Well, the short answer is you can still not disconnect one SFDC from your existing Marketo instance and replace it with another instance. So if you have a native connection running, you do need to migrate to a new Marketo instance if you want to replace it.
How complex you make the migration can take different shapes. If you have an instance where you are generally happy with the way it is set up, you could run an instance copy. That will copy across all your folders, database structure, programs and assets. It will however not copy across any data, so that would need to be done manually or via API, including Program Memberships. The instance copy can be done by Marketo Support, but for data migration you would need the help of Marketo Professional Services if you cannot do it yourself. Please note that activity history is not copied across as a standard.
If you are less happy with how your instance is set up, it would be a good opportunity to design things differently in your new instance. That would require more work. You can still import programs from your old instance in that scenario, but control yourself where they are stored in the new instance.
Hope this provides a good basic indication of what's involved.
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