You can, but only if the data is unique. If you want to update records in the CMDB, and you choose Active Directory usernames as your key, those are going to be unique, so no problem -- the data from your spreadsheet that matches the record in the CMDB whose username is 'mclemson' is updated.
But if you want to update values in the CMDB that are non-unique, such as records based on Company Asset Tag, and your techs happened to accidentally enter two computers whose Company Asset Tag are both set to 048938, and you want to match that to a physical inventory you performed in a spreadsheet where Column A - Company Asset Tag is 048938 and Column B - Owner is 'mclemson', Altiris won't know whether you want to set one company's owner to mclemson or the other's.
So likely your data is non-unique. Because you're using a spreadsheet, you're right -- GUID is not an option. Instead, look at what you are using as the foreign key. Check for duplicate foreign keys in the CMDB or in the spreadsheet, and resolve them.
Does this help?