Biomarkers for personalized therapy in myeloma Mike Chapman University of Cambridge Department of Haematology

Novel agents have improved survival

What is a biomarker? For the purposes of today… “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”

Why is this important? For the patient Maximizing efficacy Minimizing risk of side effects Avoiding development of resistant clones

Why is this important? Health economics Exponential increases in drugs spending probably not sustainable US/Canada per capita medication expenditure

Why is this important? Health economics Exponential increases in drugs spending probably not sustainable US/Canada per capita medication expenditure Already capped in the UK? NHS per capita medication expenditure (red)

Why is this important? For the pharmaceutical industry

Why is this important? For the pharmaceutical industry Iressa (gefitinib) Tarceva (erlotinib)

Why is this important? For the pharmaceutical industry Iressa (gefitinib) Tarceva (erlotinib) Tarceva: Genentech USA, Roche elsewhere Iressa: AstraZeneca

Properties of an ideal biomarker Cost effective Easy to sample Safe to sample Easy to perform Reproducible in different diagnostic labs Rapid processing Guides choice of treatment

Properties of an ideal biomarker Cost effective Easy to sample Safe to sample Easy to perform Reproducible in different diagnostic labs Rapid processing Guides choice of treatment

International Staging System (ISS) in myeloma Out of date Does not reflect response to individual treatments

Improving ISS: ISS-FISH ISS I/II & negative FISH ISS III & negative FISH or ISS I & positive FISH ISS II/III & positive FISH

Improving ISS: Revised-ISS ISS I AND FISH negative AND LDH normal ISS III AND FISH positive OR LDH high

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 robust

Biomarkers in Multiple Myeloma? Gene expression profiling 70 gene signature defined poor prognosis Derived 17 gene signature made available as RT-PCR kit Does not alter treatment decisions

Additive effects of predictive microarray signatures Incorporation of different signatures is additive for prognosis Signatures do not predict effective treatment

Actionable mutations: BRAF

Actionable mutations: BRAF

Vemurafenib active in myeloma

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…

Challenges for identifying novel monoclonal antibody targets Poor correlation between mRNA expression and protein expression Variable quality of antibodies Difficulty quantifying proteins Difficulty enriching for plasma membrane proteins

Plasma membrane profiling (PMP) Oxidation of sugar groups by periodate creates aldehydes. These react with hydroxylamines to form stable oxime bonds. Use aminooxy-biotin to label oxidized glycoproteins.

PMP in myeloma: high inter-run consistency JIM3 KMS12BM

PMP in myeloma: close correlation with flow cytometry

Prioritizing targets CD38

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