i've only really gotten serious about multi-race wagers in the last year or so because i realized that i was spending too much time and money trying to get a longshot to run 3rd in a race. Since I've switched over to mainly win, exacta, and multi-race wagers I've seen a dramatic improvement in my winnings -- though still far from where I'd like to be
I tend to base it around a race with a single, especially if i think that single is a live longshot in the 8/12-1 area. I try to keep pick-4 plays around $48-60. If I can find a single of any type then I base the entire ticket around that -- with a single on a $60 pick-4 ticket, that allows me to go 3/4/5 deep in the other legs which leaves me feeling pretty confident.
Another angle I love is waiting for a race that opens up a multi-race wager with a huge favorite that I don't like a bit. I found one in a maiden race at Turfway a few weeks back. The favorite was 3/5 and on all numbers and race results, seemed only about a half length better than the rest who were all going off in the 6-1 range. I basically crafted that ticket AGAINST the favorite and went four deep on the first leg. The favorite didn't do his job and led to a really overblown pick-3 payoff of something like $1000 when the final two legs were won by a 7-2 winner and a 5-1 winner....all for knocking the huge favorite out on the first leg.
So long story short -- I like to look for a single winner, or a heavily bet single play-against.