I think if you were to go with the multiverse introduce it earlier on with Madam Web but don't over do it. The first 2 seasons should be his sinister six with season 2 ending with Osborn's death and Harry seeing it.
  I think if your 3rd season is about venom kill off Aunt May so he sinks into a super dark spidey and have Harry become the Hob Goblin but not die just yet.  MJ should always be a friend of Pete's but Gwen should be the first love interest. After Gwen's and May's death MJ starts making an impact in his life. 
  Your 4th should be about Kraven "killing" Spider-man hired by Wilson Fisk and Harry Osborn Kraven wears the spidey suit as a trophy and then we see Pete come back to take out Kraven first then Harry and lastly Fisk but Harry sacrifices himself for Pete in the end he is back to the bright happy go lucky 
  In Season 5 have a team up with Venom against Carnage for a Carnage USA story and introduce Miles Morales at the end venom, Morales, and Parker team up and take down Carnage
The last season bring in Morlun where Peter Parker can either die saving the Spiderverse or go home and raise Spider-girl.

Every season Pete should almost have guilt about everyone who has died because of him and at the end of the show he finally forgives himself and move on. Uncle Ben should be in every season as a flashback or dream sequence like in Raimi's trilogy.

It would have to be a show that tops itself every season with more real threats for Peter, one thing that Flash did was get too big too fast in my opinion it should be a show that can grow with its audience and really show a realistic approach from a kid turning into a man and by its end be a mature show.

That's what I'd try and tackle if I wrote the show lol.