Update Presented About Cereblon And Resistance To Pomalyst, Revlimid, And Thalidomide In Myeloma Patients (IMW 2013)
Published: Apr 12, 2013 2:16 pm
During a session at the International Myeloma Workshop (IMW) held in Japan last week, Dr. Keith Stewart from the Mayo Clinic summarized the latest findings from research related to the protein cereblon and its impact on certain myeloma treatments.
Dr. Stewart reported that low levels of cereblon are associated with lower response rates and reduced survival outcomes in multiple myeloma patients treated with the immunomodulatory agents Revlimid (lenalidomide), thalidomide (Thalomid), and Pomalyst (pomalidomide).
He explained that, with further investigation, these findings may eventually help physicians customize therapy for individual myeloma patients by identifying those who are more or less likely to respond to immunomodulatory agents.
He added that further research is needed to determine how best to measure cereblon levels, the value of cereblon as a disease marker, the mechanism by which cereblon regulates immunomodulatory drug activity, and potential new drugs that target cereblon.
Cereblon is a protein that has been linked to thalidomide’s tendency to cause birth defects. Cereblon is important for the growth of limbs in fetuses. Thalidomide, however, binds to and inhibits the activity of cereblon, leading to birth defects in babies born to women exposed to thalidomide during pregnancy.
Researchers began investigating the role of cereblon in the treatment of multiple myeloma several years ago. Initial results of these investigations were presented at major conferences in 2011 and 2012, and, in both years, cereblon-related research appeared in the Beacon's annual "top myeloma research" surveys (see related Beacon news 1 and 2).
Research On Cereblon In Myeloma
In his presentation, Dr. Stewart reported on recent studies that investigated the impact cereblon has on the efficacy of treatment with immunomodulatory agents for multiple myeloma.
Dr. Stewart described results of a study that showed that Revlimid-resistant myeloma cells have very low levels of cereblon.
Results of another study showed that myeloma cells engineered not to have cereblon do not respond to Revlimid or Pomalyst.
This result has been confirmed, Dr. Stewart explained, in studies which have shown that low levels of cereblon are common in patients who do not respond to Revlimid.
Dr. Stewart then described results of a recent U.S. study that showed that patients with low levels of cereblon are also less likely to respond to Pomalyst.
In this study, researchers measured cereblon levels in 61 relapsed and refractory multiple myeloma patients who were treated with 2 mg to 4 mg of Pomalyst daily and 40 mg of dexamethasone weekly.
In the study, 16 percent of patients were classified as having low levels of cereblon, 25 percent as having intermediate levels, and 59 percent as having high levels.
None of the patients with low levels of cereblon responded to Pomalyst. In contrast, 19 percent of patients with intermediate levels of cereblon responded, and 33 percent with high levels responded.
To compare progression-free survival outcomes, patients were divided into the lowest 25 percent and highest 25 percent of cereblon levels. Patients in the low group had a median progression-free survival of 3 months, compared to 17 months for the high group.
The trend was similar with regard to overall survival. The 25 percent of patients with the lowest cereblon levels had a median overall survival of 9.1 months, while the remaining 75 percent of patients had a median overall survival of 27 months.
The final study results that Dr. Stewart discussed involved patients in a European study who were treated with either thalidomide or Velcade (bortezomib). Among the patients treated with thalidomide, those with lower levels of cereblon had poorer progression-free survival and overall survival than those with higher levels of cereblon.
Among the patients treated with Velcade, in contrast, cereblon levels did not have an impact on survival outcomes.
Near the end of his presentation, Dr. Stewart noted that there currently is no standard way to measure cereblon levels in myeloma patients. Cereblon measurements made at one cancer center are not necessarily comparable to those made at another center.
This lack of standardization will need to be overcome for measurement of cereblon levels to be used regularly in both clinical trials and day-to-day treatment decision making.
For more information, please see Dr. Stewart's presentation slides, which he has made available for download and viewing as a courtesy to The Beacon's readers.
- Pomalyst Plus Low-Dose Dexamethasone Is Active In High-Risk Relapsed Myeloma Patients (IMW 2013)
- ASH 2011 – The Meeting’s Myeloma-Related “Hidden Gem”
- Revlimid And Pomalidomide Elicit High Response Rates In Multiple Myeloma Patients Who Relapsed After Thalidomide Or Revlimid (ASH 2010)
- Kyprolis Or Pomalyst For Dual-Refractory Myeloma - What Is The Survival Impact?
- Additional Analyses Of Pomalyst Plus Low-Dose Dexamethasone Studies Presented At ASH 2013