Marks apply a penalty when you make an attack that doesn't include the person/creature who marked you. It's resolved per attack, not per power usage.
In the case of Twin Strike, the power tells you to make 2 different attacks, 1 with your main and 1 with your offhand (or just 2 attacks in the case of the ranged version). For each of these attacks, look at who your target is. Is the target of your first attack the person who marked you? Yes, then no penalty. Target of the 2nd attack the person who marked you? No, then you suffer the penalty.
Area Blasts/bursts are different. You make 1 attack, that targets each creature in the area. If this single attack (that may or may not hit multiple creatures) includes the person who marked you, none of them suffer the penalty.