Berlin multiple myeloma researchers wanted to know why patients relapse after using the immunomodulators lenalidomide and pomalidomide. Using a method called proteomics, they found that the production of CDK6, a cell division-promoting cell cycle regulator, was very high when patients became resistant to treatment. They believed that inhibiting CDK6 could help. 

Dr. Philipp Mertins, lead researcher, noticed that the reason for relapse is rarely linked to myeloma genetic mutations, like a gene deletion or gene addition. He believed that a different change was taking place within the cancer cell to make the cells resistant to immunomodulator therapy. 

Using a method called mass spectometry, they tested whether protein changes were the cause of resistance. They tested pre-relapse and post-relapse samples, evaluating over 6,000 proteins. CDK6 was identified as a key protein in cell division that leads to relapse. 

When they increased the amount of CDK6 in myeloma cells in a a petri dish, they stopped responding to lenalidomide and pomalidomide. Then they added a CDK6 inhibitor and the drugs started working again to kill the myeloma cells. This showed that CDK6 enabled at least a partial reversal of the myeloma cells' treatment resistance.

They then tested a CDK6 inhibitor in combination with pomalidomide in mice, and while the drug (palbociclib) had no to moderate activity on the myeloma cells directly (with 5 out of 10 mice responding), there were significant improvements in the impact of lenalidomide or pomalidomide. Remarkably, the activity included cells that were known to be resistant to lenalidomide. the combination of palbociclib and lenalidomide returned the treatment to full myeloma cell killing activity.

When they combined pomalidomide andthe CDK6 inhibitor, the two drugs eliminated the myeloma cells after two weeks. When the treatment was stopped, myeloma cells started regrowing again, showing that continual treamtent with both drugs would be needed to prevent myeloma relapse. 

Having higher CDK6 levels seemed to relate only to the immunomodulators and not to other myeloma drugs like melphalan, bortezomib or dexamethasone. 

CDK6 inhibitors are already being used in breast cancer and are being investigated in blood cancers such as acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

Both drugs can cause low blood counts (cytopenia), however their data showed that low doses of the CDK6 inhibitor could be sufficient to sensitize the myeloma cells to the immunomodulators. 

The researchers conclude that more work is needed to use protein analyses to study myeloma responses and other cancers. They are hopeful this will unveil additional treatment targets and ways of personalizing therapy.