I don't think the Wax and Wayne series is technically part of the "trilogy of trilogies," (the series is four books after all). The original trilogy is Era 1, Wax and Wayne is Era 2, and then Era's 3 and 4 are the second and third Mistborn trilogies. The second trilogy is supposed to be set in the early computer age with 1980s technology, and the third trilogy is supposed to be a grand space-opera with FTL technology powered by Allomancy. I believe both should be similar in scope to the original trilogy.
As other people have said, going from the end of HoA to the Wax and Wayne books is a little jarring as they aren't supposed to be quite as "fate of the entire planet is literally determined right now by these characters" serious. The overall mood of the books is more joke-y and lighthearted, and they are all shorter than the books in the original trilogy. I'd maybe read Elantris or Warbreaker first and then come back to them so the difference isn't as noticeable. The Wax and Wayne series are good books and interesting glimpses into what happened ~300 years after the original trilogy - not to mention the Cosmere implications - and in my opinion they're definitely worth it. Just maybe not right after HoA on your first read-through.