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

2. AIMING FOR EXCELLENCE IN OUTCOMES IN HAEMATOLOGIC MALIGNANCIES How to approach initial treatment?

3. The presence or absence of monoclonal protein is used to divide MM into secretory and nonsecretory types Revised IMWG diagnostic criteria for MM Reference: Rajkumar SV et al. Lancet Oncol. 2014;15(12):e538-e548. 3 Evidence of end organ damage Calcium elevation (>0.25 mmol/L higher than the upper limit of normal or >2.75 mmol/L) Renal insufficiency: creatinine clearance 177 μmol/L) Anaemia: haemoglobin value of >20 g/L below the lower linit of normal, or a haemoglobin value <100 g/L Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT ‡ Biomarkers of malignancy Clonal bone marrow plasma cell percentage* >60% Involved:uninvolved serum free light chain ratio § ≥100 >1 focal lesions on MRI studies ¶ * Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used. § These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved free light chain must be ≥100 mg/L. ¶ Each focal lesion must be 5 mm or more in size † Measured or estimated by validated equations ‡ If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement.

4. Initial treatment is dependent on transplant eligibility Reference: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ): Multiple Myeloma (Version 4.2015). © 2015 National Comprehensive Cancer Network, Inc. Available at NCCN.org. Accessed January 8, 2015. 4

5. HDT-ASCT may improve OS compared with IMiD-based consolidation therapy after induction Reference: Palumbo A et al. N Engl J Med. 2014;371(10):895-905. 5 Adapted from Palumbo et al, N Engl J Med, 2014. (n= 141) (n= 132) No. at Risk HDT-ASCT IMiD-based therapy 141 132 136 131 129 124 121 115 117 111 106 105 94 88 82 42 27 7 5

6. Early vs delayed ASCT may result in similar OS 1 References: 1. Fermand J-P et al. Blood. 1998;92(9):3131-3136. 2. ClinicalTrials.gov website https://clinicaltrials.gov/ct2/show/NCT01191060. Adapted from Fermand et al, Blood, 1998. 1 6 (n= 91) (n= 94)

7. Goals of initial treatment 1,2 Alleviate disease-related complications Achieve effective disease control Extend disease control Improve overall survival Use a regimen that is well tolerated Maintain QoL Facilitate stem cell collection References: 1. Kumar S. Cancer Treat Rev. 2010;36(suppl 2):S3-S11. 2. Lonial S et al. Leukemia. 2014;28(2):258-268. 3. Lahuerta JJ et al. J Clin Oncol. 2008;26(35):5775-5782. 4. Wang M et al. Bone Marrow Transplant. 2010;45(3):498-504. 5. Barlogie B et al. Cancer. 2008;113(2):355-359. 6. Chanan-Khan A et al. J Clin Oncol. 2010;28(15):2612-2624. Mounting evidence correlates depth and duration of initial response with clinical outcomes 3-6 7

8. Depth of response correlates with improved outcomes in transplant-eligible patients 1-4 References: 1. Chanan-Khan AA et al. J Clin Oncol. 2010;28(15):2612-2624. 2. Lahuerta JJ et al. J Clin Oncol. 2008;26(35):5775-5782. 3. Moreau P et al. J Clin Oncol. 2011;29(14):1898-1906. 4. Attal M et al. N Engl J Med. 1996;335(2):91-97. 8 Adapted from Lahuerta et al, J Clin Oncol, 2008. 2

9. Novel agent-based induction therapy in transplant improves depth of response 1,2 Objectives of induction treatment 1,2 –Reduce tumour burden to improve depth of response –Improve stem cell collection by decreasing plasma cell infiltration Induction regimens incorporating novel agents have significantly improved pre- and post-ASCT response rates and depth of response 1-3 Adapted from McCarthy et al, Hematology Am Soc Hematol Educ Program, 2013. 2 21 References: 1. Harousseau JL. Ann Oncol. 2012;23(suppl 10):334-338. 2. McCarthy PL et al. Hematology Am Soc Hematol Educ Program. 2013;2013:496-503. 3. Moreau P et al. J Clin Oncol. 2011;29(14):1898-1906.

10. Defining the role of tandem ASCT in the era of novel agents References: 1. Attal M et al. N Engl J Med. 2003;349(26):2495-2502. 2. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01109004. 10 Adapted from Attal et al, N Engl J Med, 2003. 1 (n= 200) (n= 199)

11. Depth of response may correlate with improved outcomes in transplant-ineligible patients Reference: Gay F et al. Blood. 2011;117(11):3025-3031. 11 Adapted from Gay et al, Blood, 2011. (n= 195)(n= 212)(n= 397)

12. Achieving a deep response must be balanced with treatment tolerability in transplant-ineligible patients Patient characteristics Heterogeneous group Frail Comorbid conditions Physical disabilities Reduced treatment tolerability Reference: Mateos M-V et al. Hematology Am Soc Hematol Educ Program. 2013;2013:488-495. 12

13. 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/1508/0047b(1) Date of preparation: April 2016