According to
this article the picture of Spidey sitting mournfully in teh rain is not in black and white. If that is the case then he is wearing a black suit. A black suit means that he is being mournful over a death or it is when he first gets the Venom suit (a symbiotic alien lifeform Spidey suit). Don't forget that Topher Grace is constantly listed and mentioned as a villain, but never listed as who.
I would imagine the storyline going along the lines of Harry Osborne sending Sandman out to kill Spiderman. Spiderman manages to stop Sandman along the way. Now this can go one of multiple ways at this point.
1) While fighting Sandman Mary Jane gets killed and Peter creates a black Spiderman suit in mourning. Harry in his anger finally decides to become the Green Goblin. He did discover his father's hidden room at the end of the first movie. In this case we close out a trilogy the way we started it, with Spiderman having to fight a vile Green Goblin who knows Peter's secret identity and can use it against him. Maybe even Aunt May gets killed by Harry, who is insane like his father but also being driven by pure emotion. He doesn't care who he kills. After all of this death Peter Parker decides to never be Spiderman again because as he feared he cannot be Spiderman and expect those around him to be safe. Or he eventually dies from his wounds. Not true to the comic, but he goes out a hero and it gives closure to a trilogy. (In this I have no clue who Topher Grace would be, although early rumors were Electro)
2) Somehow Peter discovers the Venom suit. He feels weird when he uses it even though his powers are reliable and much greater. He puts it aside because Mary Jane doesn't like who he becomes when he is wearing it. Then when he battles Sandman he must use the Venom suit so that he can defeat him. The battle gives Venom enough power to find a new symbiotic host (Topher Grace) and he becomes the most powerful villain Spiderman has ever met. He defeats Venom in the end, hopefully not completely. Venom was shot into space only to return to Earth and finding his host Eddie Brock, who hates Peter Parker (creating the perfect symbiotic relationship) and freeing him from prison. Venom does know Spiderman's identity in the comics. After Venom is defeated Harry decides the only way that Peter will be taken care of will be to kill him himself and we see him holding the Green Goblin mask as the movie ends. This leads us into a sequel.
3) Aunt May dies early on by natural causes, at Sandman's hands, or in the Sandman battle and Peter puts on the black Spidey suit. Then Harry becomes Green Goblin. This would be extremely wrong since Aunt May has always been the solid rock that Peter can return to, even when Peter had problems with Mary Jane. Aunt May is his only unconditional solid foundation. I am hoping it isn't this once, which is why I haven't thought enough about this scenario to give many details of the possibilities.
Black Suit - aka Spider-Venom
Now, Kirsten Dunst let slip in an interview that Topher Grace would be playing Venom. However, Sam Raimi is on record saying that Venom will never be in the movies as a villain. Of course, Venom is known to avoid killing innocents, but Eddie Brock is also insane and necessary casualties and innocents are hard to separate. Perhaps the movie Venom will just be a rival superhero, much like Eddie Brock is a rival photographer who was jealous because he could never get a picture of Spiderman and Peter always did. Perhaps he becomes Venom to gain his own superhero status and get his own exclusives.
Rumors, rumors.
I am hoping for a good hardcore evil insane Venom. They already opened the door with Jonah Jameson's son as the astronaut in Spiderman 2. In the animated series he is the one who unknowingly brings Venom back. Too much connects for the Venom storyline to work.