Hematology/Oncology

53rd ASH Annual Meeting

SAN DIEGO — Absence of the gene cereblon was associated with resistance to thalidomide and lenalidomide in patients with multiple myeloma, according to findings presented here.

Keith Stewart, MD, professor of medicine in the Division of Hematology-Oncology at Mayo Clinic in Scottsdale, Ariz., recalled that thalidomide (Thalomid, Celgene) was “serendipitously” discovered to be active in multiple myeloma in 1999.

“Until recently, though, the mechanism of action was completely unknown,” he said at a press conference. “These drugs do many things, but how they get there was a black box until recently a group in Japan discovered that thalidomide had to bind to a protein called cereblon.”

Binding to cereblon was essential for thalidomide to cause the birth defects that are a hallmark of thalidomide, Stewart said.

“When we saw that, we concluded that this may also explain the reason this class of drugs kills many cancer cells,” Stewart said. “They would have to work through this protein cereblon.”

Stewart noted that, in the absence of cereblon, the drugs have no activity.

“Cereblon is required if the patient is going to respond to thalidomide or lenalidomide,” he said. “Therefore, this could potentially serve as a biomarker to responsiveness of whether select patients will respond or not respond to these drugs.”

In the current study, the researchers examined MM cell lines that were resistant to immune modulator drugs, including lenalidomide (Revlimid, Celgene) and pomalidomide. When there was minimal or no presence of cereblon, the cells were resistant to the drugs.

Stewart and colleagues lowered the level of cereblon in five human-derived MM cell lines. Compared with control cell lines, those with lowered cereblon became almost completely resistant to lenalidomide. However, these cell lines were sensitive to other treatments for myeloma, including melphalan (Alkeran, GlaxoSmithKline), dexamethasone and bortezomib (Velcade, Millennium Pharmaceuticals).

The DNA of 10 MM patients with immune modulator resistance was analyzed. The researchers found low levels of cereblon expression in eight of those patients. However, normal cereblon levels were observed in some of the resistant patients.

“Our data suggest that cereblon is a critical molecule but not the unique source of drug resistance in this patient population,” Stewart said.

The data also indicated that interferon regulatory factor 4 is a common link between immune modulator drugs and cereblon function.

Disclosure: Dr. Stewart reports receiving consulting fees and honoraria from Celgene, Onyx and Millennium Pharmaceuticals.

It is important for all of us to note that understanding the various survival pathways that allow the lipid cells to proliferate and grow, and, similarly, understanding why some of these cells are resistant to our attempts at therapy, is at the forefront of research at the current time. Dr. Stewart has provided us with some exciting new insights about understanding resistance. His findings are also telling us about survival pathways. These findings are also illustrating what mechanisms are at work in survivors who don’t respond to our strategies, and providing information about what new agents might make patients sensitive to these new therapies.

Jane N. Winter, MD
Professor of medicine-hematology/oncology
Northwestern University Feinberg School of Medicine

For more information:

• Stewart K. Abstract #127. Presented at: 53rd Annual Meeting of the American Society of Hematology; Dec. 10-13, 2011; San Diego.

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