose 2 engines on crossing to Hawaii. It remained airborne, but with increased fuel burn, they had no hope of reaching land. What they did was find out by radio that there was a coast guard ship somewhere in the middle of ocean, then they flew there and I think burned off some more fuel, and ditched in midocean. The fuselage broke apart on ditching; but the captain had feared it would happen, and moved passengers so they all stayed in one piece and unhurt. Then they were picked up by the ship with no injuries.
As for passenger comfort, some propliners featured lower and upper sleeping berths.