Is there a way to block multiple RSVPs from the same e-mail address?

I would put that in text that it each submission needs to be a unique email address. Make sure they realize that a second registration will not be counted. And then in the smart campaign you could say go through flow only one time.

I always have issues with RSVPs and ppl RSVPing for their spouses, etc.

+1 for Kim. Marketo uses the email address to dedupe multiple RSVPs.

While what Kim suggests sounds like it will work, mentioning in the text is the key.  Setting the smart campaign to go through flow only once doesn't actually prohibit them from submitting more than one entry.  It doesn't send the follow up e-mails and doesn't add multiple entries to the list, but without strong language in the text, the recipient has no way to know their second entry wasn't counted.

Is there a way that if the form has already been submitted with that e-mail address it can be set to reject subsequent submissions?

Yeah maybe you could also include a text warning on the follow-up thank you page?

You could create an smart campaign with the filter of (if lead is already member of program) that sends an alert to you and / or the registrant saying "There was a duplicate registration.  If you are trying to register multiple people please... (steps you choose)"