Results of a new study involving a fluorescent assay may help to identify patients with myeloma who will respond to treatment and those who will not respond to the new proteasome inhibitor carfilzomib (Hawley TS, et al. Am J Hematol. 2013. Epub ahead of print).
“Our hope is that the fluorescent assay we have developed will help physicians monitor the newest treatment option for multiple myeloma patients and determine how well it is working,” said lead author Robert G. Hawley, PhD, Professor and Chair, Department of Anatomy and Regenerative Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC.
Dr Hawley and colleagues tested the hypothesis that drug resistance in myeloma may be mediated by mechanisms similar to those that protect normal stem cells from toxic agents. Their approach involved the use of a new stem-cell–specific fluorescent dye CDy1, which revealed that myeloma cells that stained brightly with CDy1 have a stem-cell–like pattern of gene expression.
“We are interested in the potential role these ‘cancer stem cells’ might have in tumor relapse,” Dr Hawley told Value-Based Care in Myeloma.
At the same time, they discovered that dim CDy1 staining was caused by increased expression of the multidrug efflux transporter P-glycoprotein, encoded by the ABCB1 gene, which efficiently pumped the CDy1 dye out of the cells. In the 1980s and 1990s, increased expression of ABCB1 was associated with drug resistance that developed in up to 75% of patients with myeloma who received the VAD (vincristine/doxorubicin/dexamethasone) regimen: vincristine and doxorubicin are efflux substrates of ABCB1.
“We subsequently demonstrated that increased expression of ABCB1 conferred resistance to carfilzomib, and that efflux of CDy1 could be used as a surrogate assay of carfilzomib efflux or resistance,” Dr Hawley said.
Clinical Implications
Asked if there may be a time when CDy1 efflux could be assayed in the clinic to evaluate ABCB1 expression in patients with myeloma and therefore to predict carfilzomib response, Dr Hawley responded, “It is important to stress that our preclinical studies were carried out in vitro with myeloma cell lines. It remains to be demonstrated whether increased ABCB1 expression is relevant to drug resistance that might develop during carfilzomib treatment in the clinic. It seems possible that it might be involved to some extent based on the previous experience with VAD, and we are preparing to screen patient samples with CDy1 to determine whether this is indeed the case.”
The preclinical data further showed that hedgehog inhibitors, such as the new drug vismodegib, could modulate this resistance to carfilzomib, suggesting that pairing these drugs with carfilzomib may combat the development of resistance, Dr Hawley said.
“However, a caveat is whether combining carfilzomib with hedgehog pathway inhibitors or other drugs that are ABCB1 inhibitors would significantly alter its safety profile,” Dr Hawley cautioned. “For example, there have been a couple of reports of increased toxicity of lenalidomide, which is a weak ABCB1 substrate, when it was inadvertently combined with ABCB1 inhibitors. In one instance, the patient was also being treated with the anti-fungal agent itraconazole, which is similar to vismodegib in that it exhibits both hedgehog pathway inhibitory and ABCB1 inhibitory properties.”
Putting the laboratory research into a broader context, Dr Hawley added, “It probably goes without saying, but a better understanding of drug resistance mechanisms will aid in the design of new therapies. I would also like to point out that we found carfilzomib to exhibit potent cytotoxic activity against the vast majority of myeloma cell lines that we tested, so I fully expect that it will be an effective treatment approach for many patients with advanced disease.”