Dude, lets use the life debt as part of it. And Mal's canon. Something nasty happens in canon, she asks Sands to come too. And possibly drags Ramon in, which drags Random in, and then BAM. We have a quest.

Any kind of ritual/quest/avoidance thingy she could go through? Something as simple as a flood in the place she calls home and needing some help in relocation of dangerous/mundane/whatever things. Or maybe Santino as a part of it.

Which would be great, actually, as it'd bring the DEBT really into play. As Random would gladly help Mal, but would rather chew tinfoil than help Santino.