If you have big hands the 21 is nice. A 4th gen or a 21 SF is more comfortable to me. But the 21 has a good low bore axisa predictable (not great, but predictable trigger), and is a very shootable 45.
I just got a M&P .40 and find it to be one of the most pleasant shooting .40s.
As an option, The M&P .45 is a good fitting gun too. Trigger is a little funkier than Glock, but hear that the Pro series guns have a nicer trigger.
I don't plan on getting rid of my 3rd gen 21 or my M&P .40.