It wouldn't work if you had to share a single screen with everyone huddled around a single TV, but handheld systems don't need to. Each played gets his/her own display that stays focused on their respective character. So they can wander further ahead if they wish, you're not stuck within a certain range of one another like the Wii game.
You could have multiplayer of 2-4 people racing through the levels trying to get to the goal first. This was actually used in Super Mario Bros Deluxe on GBC. There's a number of things they can do with the multiplayer. Even NSMB DS had a primitive form of multiplayer (originally the game was intended to have co-op like NSMB Wii). But it would be possible to have a somewhat similar set up to NSMB Wii, just without having you stuck to one frame onscreen at all times. Heck, as a worst case scenario, even a system similar to the classic games could be implemented where you just take turns playing through levels (I used to do that with friends in Mario World and 3 a lot). One person beats stage 1, then player two beats stage 2, then back to player one for stage 3, etc etc.
I imagine this game will have some form of multiplayer. Most of the traditional 2D Mario games have. What form it will take is the question. Nintendo seems to have realized how popular the NSMB Wii multiplayer is though, so we'll see.
NEVER judge a game you have not played. -Granville
Oh of COURSE... how silly of me... I was thinking the same as TC, but then I realised that you play on your own 3DS with your own screen, and you don't have some ridiculously small split-screen multiplayer thing going on.... I mean, how on Earth could I have not realised that </sarcasm>