Myeloma 11. A Summary of results to date. G.H.Jackson Lots of qualifications

CTD CRD KCRD Myeloma XI – TE pathway Induction 1 Induction 2 Maintenance Max. response VGPR CR MR PR PD SD CTD CRD CVD No CVD R 1:1 ASCT Lenalidomide Observation R 1:1 R 1:1 KCRD Primary endpoints: PFS and OS for each randomisation Patients were ineligible for the CVD randomisation if they had achieved a CR or VGPR to induction (went straight to ASCT if eligible or maintenance if not) or had PD or SD to induction (all primary refractory received CVD). Patients were ineligible for the maintenance randomisation if they failed to respond to lenalidomide as their induction IMiD or failed to respond to all trial induction treatment, had PD or had previous or concurrent active malignancies. Dose adjustments for renal impairment and following AEs were permitted.

Response to initial induction Lenalidomide led to deeper responses than thalidomide 79.5% 60.8% 52.8%

Response to initial induction Quadruplet KCRD led to deeper responses than either triplet 79.5% 60.8% 52.8%

Response to initial induction Quadruplet KCRD achieved the highest speed and depth of response

PFS Patients with IMiD refractory disease had a significantly shorter PFS than those who responded

for primary refractory patients Induction 2 for primary refractory patients Induction 1 Induction 2 CVD C: 500mg D1,8,15 V: 1.3mg/m2 D 1,4,8,11 D: 20mg D1,2,4,5,8,9,11,12 NDMM Completed at least 4 cycles of induction therapy with a response of SD or PD. ITT n=137 TE = 75, TNE = 62 Median follow up: 36 months (IQR 24-52) This is an ITT analysis of those who entered the CVD induction 2 consolidation treatment. The responses of these patients at the end of IMiD triplet (after central review) were: CR 0%, VGPR 8%, PR 23%, MR 12%, NC 15%, PD 39%, UTD 0.7%, Missing 1.5%

for primary refractory patients Induction 2 for primary refractory patients ITT analysis: 137 patients received CVD 54% of primary refractory patients did not receive CVD due to death 23% withdrawal 22% other 9%

PFS – per protocol analysis Patients with IMiD refractory disease who received CVD and responded had a significantly longer PFS than those who were dual refractory

Myeloma XI CVD No CVD N = 583 Median follow up: 30 months (IQR 17-46) Induction 2 NDMM Completed at least 4 cycles of either CRD or CTD) with response of <VGPR N = 583 (TE = 367, TNE = 216) CVD C: 500mg D1,8,15 V: 1.3mg/m2 D 1,4,8,11 D: 20mg D1,2,4,5,8,9,11,12 R 1:1 No CVD Median follow up: 30 months (IQR 17-46) Exclusion criteria: Patients were ineligible for the CVD randomisation if they achieved a CR or VGPR or had PD or SD to induction (all primary refractory patients received CVD).

Transplant non-eligible pathway Significant improvement in PFS from 8 to 20 months for patients receiving CVD, HR 0.72 Median PFS [95% CI] No CVD (n=110) 8m [6, 15] CVD (n=106) 20m [15, 24] HR : 0.72 95% CI [0.51, 1.00] Log-Rank P = 0.0525

Post ASCT PFS (CVD vs no CVD) Median PFS [95% CI] No CVD (n=126) 32m [26, 38] CVD (n=140) 50m [31, ∞] HR : 0.69 95% CI [0.47, 1.02] Log-Rank P = 0.1103

Response after ASCT Deeper responses with KCRD persisted after ASCT 92.1% 81.8% 77.0%

CRD was associated with significantly longer PFS and OS than CTD I presented data yesterday which demonstrated that the deeper responses seen with CRD than CTD translated into a significant PFS and OS benefit PFS data for KCRD patients are anticipated later this year..... PFS results for KCRD are accepted for ASH 2018 Jackson GJ et al ASCO 2017 Pawlyn C et al EHA 2017

On behalf of the UK NCRI Haemato-oncology Clinical Studies Group Thrombotic Events in Patients with Myeloma Treated with Immunomodulatory Drugs; Results of the Myeloma XI Study Charlotte A Bradbury, PhD, MD, MSc, Matthew W Jenner, MD, Alina Striha, MSc , Gordon Cook, Charlotte Pawlyn, MBBChir, PhD, John R Jones, MD, David Cairns, BSc, MSc, PhD , Anna Hockaday, Andrea Paterson , Mark T Drayson, MD, PhD, Roger G Owen, MD, Martin F Kaiser, MD , Walter M Gregory, PhD, Faith E Davies, MD, Gareth J. Morgan and Graham H Jackson, MD, PhD On behalf of the UK NCRI Haemato-oncology Clinical Studies Group Lots of qualifications

Results A Intensive induction B Attenuated induction Intensive induction (TE) Attenuated induction (TNE) Induction regime KCRD (n= 511) CTD (n= 1008) RCD (n= 1014) CTDa (n= 910) RCDa (n= 916) Total (n= 4359) Patients with thrombosis (%) Event no. 76 ( 14.9%) 86 118 (11.7%) 126 113 (11.1%) 127 87 ( 9.6%) 93 91 ( 9.9%) 97 485 (11.1%) 529 DVT 52 (68.4%) 55 60 (50.8%) 61 75 (66.4%) 82 42 (48.3%) 45 42 (46.2%) 43 271 (55.9%) 286 PE 23 ( 30.3%) 23 63 ( 53.4%) 65 44 ( 38.9%) 47 40 ( 46.0%) 41 39 ( 42.9%) 40 209 ( 43.1%) 216 Other 20 ( 26.3%) 24 20 ( 16.9%) 21 22 ( 19.5%) 23 15 ( 17.2%) 17 26 ( 28.6%) 26 103 ( 21.2%) 111 A Intensive induction B Attenuated induction

Results Thromboprophylaxis prior to first thrombosis 61 80.3% 102 Intensive induction (TE) Attenuated induction (TNE) Patients developing thrombosis in induction KCRD (n=76 of 511) CTD (n=118 of 1008) RCD (n=113 of 1014) CTDa (n=87 of 910) RCDa (n=91 of 916) Total (n=485 of 4359) Thromboprophylaxis prior to first thrombosis 61 80.3% 102 86.4% 101 89.4% 81 93.1% 80 87.9% 425 87.6%

Results Intensive induction (TE) Attenuated induction (TNE) Patients developing thrombosis in induction KCRD (n=76 of 511) CTD (n=118 of 1008) RCD (n=113 of 1014) CTDa (n=87 of 910) RCDa (n=91 of 916) Total (n=485 of 4359) Thromboprophylaxis prior to first thrombosis 61 (80.3%) 102 (86.4%) 101 (89.4%) 81 (93.1%) 80 (87.9%) 425 (87.6%) Aspirin 11 (14.5%) 33 (28.0%) 39 (34.5%) 34 (39.1%) 36 (39.6%) 153 (31.5%) Treatment dose warfarin 1 ( 1.3%) 3 (2.5%) 6 (5.3%) 3 (3.4%) 2 (2.2%) 15 (3.1%) Prophylactic dose LMWH 39( 51.3%) 58 (49.2%) 47 (41.6%) 42 (49.4%) 34 (37.4%) 222 (45.8%) Treatment dose LMWH 10 (13.2%) 6 (5.1%) 13 (11.5%) 6 (6.9%) 11 (12.1%) 46 (9.5%) Clopidogrel   2 (1.7%) 1 (0.9%) 1 3 ( 0.6%) Dabigatran 1 ( 1.3%) 1 1 ( 0.2%) Rivaroxaban Missing 21 ( 27.6%) 20 ( 16.9%) 20 16 ( 14.2%) 17 7 ( 8.0%) 7 12 ( 13.2%) 13 76 ( 15.7%) Out of patients developing thrombosis in induction (n=485) 290 (59.8%) had been assessed as high thrombosis risk and of these: 34 (11.7%) were not on thromboprophylaxis, 82 (28.3%) on aspirin, 155 (53.4%) on LMWH and 19 (6.6%) on other 195 (40.2%) had been assessed as low thrombosis risk and of these: 35 (18.0%) were not on thromboprophylaxis, 70 (35.9%) on aspirin, 85 (43.6%) on LMWH and 5 (2.6%) on other

Results of the Myeloma XI Trial Lenalidomide Maintenance Significantly Improves Outcomes Compared to Observation Irrespective of Cytogenetic Risk: Results of the Myeloma XI Trial

Myeloma XI N=1971 TE = 1248, TNE = 723 Lenalidomide Observation Induction Maintenance Lenalidomide 10mg/day, days 1-21/28 Observation NDMM Treated on Myeloma XI induction protocols R 1:1 N=1971 TE = 1248, TNE = 723 Median follow up: 30.6 months (IQR 17.9-50.7) Exclusion criteria Failure to respond to lenalidomide as induction IMiD or progressive disease Previous or concurrent active malignancies

MRD assessment Lenalidomide Observation NDMM 21 Induction Maintenance Lenalidomide 10mg/day, days 1-21/28 Observation NDMM Treated on Myeloma XI induction protocols R 1:1 n= 409 MRD MRD

Progression-free Survival Lenalidomide improved PFS from 20 to 39 months, hazard ratio of 0.46 Median PFS [95% CI] Lenalidomide (n=1137) 38.9m [35.8, 42.1] Observation (n=834) 20.0m [18.2, 22.1] HR : 0.46 95% CI [0.41, 0.53] Log-Rank P < 0.0001 PFS: progression-free survival

Impact of MRD at 6M post maintenance randomisation PFS not reached versus 24 months for MRD-positive patients, HR 0.22 Median PFS MRD neg Not reached MRD pos 24m HR : 0.22, 95% CI [0.14, 0.34] Log-Rank P < 0.0001

Impact of MRD at 6M post maintenance randomisation Superior OS seen in MRD-negative patients, HR 0.42 Median OS MRD neg (n=205) Not reached MRD pos (n=136) HR : 0.42, 95% CI [0.21, 0.87] Log-Rank P = 0.0153

Benefits of maintenance PFS advantage demonstrated in both MRD-neg and MRD-pos patients Benefit of lenolidamide can be demonstrated in both MRD-negative patients (yellow vs blue) and MRD-positive patients (green vs red).

Benefits of maintenance Possible OS benefit for MRD-negative patients on maintenance OS data not mature enough yet but trend towards benefit for MRD-neg/Main patients.

Transplant eligible pathway Lenalidomide improved PFS from 30 to 57 months, hazard ratio of 0.48 Median PFS [95% CI] Lenalidomide (n=730) 56.9m [49.7,∞] Observation (n=518) 30.1m [25.2, 32.4] HR : 0.48 95% CI [0.40, 0.58] Log-Rank P < 0.0001 PFS: progression-free survival

Transplant eligible meta-analysis All studies demonstrate improved PFS with lenalidomide maintenance Attal M, et al. N Engl J Med. 2012;366:1782-91 McCarthy PL, et al. N Engl J Med. 2012;366:1700-81 Palumbo A, et al. N Engl J Med. 2014;371:895-905 McCarthy PL et al. J Clin Oncol. 2017;35:3279-3289 Not individual patient data PFS: progression-free survival

Transplant non-eligible pathway Lenalidomide improved PFS from 11 to 26 months, hazard ratio of 0.44 Median PFS [95% CI] Lenalidomide (n=407) 26.0m [21.8, 30.7] Observation (n=316) 11.0m [5.2, 23] HR : 0.44 95% CI [0.37, 0.53] Log-Rank P < 0.0001

PFS2 TE: All: TNE:

Transplant eligible pathway Lenalidomide improved 3 yr OS from 80.2% to 87.5%, hazard ratio of 0.69 3 yr OS: 87.5% Len 80.2% Obs 3 year OS Lenalidomide (n=730) 87.5% [84.3, 90.7] Observation (n=518) 80.2% [76.0, 84.4] HR : 0.69 95% CI [0.52, 0.93] Log-Rank P = 0.0130 OS: overall survival

Transplant eligible meta-analysis Demonstrates improved OS with maintenance lenalidomide Attal M, et al. N Engl J Med. 2012;366:1782-91 McCarthy PL, et al. N Engl J Med. 2012;366:1700-81 Palumbo A, et al. N Engl J Med. 2014;371:895-905 McCarthy PL et al. J Clin Oncol. 2017;35:3279-3289 Not individual patient data OS: overall survival

Leeds Clinical Trials Research Unit: Trial Management Group: Chief Investigators: Graham Jackson, Gareth Morgan Faith Davies Nigel Russell Immunology studies: Mark Drayson Leeds Clinical Trials Research Unit: Walter Gregory David Cairns Anna Hockaday Trial Management Group: Gordon Cook Mark Drayson Matthew Jenner John Jones Martin Kaiser Roger Owen Molecular studies: Martin Kaiser Brian Walker Charlotte Pawlyn We thank all the patients and staff at over 100 centres in the UK whose participation made this study possible. We thank all principle investigators for their dedication and commitment to recruiting patients to the study. MRD studies: Roger Owen

Principal Investigators Dr Jane Tighe Dr Mark Cook Dr Jenny Craig Dr Sandra Hassan Dr Ranjit Dasgupta Dr Richard Went Dr Richard Soutar Dr Alison McCaig Dr Bhuvan Kishore Dr Henri Grech Dr Mark Grey Dr Malgorzata Rokicka Dr Jenny Buxton Dr Chetan Patalappa Dr Sam Ackroyd Dr Rachel Hall Dr Jenny Bird Dr Julie Blundell Dr Kate Rothwell Dr David Allotey Dr David Allsup Dr Claudius Rudin Dr Sally Chown Dr Robin Aitchison Dr Mamta Garg Dr Victoria Hervey Dr Caroline Harvey Dr Samar Kulkarni Dr Don Gillett Dr Heather Eve Dr Ram Jayaprakash Dr John Ashcroft Dr Helen Jackson Dr Peter Toth Prof John Snowden Dr Michael Hamblin Dr David Howarth Dr Gillian Brearton Dr Stephen Hawkins Dr Tariq Shafi Dr Martin Kaiser Dr Hannah Hunter Dr Hayley Greenfield Dr Levison-Keating Dr Joe Joseph Dr Kamaraj Karunanithi Dr Dietman Hofer Dr Craig Taylor Dr Alberto Rocci Dr Lynny Yung Dr Sarah Arnott Dr Beth Harrison Dr Iain Singer Dr Ceri Bygrave Dr Nilima Parry-Jones Dr Lorna McClintock Dr Supratik Basu Dr Carolina Arbuthnot Dr Duncan Gowans Dr Huw Roddie Dr Martin Auger Dr Laura Munro Prof Graham Jackson Dr Simon Jowitt Dr Mekkali Narayanan Dr Jonathan Cullis Dr Earnest Hartin Dr Farooq Wandroo Dr Claire Hall Dr Sanjeev Jalihal Dr Lisa Robinson Dr Hamdi Sati Dr Matthew Jenner Dr Isobel Chalmers Dr Alastair Whiteway Dr Raymond Dang Dr Toby Nicholson Dr Cesar Gomez Prof Gordon Cook Dr Jindriska Lindsay Dr Sarah Janes Dr Mark Kwan Dr Montaser Haj Dr Tim Moorby Dr Salim Shafeek Dr Paul Kerr Dr Santosh Narat Prof Nigel Russell Dr Cathy Williams Dr Simon Watt Dr Sally Evans