A shot towards the end of the show's fifth season finale 'The Phantom' sees Don (Jon Hamm) walking away from his wife, having used his professional contacts to land her an acting job in a commercial.
Weiner has suggested that this event could signal the end of Megan's time both on the show and as Don's wife.
"We see her on the [Butler Shoes commercial] set and we realise that she's gone," Weiner said in an AMC behind-the-scenes segment.
"Don knows that if he gives Megan what she wants, she could possibly leave him," he went on. "I think it's almost a story of sacrifice, that he sees her on that film and falls in love with her again and realises that he has to do this."
Cast information for the show's sixth season has not yet been confirmed, with rumors that Elisabeth Moss is leaving also yet to be officially commented upon.
> Mad Men 'The Phantom' series five finale: Your verdict
Watch a promo for 'The Phantom' below: