Multi-site can easily handle 65 sites. The question is can your hosting handle that many sites if they become busy. You’ll want to take advantage of caching and I’d recommend running CloudFlare in front of all the sites.
I’d also have an upgrade path in mind and I’d run nothing but the website itself from that server. No email, No DNS, or any other services. If you have to, you can engage a second server for those utilitarian tasks.
You might need to look into sharding your database by spreading the load across several databases if needed. You’ll need to switch to HyperDB in order to do that. That wouldn’t be an immediate concern until traffic built up and it’s quite possible you’ll never need it.
One way to consider the load might be to consider if you had all the pages running from one single website. Would that site then handle the load? The overhead for a multi-site doesn’t need to be any heavier than a single site. You’re still invoking the WordPress itself once for each page served with a tiny bit of extra code to handle the Multi-site housekeeping.
Caching would help that immensely. CloudFlare will help some and an actual CDN for serving up media and static files would make a great difference.
You also mentioned running one main theme and making small changes on the individual sites when necessary. My choice would be to run the main theme and then create child themes based on that theme if I needed specific changes.
If you start seeing ‘500’ errors from CloudFlare then you’ll need to upgrade the server or find that extra horsepower. The ‘500’ errors are telling you that you are not answering CloudFlare fast enough. If your actual server starts showing database connection problems then you’ll need to move up to the fancier database or a better, faster server. You don’t need to run your database on the same server either.
