I would love to see the statue of David and the da Vinci last supper on this trip as well anyone know how to do that? I know one is in Florence and the other one is in the Milan...
I actually think that is achievable and actually reasonably simple. You are just adding in an extra bit of travel time - and you will need to be prepared to wrangle luggage - but probably no worse than any other pre trip scenario (although I find that provides inspiration not to overpack)
I think I said earlier I was thinking of flying in and out of MXP (Milan). While it isn't anywhere the boat is going it has the benefit of being an easy (direct) fast train to/from Rome, Venice and Florence - actually Milan is probably the easiest Italian city to get to from most of the rest of Europe.
You can have a look at train timetables and fares here
http://www.trenitalia.com/tcom-en? Or check out
http://seat61.com/international-trains/trains-from-Milan.htm#Milan-Italy for everything you could ever possibly ever want to know about catching a train in Italy (or anywhere else in the world in fact - it will even provide advice on getting to Europe by train from Asia - my advice, fly).
It's about a 3 hour trip from Milan to Rome, or from Florence it's a 1½ hour journey to Rome. It's 2½ hours from Venice to Milan.
Milan is a really well serviced hub airport with a good number of carriers flying in direct from the US/Europe/Asia.
From my side of the world I will fly Qantas/Emirates from here to Milan (interestingly the Dubai-Milan flight continues to New York for people looking for another option from NY), I'm thinking of spending a couple of days by the lake in Como, then catching the train down to Florence, then the train to Rome.
Then from Venice I will catch the train back to Milan for a couple of nights before flying home.
It's still a year away and that is all subject to change, but will try for a nice frequent flyer seat/suite so will probably book flights in the next month.
In most circumstances if paying cash I usually find that buying a return flight to a single destination is significantly cheaper than a open jaw (ie home-Rome; Venice-home) flight but YMMV and the pricing model for flights is just designed to be confusing anyway.
Just on the seeing of the last supper, I think Kevin and/or John mentioned in the Dreams podcast the other day that you need to book in advance - when we did it we worked with the hotel (the very very nice Park Hyatt) to arrange tickets.
I just went and found the emails - we asked the hotel concierge in February for tickets and they were 100% booked out for the days we were in Milan in May (In addition Museums in Milan were closed every Monday). We were only able to see it by booking into a city tour (which was a little bit weird but that's another story) which the hotel arranged for us.
If this is something you want to do (and I think it is a must if you are in Milan) my advice would be to book a hotel in Milan early and get the hotel concierge to do the work for you.
Matt