Any large city could handle a mega-convention. I've been to professional conventions in Atlanta, Chicago, NYC, Dallas, New Orleans and San Francisco. The problem is that those are some of the most expensive cities to visit. A mid sized city like Indianapolis, Cleveland, St, Louis or Louisville is much cheaper, generally. I mean, it's not like the gaming industry is producing millionaires.
Convenience of location is a concern too. Someone else mentioned direct flights, but having the con located in the middle of the continent, roughly, is probably spreading the inconvenience around evenly. (Well, not for me, but I'm already in the middle of the continent.) If you put it on the east or west coast, it may be out of reach, financially and distance-wise, for many more fans.