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Researchers Uncover Root Cause of Multiple Myeloma Relapse

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Key Points

  • The study identified two genes—IRE1 and XBP1—that control response to proteasome inhibitors such as bortezomib and carfilzomib.
  • An intrinsic resistance found in immature tumor progenitor cells was revealed to be the root cause of multiple myeloma and also the mechanism that leads to recurrence.

Researchers have discovered why multiple myeloma frequently recurs after an initially effective treatment that can keep the disease at bay for up to several years. The study, published in Cancer Cell, was a collaboration between researchers at Princess Margaret Hospital in Toronto, Mayo Clinic in Arizona, and the Translational Genomics Research Institute in Phoenix.

Study Details

The research team initially analyzed 7,500 genes in multiple myeloma cells to identify genes which when suppressed made cancer cells resistant to proteasome inhibitors such as bortezomib (Velcade) or carfilzomib (Kyprolis). Then, the team 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 revealed that an intrinsic resistance found in immature tumor progenitor cells is the root cause of multiple myeloma and 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 appeared to be in complete remission.

Study Identifies Progenitor Cell as Target for Treatment

"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 corresponding author Rodger Tiedemann, MD, a hematologist specializing in multiple myeloma and lymphoma at Princess Margaret. "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."

"Some myeloma cells are too immature to be caught by the drugs and thus hide underground only to reemerge later," said Keith Stewart, MB, ChB, Dean for Research at Mayo Clinic in Arizona and contributor to the study. "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."

The study was funded by the National Cancer Institute, Multiple Myeloma Research Foundation, Leukemia and Lymphoma Society, Canadian Cancer Society, the Arthur Macaulay Cushing Estate, and The Princess Margaret Cancer Foundation.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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