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

AIMING FOR EXCELLENCE IN OUTCOMES IN HAEMATOLOGIC MALIGNANCIES What is the optimal duration of therapy?

Overall survival has improved in patients with MM Reference: Kumar SK et al. Leukemia. 2014;28(5): newly diagnosed patients with MM seen at Mayo Clinic between January 1, 2001, and December 31, Adapted from Kumar et al, Leukemia, 2014.

Despite treatment advances, relapse remains inevitable for most patients 1 References: 1. Munshi NC et al. J Clin Oncol. 2013;31(20): Durie BGM. Multiple myeloma: cancer of the bone marrow. International Myeloma Foundation. Accessed February 9, Adapted from Durie,

Is treating to CR enough? References: 1. Dingli D et al. Cancer Sci. 2007;98(7): Dingli D et al. J Clin Oncol. 2007;25(31): Munshi NC et al. J Clin Oncol. 2013;31(20):

Measuring minimal residual disease (MRD) in MM The definition of CR has evolved with the changing treatment landscape 1,2 Residual tumour cells can often be detected in patients achieving a CR 3 Sensitive assays have been developed to measure MRD 4 : –Allele-specific oligonucleotide PCR (ASO-PCR) –Multiparameter flow cytometry (MFC) –Next-generation sequencing (NGS) References: 1. Munshi NC et al. J Clin Oncol. 2013;31(20): Hart AJ et al. Biol Blood Marrow Transplant. 2012;18(12): Martinez-Lopez J et al. Blood. 2014;123(20): Biran N et al. Curr Hematol Malig Rep. 2014;9(4):

MRD-negativity is associated with improved OS 1 Outstanding questions 2,3 : Implications of MRD-negativity? Optimal assay to measure MRD? Impact of MRD status on treatment decisions? References: 1. Rawstron AC et al. J Clin Oncol. 2013;31(20): Munshi NC et al. J Clin Oncol. 2013;31(20): Hart AJ et al. Biol Blood Marrow Transplant. 2012;18(12): Adapted from Rawstron et al, J Clin Oncol, MRD measured 100 days post ASCT by MFC MRD positivity defined as  50 in 500,000 cells

Importance of maintaining a deep response Studies have demonstrated that durability of response may also have prognostic value 1,2 References: 1. Barlogie B et al. Cancer. 2008;113(2): Durie BGM et al. J Clin Oncol. 2004;22(10): Adapted from Barlogie et al, Cancer,

Achieving sustained disease control with long-term therapy Reference: Durie BGM. Multiple myeloma: cancer of the bone marrow. International Myeloma Foundation. Accessed February 9, Adapted from Durie,

References: 1. Palumbo A et al. Leuk Res. 2012;36(suppl 1):S19-S McCarthy PL et al. Hematol Oncol Clin North Am. 2014;28(5): Palumbo A et al. Blood. 2011;118(17): Brioli A et al. Br J Haematol. 2014;165(4): Considerations for long-term therapy 10

MM is a complex disease Studies demonstrate clonal heterogeneity and complex patterns of clonal evolution in MM with potential clinical implications 1,2 Bone marrow microenvironment is essential for MM pathogenesis and progression—important therapeutic targets 3 Depth of initial response correlates with improved clinical outcomes in transplant-eligible and -ineligible patients 4-6 Most patients eventually relapse, including those who achieve a CR 3,7 Growing evidence supports long-term therapy with novel agents to provide sustained disease control and ultimately improve PFS and OS References: 1. Keats JJ et al. Blood. 2012;120(5): Bolli N et al. Nat Commun. 2014;5:2997. doi: /ncomms Borrello I. Leuk Res. 2012;36(suppl 1):S3- S Chanan-Khan AA et al. J Clin Oncol. 2010;28(15): Lahuerta JJ et al. J Clin Oncol. 2008;26(35): Gay F et al. Blood. 2011;117(11): Martinez-Lopez J et al. Blood. 2014;123(20): McCarthy PL et al. Hematol Oncol Clin North Am. 2014;28(5): Ludwig H et al. Blood. 2012;119(13): Moreau P et al. Hematol Oncol North Am. 2014;28(5): Palumbo A et al. J Clin Oncol. 2014;32:5s (suppl; abstr 8515). 11

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/1508/0047c(1) Date of preparation: April 2016