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You'll only need to do the procedure every time you update the bootloader (which is a pretty rare event). It does look like there is a 16-device limit per VM with passthrough. This is only passing through a single device, though: The LSI controller. ESXi isn't managing the individual hard drives, and has no knowledge they even exist once the LSI card is passthrough-enabled. You would need some pretty esoteric hardware to even have 16 PCIe devices available for passthrough.

@Polanskiman I finally managed to get it to work :) I got my new Dell R510 up and running and used this opportunity to upgrade to ESXi 6.7. This enabled me to use this guide: https://advanxer.com/blog/2018/12/install-xpenology-dsm-6-2-1-on-esxi-6-7-ready-made-ova-file/ It worked very nicely and now I am able to edit SN and MAC address. So I made a couple of new Xpenologies and this time they remain on the same SN and MAC after a power cycle. And editing with the "c" during boot works as well. Thanks for your help along and support during these somewhat challenging weeks :)