1. AIMING FOR EXCELLENCE IN OUTCOMES IN HAEMATOLOGIC MALIGNANCIES Taking a Deeper Approach to Multiple Myeloma Treatment UK/NP/1508/0047a (1) April 2016 A MEDICAL EDUCATION RESOURCE PROVIDED BY TAKEDA ONCOLOGY

2. AIMING FOR EXCELLENCE IN OUTCOMES IN HAEMATOLOGIC MALIGNANCIES The complex disease biology of multiple myeloma

3. Initiation and progression of multiple myeloma (MM) involves numerous genetic events Adapted from Morgan et al, Nat Rev Cancer, 2012. Reference: Morgan GJ et al. Nat Rev Cancer. 2012;12(5):335-348. MGUS - Monoclonal gammopathy of unknown significance; IGH@ - immunoglobulin heavy chain locus

4. Malignant plasma cells may not evolve in a linear manner 1,2 Tumour progression is an evolutionary process 3 Evidence from multiple tumour types suggests a more complex branching model of tumour progression, resulting in substantial clonal diversity 1,4,5 Adapted from Morgan et al, Nat Rev Cancer, 2012. 2 References: 1. Bahlis NJ. Blood. 2012;120(5):927-928. 2. Morgan GJ et al. Nat Rev Cancer. 2012;12(5):335-348. 3. Nowell PC. Science. 1976;194(4260):23-28. 4. Gerlinger M et al. N Engl J Med. 2012;366(10):883-892. 5. Anderson K et al. Nature. 2011;469(7330):356-361. 4

5. Subclonal heterogeneity is characteristic of MM 1,2 References: 1. Keats JJ et al. Blood. 2012;120(5):1067-1076. 2. Walker BA et al. Blood. 2012;120(5):1077-1086. 3. Bahlis NJ. Blood. 2012;120(5):927-928. 4. Bolli N et al. Nat Commun. 2014;5:2997.doi.10.1038/ncomms3997. Adapted from Bahlis, Blood, 2012. 3 Combination therapy may be preferential over sequential single agents to control all coexisting subclones. Additional clinical research is needed to validate these preclinical findings 1,3,4 5

6. Selective pressures from treatment can result in alternating clonal dominance 1-3 Preclinical observations suggest complex clonal relationships with competing or collaborating clones 2,4 References: 1. Egan JB et al. Blood. 2012;120(5):1060-1066. 2. Keats JJ et al. Blood. 2012;120(5):1067-1076. 3. Bolli N et al. Nat Commun. 2014;5:2997. doi:10.1038/ncomms3997. 4. Bahlis NJ. Blood. 2012;120(5):927-928. Adapted from Keats et al, Blood, 2012. 2 Treatment may control an indolent or sensitive clone, allowing a more aggressive clone to expand 2,4 Retreatment may be effective due to the reemergence of a sensitive clone with clonal shifting 2,4 Treatment may control an indolent or sensitive clone, allowing a more aggressive clone to expand 2,4 Retreatment may be effective due to the reemergence of a sensitive clone with clonal shifting 2,4 6

7. The development of MM is dependent on the bone marrow microenvironment 1-3 References: 1. Manier S et al. J Biomed Biotechnol. 2012;2012:157496. 2. Podar K et al. Leukemia. 2009;23(1):10-24. 3. Borrello I. Leuk Res. 2012;36(suppl 1):S3-S12. 7 Illustrative depiction of myeloma cells surrounding stromal cells.

8. Cellular and noncellular components are important for MM pathogenesis and progression 1,2 References: 1. Hideshima T et al. Nat Rev Cancer. 2007;7(8):585-598. 2. Podar K et al. Leukemia. 2009;23(1):10-24. 3. Manier S et al. J Biomed Biotechnol. 2012;2012:157496. 4. Borrello I. Leuk Res. 2012;36(suppl 1):S3-S12. 5. Kawano Y et al. Immunol Rev. 2015;263(1):160-172. 6. Harousseau JL et al. N Engl J Med. 2009;360(25):2645-2654. 7. Binsfeld M et al. Biochim Biophys Acta. 2014;1846(2):392-404. Cellular components 2-5 : Haematopoietic stem cells Stromal cells Erythrocytes Osteoclasts Osteoblasts Immune cells Endothelial cells Noncellular components 2-5 : Extracellular matrix Cytokines Growth factors Chemokines Adapted from Harousseau et al, N Engl J Med, 2009 6 ; Binsfeld et al, Biochim Biophys Acta, 2014. 7 8

9. Adhesion to bone marrow stromal cells (BMSC) promotes cell growth, survival, migration, and drug resistance 1,2 In vitro studies have shown that IL-6 secretion by BMSCs is significantly increased following adhesion to MM cells 4 References: 1. Hideshima T et al. Nat Rev Cancer. 2007;7(8):585-598. 2. Borrello I. Leuk Res. 2012;36(suppl 1):S3-S12. 3. Anderson KC et al. Annu Rev Pathol. 2011;6:249-274. 4. Chauhan D et al. Blood. 1996;87(3):1104-1112. Adapted from Anderson et al, Annu Rev Pathol, 2011. 3 9 BMECs – Bone marrow endothelial cells

10. Bone marrow angiogenesis is increased in MM compared with earlier stages of disease 1-4 References: 1. Manier S et al. J Biomed Biotechnol. 2012;2012:157496. 2. Giuliani N et al. Cancer Microenviron. 2011;4(3):325-337. 3. Bhutani M et al. Leukemia. 2014;28(2):413-416. 4. Rajkumar SV et al. Clin Cancer Res. 2002;8(7):2210-2216. Microvessel density of bone marrow samples measured by CD34 staining. From Rajkumar et al, Clin Cancer Res, 2002. 4 MGUSMM 10

11. Myeloma cells disrupt bone remodelling resulting in osteolytic lesions 1,2 References: 1. Roodman GD. Leukemia. 2009;23(3):435-441. 2. Kawano Y et al. Immunol Rev. 2015;263(1):160-172. 3. Raje N et al, Clin Cancer Res. 2011;17(6):1278-1286. 4. Healy CF et al. Bone Marrow Res. 2011;2011:583439. Diffuse lytic lesions in the skull. From Healy et al, Bone Marrow Res, 2011. 4 11 Adapted from Raje et al, Clin Cancer Res, 2011. 3

12. Immunosuppression important for MM pathogenesis Reference: Binsfeld M et al. Biochim Biophys Acta. 2014;1846(2):392-404. 12 Adapted from Binsfeld et al, Biochim Biophys Acta, 2014.

13. Combining agents with different mechanisms of action may have a synergistic effect 1 References: 1. Hideshima T et al. Mol Cancer Ther. 2011;10(11):2034-2042. 2. Harousseau JL et al. N Engl J Med. 2009;360(25):2645-2654. 3. Binsfeld M et al. Biochim Biophys Acta. 2014;1846(2):392-404. 4. Kawano Y et al. Immunol Rev. 2015;263(1):160-172. 5. Qiang YW et al. Semin Hematol. 2012;49(3):243-248. 6. Quach H et al. Leukemia. 2010;24(1):22-32. Adapted from Hideshima et al, Mol Cancer Ther, 2011 1 ; Harousseau et al, N Engl J Med, 2009 2 ; Binsfeld et al, Biochim Biophys Acta, 2014 3 ; Kawano et al, Immunol Rev, 2015 4 ; Qiang et al, Semin Hematol, 2012 5 ; Quach et al, Leukemia, 2010. 6 13

14. AIMING FOR EXCELLENCE IN OUTCOMES IN HAEMATOLOGIC MALIGNANCIES Takeda Oncology and are registered trademarks of Takeda Pharmaceutical Company Limited. Other trademarks are the property of their respective owners. Copyright © 2016, Millennium Pharmaceuticals, Inc. UK/NP/1508/0047a(1) Date of preparation: April 2016