I wouldn't mind a real prequel ...say, set during the Prothean culling (we'd get to see our favorite aliens as cavemen) or even earlier. Where yes we know how it ends but there would still be drama and events left unexplored in a rich setting. Hell, the Protheans had their isht together so they likely had centuries if not millennia of conflicts before the Reapers (like their conflict with their version of the Geth). I suppose alternatives might include some other threat coming, set in a galaxy a few centuries in the future that is so large that no matter what your decisions in Mass Effect were, the universe is largely the same. So the Reapers are likely all gone (or all BACK), Geth/Quarian, Krogan/Rachni all have their values set the same regardless. All wiped out is the easiest, but just as possible to be hugely reduced in number and just fill in fluff for why (wiped out but brought back a little through benevolent science, weren't helped and slowly dying off, etc). Another would be going full on sci-fi and have a time travel or alt dimensional version of Mass Effect's story.
I personally would like a smaller story where your crew might be awesome badasses but not tasked with saving all life in the galaxy. I would like a Star Trek story, where a crew is tasked with re exploring space following the Reapers.
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