Even if the reward had significantly decreased by that point, it would still be worthwhile given how much the price of bitcoin would have increased. And given how expensive mining equipment is become, we might also see a decline in the number of miners.
In my onion, all Bitcoin (21 Million) are mined the miners may charge higher fee for validating the transactions because this will be only source of their income as mining rewards will diminish. It is also possible that number of miners will decrease as there won't be much revenue in mining activity, however it could be potentially offset by increase in Bitcoin price overtime.