Mike Chapman University of Cambridge Department of Haematology Novel agents have improved survival What is a biomarker A characteristic that is objectively measured and evaluated as an indicator of normal biological processes pathogenic processes or pharmacologic responses to a therapeuti ID: 611966
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Slide1
Biomarkers for personalized therapy in myeloma
Mike Chapman
University of Cambridge Department of HaematologySlide2
Novel agents have improved survivalSlide3
What is a biomarker?
“A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”
For the purposes of today…
“A measurable characteristic that is predictive of the response to a therapeutic intervention”Slide4
Why is this important?
Maximizing efficacy
Minimizing risk
of side effects
Avoiding development
of resistant clones
For the patientSlide5
Why is this important?
Exponential increases in drugs spending probably not sustainable
US/Canada
per capita
medication expenditure
Health economicsSlide6
Why is this important?
Exponential increases in drugs spending probably not sustainable
Already capped in the UK?
NHS
per capita
medication expenditure (red)
US/Canada
per capita
medication expenditure
Health economicsSlide7
Why is this important?
For the pharmaceutical industrySlide8
Why is this important?
For the pharmaceutical industry
Iressa
(
gefitinib
)
Tarceva
(
erlotinib
)Slide9
Why is this important?
For the pharmaceutical industry
Iressa
(
gefitinib
)
Tarceva
(
erlotinib
)Slide10
Properties of an ideal biomarker
Cost effective
Easy to sampleSafe to sample
Easy to performReproducible in different diagnostic labsRapid processingGuides choice of treatmentSlide11
Properties of an ideal biomarker
Cost effective
Easy to sampleSafe to sample
Easy to performReproducible in different diagnostic labsRapid processingGuides choice of treatmentSlide12
International Staging System (ISS) in myeloma
Out of date
Does not reflect response to individual treatmentsSlide13
Improving ISS: ISS-FISH
ISS I/II & negative FISH
ISS III & negative FISH or
ISS I & positive FISH
ISS II/III & positive FISHSlide14
Improving ISS: Revised-ISS
ISS I AND
FISH negative AND
LDH normal
ISS III AND
FISH positive OR LDH highSlide15
Biomarkers in Multiple Myeloma?
Gene expression profiling (GEP)
Myeloma profiled by John Shaughnessy’s group
Some prognostic significance
But…
Expensive
User/batch dependent
Largely reflects
cytogenetics
Difficult to class individual samples
Clustering not robustSlide16
Biomarkers in Multiple Myeloma?
70 gene signature defined poor prognosis
Derived 17 gene signature made available as RT-PCR kit
Does not alter treatment decisions
Gene expression profilingSlide17
Additive effects of predictive microarray signatures
Incorporation of different signatures is additive for prognosis
Signatures do not predict effective treatmentSlide18
Actionable mutations: BRAFSlide19
Actionable mutations: BRAFSlide20
Vemurafenib active in myelomaSlide21
How to identify new biomarkers?
Incorporation of genomics into clinical trials
IRF4 predictive of lenalidomide
responsiveness (Myeloma XI)RNAseq signature specifically predictive of bortezomib responsiveness (PADIMAC)Sequential whole exome sequencing at diagnosis and relapse (CARDAMON)Cell surface proteomics…Slide22
Challenges for identifying novel monoclonal antibody targets
Poor correlation between mRNA expression and protein expression
Variable quality of antibodies
Difficulty quantifying proteinsDifficulty enriching for plasma membrane proteinsSlide23
Plasma membrane profiling (PMP)Slide24
PMP in myeloma: high inter-run consistency
JIM3
KMS12BMSlide25
PMP in myeloma: close correlation with flow
cytometrySlide26
Prioritizing targets
CD38Slide27
Conclusions
Need to focus on biomarkers that inform treatment decisions
Incorporation of “-omics
” technologies in clinical trials essential Monoclonal antibody therapy is ideal for personalized medicine