International Myeloma Foundation

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2 Black Swan Research Initiative Towards the Cure for Myeloma Brian GM Durie Friday, July 25, 2014 The IMF Initiatives

3 Black Swan Research Initiative Purpose The Black Swan Research Initiative is a global collaborative approach which focuses on the use of the best MRD testing to track myeloma at the lowest levels as a basis for treatment decisions to achieve cure. PROVIDES A STANDARDIZED FRAMEWORK TO ACHIEVE CURE

4 Black Swan Research Structure

5 Black Swan Research Structure The BSRI is made up of 5 primary lead investigators who oversee the development of 4 different workstreams. Brian Durie Jesus San Miguel Black Swan Investigator Team S. Vincent Rajkumar Ola Landgren Michael Kauffman MRD definitions Myeloma new definitions FDA meetings and follow-up Flow DNA Hevylite/Freelite PET/CT Retrospective Global education Protocol/Trial development Comparative trials Designed to achieve MRD- Neg/Zero

6 Black Swan Research Structure The BSRI consists of nearly 30 global myeloma experts and has current collaborations with several partners / institutions Vincent Rajkumar Shaji Kumar Brian Durie Bruno Paiva Alberto Orfao Jesus San Miguel Alberto Orfao Roman Hajek Bruno Paiva Heinz Ludwig Ola Landgren Meletios Andrew Spencer Dimopoulos Jens Hillengass Hartmut Wee Joo Chng Goldschmidt Hareth Nahi Mario Boccadoro Philippe Moreau Saad Usmani Juan Du Evangelos Terpos Ola Landgren Jesus San Miguel Brian Durie Shaji Kumar Antonio Palumbo Herve Avet Loiseau Current Full Industry Partners Onyx Pharmaceuticals Binding Site Celgene Academic Institutions Universities of Salamanca/ Pamplona Mayo Clinic NCI MSK NY Karolinska, Sweden Myeloma Team, Torino, Italy Heidelberg University, Germany University of Melbourne, Australia Shanghai University Singapore University

7 Definitions of Myeloma and Early Myeloma FEATURES CRAB Criteria Ultra-HR-SMM Pre-CRAB PC>60% High FREELITE MRI/Other Changes HR-SMM LR-SMM Spanish Criteria Mayo Criteria MGUS

8 Importance of stringent CR (scr)* scr at 2 years scr sustained for 6 months 7 year OS = 86% * Kapoor et al JCO 31: , 2013

9 Impact of flow MRD-negative No Relapses for MRD-Neg Roussel et al JCO July 2014

10 New definition of cure? Years PFS No Relapse Time

11 New response criteria RESPONSE SUBCATEGORY NEW MRD-NEGATIVE CATEGORY scr PLUS RESPONSE CRITERIA Flow- zero in marrow FDG- negative on PET/CT Normal hevylite ratio scr CR PLUS Clonal cells negative: immunochemistry and/ or immunofluorescence Normal Freelite ratio Negative IEP/IFE serum/urine Shaji Kumar, et al: in development 2014

12 MRD in MM: correlation between flow and next generation sequencing (NGS) using old flow test * NGS applicability: 91%; NGS sensitivity :<10-5 ** 2 cases excluded in the final publication Martinez-Lopez et al, Blood 2014

13 Key points about new flow test Objective endpoint: with computer analytics and standardized output avoids observer error Sensitive: quantitative at 10-5 level; under review at 10-6 ; new method just as sensitive as NGS Cheap: can be commercialized at ~$150/test Available: immediate turnaround at local/center lab Detects all clones: antibody panel includes all subtypes/variants Allows further/follow-up testing Multiple outputs: negative; number/million; specific MDS/MGUS signatures and/or subclone identification

14 Clinical Trials 1 Combo Comparisons: BSRI coordinates MRD testing Multiple in Development / Underway: Torino: Forte trial IFM: several trials MRC: correlations with Freelite/Hevylite SWOG/ECOG/Alliance in US many more 2 To Achieve MRD-Negative: Trials designed by BSRI team members Salamanca trial: San Miguel/Mateos Ola Landgren: HR SMM: CRd regimen Mayo team (Shaji Kumar): in development 3 To Overcome Resistant Clones: IITs* by BSRI investigators CAR/POM/DEX: ongoing Rd + anti-cd 38: in development CAR T-cells

15 Investigator Meetings and MRD Workshops Short Hills, NJ, 20 Participants New Orleans, 20 Participants MRD Flow, Salamanca, Spain, 70 Participants FDA Flow, Bethesda, MD, 30 Participants Chinese Meeting, Hangzhou, China, 20 Participants International Meeting, Milan, Italy US Flow, NYC, Plan Participants FDA Flow, Silver Spring, MD Investigator Meeting, SF, CA Investigator Meeting MRD Workshop

16 Ongoing Plans 1. FDA meetings 2. New tests 3. Further validation 4. New trials to: Identify new agents Achieve cure

17 MRD: Looking for the odd cat out!

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