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

2. 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.

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

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

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

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

7. 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%

8. 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%

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

10. 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).

11. 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 : % CI [0.51, 1.00]
Log-Rank P =

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

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

14. 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

15. 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

16. 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

17. 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%

18. 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

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

20. 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 )
Exclusion criteria
Failure to respond to lenalidomide as induction IMiD or progressive disease
Previous or concurrent active malignancies

21. MRD assessment Lenalidomide Observation NDMM21
Induction
Maintenance
Lenalidomide
10mg/day, days 1-21/28
Observation
NDMM
Treated on Myeloma XI induction protocols R
1:1
n= 409
MRD
MRD

22. 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 : % CI [0.41, 0.53]
Log-Rank P <
PFS: progression-free survival

23. 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 <

24. 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 =

25. 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).

26. 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.

27. 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 : % CI [0.40, 0.58]
Log-Rank P <
PFS: progression-free survival

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

29. 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 : % CI [0.37, 0.53]
Log-Rank P <

30. PFS2
TE:
All:
TNE:

31. 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 : % CI [0.52, 0.93]
Log-Rank P =
OS: overall survival

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

33. 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

34. 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