Research team uncovers root cause of multiple myeloma relapse

Volume 2, Issue 4, 2013


An intrinsic resistance found in immature tumor progenitor cells causes the disease and spawns relapse.

Photograph showing Keith Stewart, M.B., Ch.B., dean for research at Mayo Clinic in Arizona

Keith Stewart, M.B., Ch.B.

A team of Mayo Clinic Cancer Center researchers in Arizona working in collaboration with researchers from other institutions have uncovered the root cause for relapse in multiple myeloma. The team's findings were published in the Sept. 9, 2013, issue of the journal Cancer Cell.

The Mayo Clinic researchers, working with colleagues at Princess Margaret Cancer Centre in Toronto and researchers at the Translational Genomics Research Institute (TGen) in Phoenix, initially analyzed 7,500 genes in multiple myeloma cells to identify genes that when suppressed made cancer cells resistant to a common class of drugs called proteasome inhibitors, such as bortezomib or carfilzomib.

The research team then studied bone marrow biopsies from patients to further understand their results. The process identified two genes, IRE1 and XBP1, that control response to the proteasome inhibitor and the mechanism underlying the drug resistance that is the barrier to cure.

The findings showed that recurrence was due to an intrinsic resistance found in immature tumor progenitor cells as the root cause of the disease and the same resistance also spawns relapse. The research demonstrates that although the visible cancer cells that make up most of the tumor are sensitive to the proteasome inhibitor drug, the underlying progenitor cells are untouched by this therapy.

These progenitor cells then proliferate and mature to reboot the disease process, even in patients who seemed to be in complete remission.

"Our findings reveal a way forward toward a cure for multiple myeloma, which involves targeting both the progenitor cells and the plasma cells at the same time," said Rodger Tiedemann, M.D., a hematologist specializing in multiple myeloma and lymphoma at Princess Margaret and lead investigator of the study. "Now that we know that progenitor cells persist and lead to relapse after treatment, we can move quickly into clinical trials, measure this residual disease in patients, and attempt to target it with new drugs or with drugs that may already exist."

Keith Stewart, M.B., Ch.B., dean for research at Mayo Clinic in Arizona and contributor to the study, said that some myeloma cells are too immature to be caught by the drugs and essentially hide underground, only to re-emerge later.

"This study has wide implications in the search for a cure of this common blood cancer, as this progenitor cell will have to be targeted," Dr. Stewart said.