Some adversaries may split communications between different protocols. There could be one protocol for inbound command and control and another for outbound data, allowing it to bypass certain firewall restrictions. The split could also be random to simply avoid data threshold alerts on any one communication.
Some Lazarus Group malware uses multiple channels for C2, such as RomeoWhiskey-Two, which consists of a RAT channel that parses data in datagram form and a Proxy channel that forms virtual point-to-point sessions.
Network intrusion detection and prevention systems that use network signatures to identify traffic for specific adversary malware can be used to mitigate activity at the network level. Signatures are often for unique indicators within protocols and may be based on the specific protocol used by a particular adversary or tool, and will likely be different across various malware families and versions. Adversaries will likely change tool C2 signatures over time or construct protocols in such a way as to avoid detection by common defensive tools. 
Analyze network data for uncommon data flows (e.g., a client sending significantly more data than it receives from a server). Processes utilizing the network that do not normally have network communication or have never been seen before are suspicious. Analyze packet contents to detect communications that do not follow the expected protocol behavior for the port that is being used.  Correlating alerts between multiple communication channels can further help identify command-and-control behavior.
- Strategic Cyber LLC. (2017, March 14). Cobalt Strike Manual. Retrieved May 24, 2017.
- Novetta Threat Research Group. (2016, February 24). Operation Blockbuster: Unraveling the Long Thread of the Sony Attack. Retrieved February 25, 2016.
- Novetta Threat Research Group. (2016, February 24). Operation Blockbuster: Remote Administration Tools & Content Staging Malware Report. Retrieved March 16, 2016.