1. Carfilzomib, Cyclophosphamide and Dexamethasone (KCd) Versus Bortezomib, Cyclophosphamide and Dexamethasone (VCd) For Treatment of First Relapse or Primary Refractory Multiple Myeloma (MM): Final Analysis of the Phase 2 MUK five Study
  Kwee L Yong, Samantha Hinsley, Holger Auner, Debbie Sherratt, Ruth M de Tute, Sarah Brown, Louise Flanagan, Catherine Williams, Jamie Cavenagh, Martin F Kaiser, Neil Rabin, Karthik Ramasamy, Mamta Garg, Stephen Hawkins, Ceri Bygrave, Gareth Morgan, Faith Davies and Roger G Owen
on behalf of the MUK five investigators and Myeloma UK Early Phase Clinical Trial Network

2. MUK five: Background
Head-to-head comparisons of carfilzomib with bortezomib have used differing dosing schedules in different patient groups
ENDEAVOR in Relapsed disease: Carfilzomib 20/56mg/m2 + Dex vs Bortezomib + Dex (Doublet, extended therapy)
CLARION in ND NTE MM: Carfilzomib 20/36mg/m2 + Melphalan + Prednisolone (MP) vs Bortezomib + MP (Triplet, nine cycles)
FOCUS in Relapsed double refractory patients: Carfilzomib 20/27mg/m2 vs Cyclophosphamide + Prednisolone (Single agent extended therapy)
Triplet regimens are standard of care in relapsed setting
We designed MUK five to assess anti-myeloma activity of carfilzomib versus bortezomib in triplet regimen with Cyclo + Dex at second line only
Need to check the literature on bortezomib triplets

3. ENDEAVOR Study Design Cd Vd Randomisation 1:1 N=929 Stratification:
Carfilzomib 56 mg/m2 IV
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)
Infusion duration: 30 minutes for all doses
Dexamethasone 20 mg
Days 1, 2, 8, 9, 15, 16, 22, 23
28-day cycles until PD or unacceptable toxicity
Randomisation 1:1
N=929
Stratification:
Prior proteasome inhibitor therapy
Prior lines of treatment
ISS stage
Route of V administration Vd
Bortezomib 1.3 mg/m2 (IV bolus or subcutaneous injection)
Days 1, 4, 8, 11
Dexamethasone 20 mg
Days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycles until PD or unacceptable toxicity
ISS, International Staging System; IV, intravenous; Cd, carfilzomib and dexamethasone; PD, progressive disease; Vd, bortezomib and dexamethasone; V, bortezomib.

4. Progression-Free Survival by Prior Lines of Therapy Intent-to-Treat Population (N=929)
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
Proportion Surviving
Without Progression
Proportion Surviving
Without Progression Cd Vd Cd Vd 6 12 18 24 30 6 12 18 24 30
Months Since Randomization
Months Since Randomization Cd
(n=232) Vd
Median PFS, months
22.2
10.1
Hazard ratio (95% CI)
0.45 (0.33–0.61)
P value
(one sided)*
<.0001 Cd
(n=232) Vd
(n=233)
Median PFS, months
14.9
8.4
Hazard ratio (95% CI)
0.60 (0.47–0.78)
P value
(one sided)*
<.0001
*Descriptive; unadjusted for multiplicity.
CI, confidence interval; Cd, carfilzomib and dexamethasone; PFS, progression-free survival; Vd, bortezomib and dexamethasone.

5. MUK five: Design 
*Stratified by:
Previous Bortezomib
β2 microglobulin
Previous ASCT
Time from diagnosis R1 R2
Primary endpoint (KCd vs. VCd)
≥VGPR at 24 weeks
Non-inferiority (NI) comparison KCd vs. VCd
NI margin of 5% (i.e. allowing KCd to be up to 5% worse)
Designed assuming ≥VGPR = 35% VCd, 45% KCd
Maintenance treatment: patient characteristics (n=141)
Maintenance treatment: patient characteristics (n=141)
Maintenance treatment: patient characteristics (n=141)
Maintenance treatment: patient characteristics (n=141)
Maintenance treatment: patient characteristics (n=141)
Carfilzomib maintenance (n=69)
Observation (n=72)
At end of KCd
Minimisation factor: local assessment of response ≥VGPR
40 (58.0%)
39 (54.2%)
ECOG: 0
43 (62.3%)
38 (52.8%)
MRD: Negative
8 (11.6%)
10 (13.9%)
At trial entry
ISS: I
39 (56.5%)
42 (58.3%)
Carfilzomib maintenance (n=69)
Observation (n=72)
At end of KCd
Minimisation factor: local assessment of response ≥VGPR
40 (58.0%)
39 (54.2%)
ECOG: 0
43 (62.3%)
38 (52.8%)
MRD: Negative
8 (11.6%)
10 (13.9%)
At trial entry
ISS: I
39 (56.5%)
42 (58.3%)
Carfilzomib maintenance (n=69)
Observation (n=72)
At end of KCd
Minimisation factor: local assessment of response ≥VGPR
40 (58.0%)
39 (54.2%)
ECOG: 0
43 (62.3%)
38 (52.8%)
MRD: Negative
8 (11.6%)
10 (13.9%)
At trial entry
ISS: I
39 (56.5%)
42 (58.3%)
Carfilzomib maintenance (n=69)
Observation (n=72)
At end of KCd
Minimisation factor: local assessment of response ≥VGPR
40 (58.0%)
39 (54.2%)
ECOG: 0
43 (62.3%)
38 (52.8%)
MRD: Negative
8 (11.6%)
10 (13.9%)
At trial entry
ISS: I
39 (56.5%)
42 (58.3%)
Carfilzomib maintenance (n=69)
Observation (n=72)
At end of KCd
Minimisation factor: local assessment of response ≥VGPR
40 (58.0%)
39 (54.2%)
ECOG: 0
43 (62.3%)
38 (52.8%)
MRD: Negative
8 (11.6%)
10 (13.9%)
At trial entry
ISS: I
39 (56.5%)
42 (58.3%)

6. MUK five: Inclusion/exclusion criteria
Key inclusion criteria
MM patients at first relapse, or refractory to 1 prior line of therapy
ECOG 0-2
Hb≥ 80g/L, neutrophils ≥1.0x109/L, platelets ≥75x109/L
GFR ≥20ml/min
LVEF ≥40%
Key exclusion criteria
Significant co-morbidity or cardiovascular disease (NYHA Class III/IV heart failure, myocardial infarction within 6 months))
Uncontrolled hypertension
Previous carfilzomib therapy
Previous refractory to bortezomib (<PR or progression within 6 months of last dose)
Significant neuropathy (G≥3 or G2 with pain) within 14 days

7. MUK five: Objectives Two Co-Primary Endpoints
≥VGPR rate at 24 weeks (non-inferiority activity of KCd)
PFS (superiority of maintenance treatment with Carfilzomib post-KCd vs no maintenance post-KCd)
Secondary Endpoints
Key: Rate of ≥G3 neuropathy or ≥G2 neuropathy with pain during the initial treatment period
Safety, toxicity, overall response, overall survival, time to next treatment
MRD at end of treatment and after 6 and 12 months of maintenance
Correlation of treatment outcomes with genetic subgroups

8. MUK five: Patient and disease characteristics
Stratification factors
KCd (n=201) n (%)
VCd (n=99) n (%)
Total (n=300) n (%)
Previous bortezomib
44 (21.9)
21 (21.2)
65 (21.7)
Previous ASCT
133 (66.2)
67 (67.7)
200 (66.7)
β2 microglobulin
<3.5 mg/L
120 (59.7)
57 (57.6)
177 (59.0)
3.5 to ≤5.5 mg/L
53 (26.4)
27 (27.3)
80 (26.7)
>5.5 mg/L
28 (13.9)
15 (15.2)
43 (14.3)
Prior bortezomib KCD=44 (21.9%), VCD=21 (21.2%), total=65 (21.7%)
Prior lenalidomide KCD=45 (22.5%), VCD=23 (23.2%), total=68 (22.7%)

9. MUK five: Patient and disease characteristics
KCd (n=200)*
VCd (n=99)
Total (n=299)
Age: Median (years) 67 69 68
≥75 years
37 (18.4%)
21 (21.2%)
58 (19.3%)
Male
115 (57.5%)
64 (64.6%)
179 (59.9%)
ECOG PS 0-1
187 (93.5%)
94 (94.9%)
281 (94.0%)
Median time since diagnosis (months)
32.5
36.1
33.7
Median time from last tmt (months)
20.1
20.5
20.2
ISS II / III
100 (50.0%)
45 (45.5%)
145 (48.5%)
Creatinine clearance <30mL/min
2 (1.0%)
2 (2.0%)
4 (1.3%)
Received previous autograft
133 (66.2%)
67 (67.7%)
200 (66.7%)
High risk disease**
44/87 (50.6%)
26/50 (52.0%)
70/137 (51.1%)
Prior bortezomib KCD=44 (21.9%), VCD=21 (21.2%), total=65 (21.7%)
Prior lenalidomide KCD=45 (22.5%), VCD=23 (23.2%), total=68 (22.7%)
*No baseline data received for one participant found to be ineligible after randomisation
**At least one of del(17p), gain(1q), t(4;14), t(14;16), t(14;20). Available in 46% of patients.

10. MUK five: Treatment received
Planned number of cycles
Note to Kwee: purple is max number of cycles they should have in that arm

11. MUK five: Treatment discontinuation reasons
Reasons for not receiving planned number of cycles
KCd (n=201)
(%)
VCd (n=99)
Total (n=300) (%)
Clinician decision
6 (3.0)
11 (11.1)
17 (5.7)
Unacceptable toxicity
11 (5.5)
18 (18.2)
29 (9.7)
Disease progression
12 (6.0)
5 (5.1)
Withdrew consent
5 (2.5)
9 (9.1)
14 (4.7)
Patient died
4 (2.0)
1 (1.0)
5 (1.7)
Other
3 (1.5)
4 (1.3)
Total
41 (20.4)
45 (45.4)
86 (28.7)
High number of withdrawals in VCd arm partly accounted for by patients withdrawing because they drew the control arm!!

12. MUK five: Response at 24 weeks
PRIMARY ENDPOINT MET
CR/VGPR Difference: 8.3, 90% CI: (-1.6, 18.2) Odds Ratio (OR): 1.48, 90% CI: (0.95, 2.31)
NON-INFERIOR
40.2
31.9
84.0
68.1
16.4
12.5
Overall response rate
Odds Ratio: 2.72, 90% CI: (1.62, 4.55)
SUPERIOR (p=0.0014)
Primary endpoint ≥VGPR: KCD 40.2%, VCD 31.9%
Overall response (≥PR): KCD 84.0%, VCD 68.1%
MRD negative rate: KCD 16.4%, VCD 12.5%
Prior bortezomib received:
≥VGPR KCD 15 (35.7%), VCD 6 (30.0%), total 21 (33.9%)
No prior bortezomib received:
≥VGPR KCD 63 (41.4%), VCD 23 (32.4%), total 86 (38.6%)
MRD Negativity
Odds Ratio: 1.40, 90% CI: (0.61, 3.24)
(Total N=134 KCd; 48 VCd)

13. ENDEAVOR STUDY: Responses by Prior Line of Therapy Intent-to-Treat Population (N=929)
1 Prior Line
≥ 2 Prior Lines Cd
(n=232) Vd
(n=233)
Best overall response, n (%)
≥ CR
27 (11.6)
18 (7.8)
31 (13.4)
11 (4.7)
≥ VGPR
144 (62.1)
71 (30.6)
108 (46.6)
62 (26.6)
Overall response rate, % (95% CI)**
81.9
(76.3–86.6)
65.5
(59.0–71.6)
72.0
(65.7–77.7)
59.7
(53.1–66.0)
P value (one sided)*
<.0001
0.0023
Median duration of response, months (95% CI)
21.3
(17.6–NE)
14.1
(8.6–NE) NE
(13.9–NE)
10.3
(9.0–12.2)
*Descriptive; unadjusted for multiplicity.
**overall response rate is a secondary endpoint of ENDEAVOR
CI, confidence interval; CR, complete response; Cd, carfilzomib and dexamethasone; NE, not estimable; Vd, bortezomib and dexamethasone; VGPR, very good partial response.

14. MUK five: Neuropathy Key secondary endpoint:
56.3%
21.4%
Key secondary endpoint:
19.8%
Treatment emergent neuropathy all grades: 21.4% KCD, 56.3% VCD
≥G3 neuropathy or ≥G2 neuropathy with pain: 1.5% KCD, 19.8% VCD,
1.5%
Difference: -18.3% 95% CI: (-26.4, -10.1) p<0.0001

15. MUK five: Safety and toxicity: SAEs
KCd (n=196)
VCd (n=96)
Number of SAEs
142 74
Number of patients with an SAE
88 (44.9%)
45 (46.9%)
Proportion of SAEs categorized as:
Neurological
0.7%
8.1%
Cardiac
4.2%
1.4%
Renal and urinary
3.5%
5.4%
Gastrointestinal
7.7%
Infections
51.4%
47.3%
Need to make clear that individual SAE’s are % of total
Neurological SAEs (MedDRA=nervous system disorders):
KCD:
Migraine (1 SAE)
VCD:
Fall. Experienced shooting pain down R leg for 2/7. Had 4 x falls at home. On admission had significant postural drop in BP (1 SAE)
Paresthesia (1 SAE)
Sensory peripheral neuropathy (4 SAEs in 3 patients)

16. MUK five: Safety and toxicity: ARs of interest
KCd (n=196)
VCd (n=96)
Proportion of patients with each AR type:
Cardiac (all grades)
17 (8.7%)
8 (8.3%)
Cardiac (≥ Grade 3)
6 (3.7%)*
0 (0%)
Grade ≥3 neutropenia
11.3%
21.9%
Grade ≥3 thrombocytopenia
11.8%
36.5%
Grade ≥3 anaemia
16.8%
10.4%
Grade ≥3 infections
12.8%
16.7%
Grade ≥2 hypertension
4.1%
2.1%
*Dilated cardiomyopathy, acute coronary syndrome, arrhythmia, myocardial infarction, hypertension, other

17. R2: Maintenance treatment: patient characteristics (n=141)
MUK five
R2: Maintenance treatment: patient characteristics (n=141)
Carfilzomib maintenance (n=69)
Observation (n=72)
At end of KCd
Minimisation factor: local assessment of response ≥VGPR
40 (58.0%)
39 (54.2%)
ECOG: 0
43 (62.3%)
38 (52.8%)
MRD: Negative
8 (11.6%)
10 (13.9%)
At trial entry
ISS: I
39 (56.5%)
42 (58.3%)

18. Maintenance carfilzomib: toxicity
MUK five
Maintenance carfilzomib: toxicity

19. Maintenance carfilzomib
MUK five
Maintenance carfilzomib
Median 8 cycles carfilzomib received: 44.3% patients completed 6 cycles, 18% completed 18 cycles
2 patients received no treatment
8 patients remain on treatment at date of download
55/67 patients (82.1%) had a dose modification
Only 11.3% of cycles were delayed
Reason for stopping treatment
Carfilzomib maintenance (n=61)
Maximum number of cycles
11 (18.0%)
Unacceptable toxicity
3 (4.9%)
Disease progression
40 (65.6%)
Withdrew consent
4 (6.6%)
Clinician decision
1 (1.6%)
Other
2 (3.3%)

20. Effect of carfilzomib maintenance on PFS
MUK five
Effect of carfilzomib maintenance on PFS
PRIMARY ENDPOINT: Progression-free survival
Median survival:
Carfilzomib maintenance: 11.9m, 80% CI (8.0, 13.1)
Observation: 5.6m, 80% CI (4.8, 6.4)
HR=0.59 (80% CI ) SUPERIOR (p=0.0086)
Median PFS from initial randomisation for maintenance group: 18.1 months, 80% CI: (14.4, 18.9)

21. MUK five: Summary and Conclusions
KCd results in higher ORR compared to VCd over 6 months fixed duration
81.6% of patients completed KCd treatment compared to 53.5% for VCd
Adverse events were consistent with known toxicity profile of each drug
More neurotoxicity with bortezomib but more cardiac AE’s and hypertension with carfilzomib
Maintenance K was well tolerated and associated with longer PFS.
Use of KCd triplet for fixed duration followed by maintenance K resulted in combined PFS of 18.1m

22. Acknowledgements MUK five participants Recruiting centres
Myeloma UK Early Phase Clinical Trial Network
Holger Auner
Catherine Williams
Jamie Cavenagh
Neil Rabin
Karthik Ramasamy
Mamta Garg
Stephen Hawkins
Ceri Bygrave
Gareth Morgan
Faith Davies
Leeds CTRU
Samantha Hinsley
Debbie Sherratt
Sarah Brown
Louise Flanagan
Paul McGarry
Saqib Saghir
Sue Bourne
Emma Ingleson
Katie Robinson
Alan Wan
Wendy Burton
Diane Hartley
Matthew Newby
Lucy Bailey
Suja George
Rachel Naylor
Walter Gregory
Alex Szubert
Jenny Fell
Trial Steering Committee
Chris Twelves
Simon Rule
Tomasz Burzykowski
Michael Brown
Data Monitoring and Ethics Committee
Alan Anthoney
Graham Jackson
James Wason
Royal Marsden Hospital
Royal Devon & Exeter
Addenbrookes Hospital
Christie
Leicester Royal Infirmary
New Cross Hospital
Nottingham City Hospital
St James
UCLH
Manchester Royal Infirmary
Countess of Chester Hospital
Grantham Hospital
Lincoln County Hospital
Pilgrim Hospital, Boston
Royal Hallamshire Hospital
Birmingham Heartlands
Royal Bournemouth General Hospital
Southampton General Hospital
Royal Cornwall Hospital
Torbay District General Hospital
St Bartholomew's Hospital
Royal Sussex County Hospital
Oxford
Kings College Hospital
Queens Hospital Burton
George Eliot Hospital
Bristol Haematology and Oncology Centre
Ninewells Hospital
University Hospital of Wales, Cardiff
Beatson West of Scotland Cancer Centre
Princess Royal University Hospital
Ayr Hospital
University Hospital of North Tees
University Hospital Coventry
Imperial College London
Institute of Cancer Research
Martin F Kaiser
Leeds HMDS
Ruth M de Tute
Roger G Owen