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

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

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.

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.

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%)

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

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

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%)

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.

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

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!!

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)

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.

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

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)

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

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%)

Maintenance carfilzomib: toxicity MUK five Maintenance carfilzomib: toxicity

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%)

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 0.46-0.77) SUPERIOR (p=0.0086) Median PFS from initial randomisation for maintenance group: 18.1 months, 80% CI: (14.4, 18.9)

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

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