Abstract
BackgroundThe response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the potential influence of different polymorphisms in the CYP enzymes on the outcome of treatment.MethodsData was analyzed from 348 patients undergoing high-dose treatment and stem cell support in Denmark in 1994 to 2004. Clinical information on relapse treatment in 243 individual patients was collected. The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion), *6, and CYP2D6 gene duplication.ResultsIn patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment. We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib.ConclusionThere was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome.
Highlights
The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed
Three-hundred and forty-eight patients were treated with High-dose treatment with stem cell support (HDT) and stem cell support
In CYP2D6 a difference was found in sex in relation to ultra rapid metabolizers (UM) + EM and intermediate metabolizers (IM) + poor metabolizers (PM) (p = 0.04)
Summary
The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Genetic polymorphisms in enzymes implicated in drug metabolism represent a source of individual variation in drug responses. Among the drug metabolizing enzymes, the Cyclophosphamide and thalidomide are used for the treatment of multiple myeloma and other cancers. Several CYP450 enzymes are implicated in the activation of cyclophosphamide including CYP2C19 [3]. The primary route of metabolism of bortezomib is oxidative deboronation by CYP2C19, CYP1A2, and CYP3A4 with contribution from CYP2D6 and several other CYP450 enzymes [5,6]. This abolishes the effect of bortezomib since the boron atom is necessary for the inhibition of the 26 S proteasome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
