The Melbourne Storm are set to head into the biggest game of the regular season so far against the Penrith Panthers without the services of star halfback Jahrome Hughes, who is out with a calf injury.

Hughes will join Ryan Papenhuyzen on the sideline for the clash, causing a major shake up of the Melbourne spine, which has ran on 162 points in the last three weeks during games against the New Zealand Warriors, Newcastle Knights and St George Illawarra Dragons.

The Storm confirmed in a statement that Hughes has suffered a calf injury and also stated they are hopeful that he will be back next week.

"Jahrome Hughes has been ruled out of tonight’s Magic Round clash against the Penrith Panthers due to a calf injury," the statement read.

"We are hoping he will be okay for next week's match against the North Queensland Cowboys in Townsville."

Craig Bellamy has already been left unsure over the best make up of his side for tonight's clash, with Reimis Smith also out.

Marion Seve has been named out of the development squad following NRL approval to play in the centres, while Papenhuyzen was tentatively replaced by Nick Meaney at fullback, with Dean Ieremia claiming the vacant spot on the wing.

That flipped around just 24 hours before kick-off though, with Ieremia out of the side and Meaney shuffled back to the wing, bringing Tyran Wishart in at fullback after he spent time during the second half last week at the back.

Bellamy has also flagged the possibility of Cameron Munster spending time at fullback during the game, although that would be less likely if Hughes was out, given the likely inexperience left behind in the halves.

Cooper Johns has been left in the 19-man squad and will likely be parachuted straight into the halves.

NRL approval could also be gained to bring Ieremia back into the squad, pushing Wishart to the halves and Meaney back to the number one jumper.

The Storm will confirm their team at 6:45pm (AEST) on Saturday evening.