Michele Cavo Seràgnoli Institute of Hematology, Bologna ... Settembre/Novita... · Michele Cavo...

Michele Cavo

Seràgnoli Institute of Hematology, Bologna University School of Medicine, Italy

Zamagni E.1, Di Raimondo F.2, Patriarca F.2, Tosi P.2, Pezzi A.1, Cellini C.2,Tacchetti P.1, Ronconi S.2, Volpe S.2, Pantani L.1, Catalano L.2, Fiacchini M.1, Angelucci E.2, Masini L.2, Gozzetti A.2, Galieni P.2, Zannetti B.1, Narni F.2, Mancuso K.1, Lazzaro A.2, Brioli A.1, Terragna C.1, Califano C.2, Ledda A.2, Testoni N.1, Cavo M1

1“Seragnoli” Institute of Hematology, Bologna University School of Medicine 2 Bologna 1996 and Bologna 2002 Studies Italian Myeloma Network

Ten year-long term survival after up-front autologous stem cell transplantation in multiple myeloma:

results from two prospective clinical trials

BO 1996 TRIAL Study Design

BO 2002 TRIAL Study Design

Cavo M. et al, Blood 2005 Cavo M. et al, JCO 2009 Cavo M. et al, JCO 2007

BO 1996 Bo 2002 N° patients 321 357 Mean age (SD) 53,1 (6,3) 55,9 (6,9) Mean 2-m (SD) 4,2 (6,4) 4,6 (5,5) % pts 2-m ≥ 3,5 % pts 2-m > 5,5

38% 15%

42% 20%

% pts DS stage > 1 80% 86%

Median LDH (range) 320 (95-1200) 296 (103-2325) % pts with t(4;14)± del (17p)*

N.D. 20%

Median follow-up Alive pts

61 months 120 months

72 months 88 months

BASELINE PATIENT CHARACTERISTICS

cut-off data analysis: October 2012

MULTIVARIATE LOGISTIC REGRESSION ANALYSIS FOR LONG-TERM SURVIVAL

VARIABLES ODDS RATIO (95% CI)

P VALUE

TTP > 42 months 0.159 (0.106-0.239) 0.000 CR (best response) 0.608 (0.415-0.892) 0.011 DOUBLE ASCT 0.584 (0.368-0.927) 0.023 PLTs 150.000/mm3 0.490 (0.249-0.964) 0.039 Hb > 10,0 g/dL 0.614 (0.409-0.921) 0.018

Bortezomib-based versus non-bortezomib-based induction

prior to ASCT in multiple myeloma: meta-analysis of phase 3 trials

Pieter Sonneveld,1 Hartmut Goldschmidt,2 Laura Rosiñol,3 Joan Bladé,3 Juan José Lahuerta,4 Michele Cavo,5 Paola Tacchetti,5 Elena Zamagni,5

Michel Attal,6 Henk M. Lokhorst,7 Avinash Desai,8 Andrew Cakana,9 Kevin Liu,10 Helgi van de Velde,11 Dixie-Lee Esseltine,12

Philippe Moreau13 1Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands; 2University Hospital of Heidelberg, Heidelberg, Germany; 3Hematology Department, Hospital Clinic de Barcelona, IDIBAPS,

Barcelona, Spain; 4Servicio de Hematología, Hospital Universitario 12 de Octubre, Madrid, Spain; 5Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Bologna, Italy; 6Department of Hematology, Hopital Purpan, Toulouse, France; 7Utrecht Medical Center, Utrecht, the Netherlands;

8Janssen Global Services, Raritan, NJ, USA; 9Janssen Research & Development, High Wycombe, UK; 10Janssen Research & Development, Raritan, NJ, USA; 11Janssen Research & Development, Beerse, Belgium; 12Millennium: The Takeda Oncology Company, Cambridge, MA, USA; 13University Hospital,

Nantes, France

Patient disposition for the integrated analysis Randomized, N=1572

Bortezomib-based induction, N=787 Non-bortezomib-based induction, N=785

Received induction, N=781 Received induction, N=778

Entered transplant stage, N=667 Received 1 ASCT, n=483 (72%) Received 2 ASCTs, n=184 (28%)

Entered transplant stage, N=624 Received 1 ASCT, n=438 (70%) Received 2 ASCTs, n=186 (30%)

Eligible for maintenance, N=459 IFM 2005-01: no maintenance stage

HOVON-65/GMMG-HD4: single-agent bortezomib PETHEMA GEM05MENOS65: 2nd randomization to bortezomib-thalidomide, thalidomide, or IFN-α-2b

Continued to maintenance stage, N=323

Eligible for maintenance, N=426 IFM 2005-01: no maintenance stage

HOVON-65/GMMG-HD4: single-agent thalidomide PETHEMA GEM05MENOS65: 2nd randomization to bortezomib-thalidomide, thalidomide, or IFN-α-2b

Continued to maintenance stage, N=340

Discontinued, n=114 AE, n=49 PD, n=19

Death, n=15 Other, n=31

Discontinued, n=154 AE, n=40 PD, n=40

Death, n=25 Other, n=49

OR for post-transplant CR+nCR rate similar across studies

u  With inclusion of study-level data from GIMEMA MM-BO2005, the pooled OR remained similar (1.96) to that for the integrated analysis

Non-bortezomib-based Bortezomib-based Study Odds ratio (95% CI) N CR/nCR (%) N CR/nCR (%) P-value HOVON-65/GMMG-HD4 2.02 (1.46, 2.79) 408 82 (20) 409 136 (33) <0.0001 IFM 2005-01 1.99 (1.34, 2.96) 238 56 (24) 236 90 (38) 0.0006 PETHEMA GEM05MENOS65 2.31 (1.40, 3.83) 126 44 (35) 130 72 (55) 0.0010 Pooled (fixed effect) 2.05 (1.64, 2.56) 772 182 (24) 775 298 (38) <0.0001 Heterogeneity I2 = 0%

Q = 0.25 with df = 2 GIMEMA MM-BO2005 1.75 (1.22, 2.52) 238 98 (41) 236 130 (55) 0.0025 Pooled (fixed effect) 1.96 (1.62, 2.37) 1010 280 (28) 10 1 1 428 (42) <0.0001 Heterogeneity I2 = 0%

Q = 0.82 with df = 3

Favor non-bortezomib-based treatment Favor bortezomib-based treatment Odds ratio and 95% CI (log scale)

0.2 0.5 1 2 5

Post-transplant CR+nCR rate consistently and significantly improved across patient subgroups in

integrated analysis Non-bortezomib-based Bortezomib-based

Group Odds ratio (95% CI) N Response (%) N Response (%) All patients 2.05 (1.64, 2.56) 772 182 (24) 775 298 (38) Age <55 2.23 (1.55, 3.22) 302 65 (22) 296 11 1 (38) ≥55 1.94 (1.47, 2.58) 470 1 17 (25) 479 187 (39) Sex Male 1.97 (1.46, 2.64) 438 105 (24) 462 175 (38) Female 2.17 (1.54, 3.05) 334 77 (23) 313 123 (39) ISS staging I 1.58 (1.12, 2.23) 289 92 (32) 288 121 (42) II 2.85 (1.90, 4.28) 252 47 (19) 283 109 (39) III 2.28 (1.40, 3.69) 191 36 (19) 168 58 (35) Cytogenetics classification High risk 2.44 (1.72, 3.46) 319 70 (22) 308 126 (41) Standard risk 1.67 (1.20, 2.31) 378 89 (24) 372 124 (33) Creatinine clearance (mL/min) <60 2.01 (1.22, 3.31) 160 37 (23) 153 58 (38) ≥60 2.08 (1.62, 2.67) 602 142 (24) 605 235 (39)

Favor non-bortezomib-based treatment Favor bortezomib-based treatment Odds ratio and 95% CI (log scale)

0.2 0.5 1 2 3 10 20

HR for PFS consistent across studies in the integrated analysis and with GIMEMA MM-BO2005

Non-bortezomib-based Bortezomib-based Median

(months) Study Hazard ratio (95% CI) Event/N Event/N P-value HOVON-65/GMMG-HD4 0.76 (0.63, 0.91) 255/416 28.1 223/417 35.0 0.0025 IFM 2005-01 0.78 (0.60, 1.01) 128/242 29.7 1 10/240 36.1 0.0577 PETHEMA GEM05MENOS65 0.65 (0.45, 0.92) 70/127 27.9 55/130 55.5 0.0152 Pooled (fixed effect) 0.75 (0.65, 0.85) 453/785 28.6 388/787 35.9 <0.0001 Heterogeneity I2 = 0%

Q = 0.76 with df = 2 GIMEMA MM-BO2005 0.63 (0.45, 0.88) Heterogeneity I2 = 0%

Q = 1.75 with df = 3

Favor bortezomib-based treatment Favor non-bortezomib-based treatment Hazard ratio and 95% CI (log scale)

0.2 0.5 1 2 3

Median (months)

OS significantly improved in bortezomib-based group in integrated analysis

u  Median follow-up ~37 months u  Median OS not reached in either group

–  3-year OS rates: 79.7% vs 74.7% –  HR 0.81, p=0.0402

u  HRs for OS consistent across studies in the integrated analysis

Non-bortezomib-based Bortezomib-based Median Median

Study Hazard ratio (95% CI) Event/N (months) Event/N (months) P-value HOVON-65/GMMG-HD4 0.82 (0.63, 1.05) 130/416 NE 109/417 NE 0.1195 IFM 2005-01 0.88 (0.58, 1.35) 45/242 NE 40/240 NE 0.5606 PETHEMA GEM05MENOS65 0.80 (0.48, 1.34) 32/127 NE 26/130 55.5 0.3932 Pooled (fixed effect) 0.81 (0.66, 0.99) 207/785 NE 175/787 NE 0.0402 Heterogeneity I2 = 0%

Q = 0.15 with df = 2

Favor bortezomib-based treatment Favor non-bortezomib-based treatment Hazard ratio and 95% CI (log scale)

0.2 0.5 1 2 3

Peripheral neuropathy (PN) in integrated analysis

u  Rates of PN (including terms ‘peripheral neuropathy’, ‘peripheral sensory neuropathy’, and ‘peripheral motor neuropathy’) assessed in integrated analysis –  Bortezomib administered IV and twice-weekly in all studies

u  During bortezomib-based vs non-bortezomib-based induction: –  Overall PN rate: 34% vs 17% –  Grade ≥3 rate: 6% vs 1% –  PN did not appear to affect receipt of subsequent ASCT

u  Across all treatment phases: –  PN rate increased to 45% vs 31%

Michele Cavo1,5, Pieter Sonneveld2, Philippe Moreau3, Joan Bladè4, Hartmut Goldschmidt2, Jesús F San Miguel4, Michel Attal3, Hervé Avet-Loiseau3, Wolgang Igor Blau2, Thierry Facon3, Norma Gutierrez4, Jean-Luc Harousseau3, Bronno van der Holt2, Juan Jose Lahuerta4, Henk Lokhorst2, Gerald Marit2, Maria Luisa Martin4, Giulia Marzocchi1,5, Antonio Palumbo1, Francesca Patriarca1, Maria Teresa Petrucci1, Laura Rosiñol4, Hans Salwender2 and Carolina Terragna1,5

Impact of Bortezomib Incorporated Into Autotransplantation On Outcomes of Myeloma Patients with High-Risk Cytogenetics:

An Integrated Analysis of 1610 Patients Enrolled in Four European Phase 3 Studies

1GIMEMA MM-BO2005 study, 2HOVON-65/GMMG-HD4 study, 3IFM 2005-01 study, 4PETHEMA GEM05MENOS65 study 5Seragnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy

VD ± DCEP ASCT1 ± ASCT2 ± Len cons. Len maint.

VAD ± DCEP ASCT1 ± ASCT2 ± Len cons. Len maint.

PAD ASCT1 ± ASCT2 Bort maint.

VAD ASCT1 ± ASCT2 Thal maint.

Study Designs

IFM 2005-01 HOVON-65/GMMG-HD4

VTD ASCT1 ± ASCT2 ± VTD cons. Dex maint.

TD ASCT1 ± ASCT2

± TD cons. Dex maint.

VTD ASCT1 VT

CHT/B ASCT1

Thal

TD ASCT1 IFN

GIMEMA MM-BO2005 PETHEMA GEM05MENOS65

2169 enrolled patients

Harousseau JL et al. J Clin Oncol 28:4621-4629, 2010 Cavo M et al. Lancet 376:2075-2085, 2010

Sonneveld P. J Clin Oncol 30:2946-2955, 2012 Rosinol L et al. Blood 120:1589-1596, 2012

PFS and OS according to B-based and non-B-based ASCT(s) in the overall population

Median follow-up – all patients: 37.42 (28.70-49.17) months Median follow-up – living patients: 40.40 (32.90-51.63) months

0 25

50

75

100

1142 1003 786 457 205 64 1015 817 620 338 161 52 Number at risk 0 12 24 36 48 60

Months

Non-B-based ASCT(s) P=0.0000

41.5 months 33 months

B-based ASCT(s)

Non-B-based ASCT(s) B-based ASCT(s)

PFS

HR 0.76 (0.67-0.85) p=0.000

1142 1060 956 643 326 100 1015 911 832 530 267 83 0 12 24 36 48 60

P=0.0684

69 %

65 % Non-B-based ASCT(s)

B-based ASCT(s)

Months

0 25

50

75

100 OS

HR 0.85 (0.71-1.005) p=0.058

Number at risk Non-B-based ASCT(s) B-based ASCT(s)

Del(17p) and/or t(4;14) positive Variables PFS OS

HR 95% CI p HR 95% CI p

Plts<150 (x 109/L) 1.64 1.17-2.32 0.005 - - -

β2m>3.5 (mg/L) 1.51 1.12-2.01 0.006 1.84 1.26-2.68 0.002

B-based ASCT(s) 0.61 0.46-0.80 0.000 0.69 0.47-0.99 0.047

Double ASCT 0.31 0.21-0.44 0.000 0.23 0.14-0.36 0.000

Multivariate analysis of prognostic factors for PFS and OS within the high-risk subgroup with del(17p) and/or t(4;14) positivity

Stratified by study

Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed

Multiple Myeloma (MM) Patients: initial results of a multicenter, open label phase II study

Sara Bringhen1,*, Federica Cavallo1, Maria Teresa Petrucci2, Francesca Gay1, Vincenzo Federico2, Concetta Conticello2, Lucia Pantani2, Vittorio Montefusco2, Giulia Benevolo2,

Valeria Magarotto1, Massimo Offidani2, Oreste Villani2, Agostina Siniscalchi2, Davide Rossi2, Giovannino Ciccone3, Peter Sonneveld4, Mario Boccadoro1, Antonio Palumbo1

1Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy;2Italian Multiple Myeloma Network, GIMEMA, Italy;

3Tumor Epidemiology Unit, Citta della Salute e della Scienza e CPO, Torino, Italy;4Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.

GIMEMA: Italian Multiple Myeloma Network

Primary objectives and Key Eligibility Criteria

Inclusion criteria• Symptomatic newly diagnosed MM• ≥ 65 years or ineligible for autologous stem cell transplantation• Measurable disease • Karnofsky performance status ≥60%

Exclusion criteria• Platelets < 50 x 109/L , ANC < 1 x 109/L • Creatinine clearance < 15 mL/minute • Peripheral neuropathy > CTCAE grade 2• Serious co-morbidities

Assessment of response was performed according to the International Myeloma Working Group criteria (Durie BGM et al, Leukemia2006: 20: 1467–1473) with the addition of nCR. Assessment of adverse events was performed according to the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE version 4.0, http://ctep.cancer.gov/forms/CTCAEv4.pdf)

• Phase II• Multicenter (10 centres)

Study design

CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5

Dexamethasone40 mg orally

Cyphosphamide300 mg/m2 orally

CarfilzomibDose (mg/m2)

Dosing

Cycle day 1 2 15 16 1 2 8 9 1516 22

20 36 36 36 36 361 2 8 9 1516 22 1 2 8 9 1516 22

CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE

36 36 361 2 15 16 1 2 15 16

36 36 36 3636 36

Response Assessments





Dosing

Cycle day 1 2 15 16 1 2 8 9 1516 22

20 36 36 36 36 361 2 8 9 1516 22 1 2 8 9 1516 22

CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE

36 36 361 2 15 16 1 2 15 16

36 36 36 3636 36






Dosing

Cycle day 1 2 15 16 1 2 8 9 1516 22

20 36 36 36 36 361 2 8 9 1516 22 1 2 8 9 1516 22

CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCECYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE

36 36 361 2 15 16 1 2 15 16

36 36 36 3636 36


CCd Induction C MaintenanceCycles 1-9 Until progression

CCd Induction C MaintenanceCycles 1-9 Until progression

Patient CharacteristicsNo. of patients 58Median age (range) 71 (55-86)

≥ 75 years 16 (28%)ISS stage

I 16 (27%)II 19 (33%)III 23 (40%)

Chromosome abnormalitiest(4;14) 9/51 (18%)Del17p 8/51 (16%)t(14;16) 1/51 (2%)Unfavorable profile* 18/51 (35%)

Frailty°Fit 21 (36%)Unfit 19 (33%)Frail 18 (31%)

No. of patients 58Median age (range) 71 (55-86)

≥ 75 years 16 (28%)ISS stage

I 16 (27%)II 19 (33%)III 23 (40%)

Chromosome abnormalitiest(4;14) 9/51 (18%)Del17p 8/51 (16%)t(14;16) 1/51 (2%)Unfavorable profile* 18/51 (35%)

Frailty°Fit 21 (36%)Unfit 19 (33%)Frail 18 (31%)

*Defined as t(4;14) or Del17 or t(14;16) °Unfit defined as: ADL 5 or IADL 6-7 or Charlson 1 or fit patient >80 yr

Frail defined as: ADL <4 or IADL <5 or Charlson >2 or unfit patient >80 yr

ConclusionsCCd MPT VMP

Response rates≥ VGPR 76% 36% 41%nCR/CR/sCR 64% 27% 30%*sCR 24% - -Grade 3-4 AEsANC 18% 16% 40%Platelets 4% 3% 37%PNP 0% 6% 14%VTE 0% 9% 1%Discontinuation 11% 35% 33%

CCd MPT VMPResponse rates≥ VGPR 76% 36% 41%nCR/CR/sCR 64% 27% 30%*sCR 24% - -Grade 3-4 AEsANC 18% 16% 40%Platelets 4% 3% 37%PNP 0% 6% 14%VTE 0% 9% 1%Discontinuation 11% 35% 33%

* CR only, nCR not reportedPalumbo at al, Lancet, 2006 ;367:825-31.Fayers et al, Blood 2011; 118:1239-47; San Miguel et al, N Eng J Med 2008;359:906-17

Subcutaneous Velcade plus prednisone (VP) or

plus Cyclophosfamide (VCP) or plus Melphalan

(VMP) in Frail, Elderly, Newly Diagnosed Myeloma Patients: a Phase II community-based Study.

Alessandra Larocca 1, Stefania Oliva 1, Massimo Offidani 2, Anna Levi 2, Caterina Musolino 2, Antonietta Pia Falcone 2, Concetta Conticello 2, Tommaso Caravita 2, Davide Rossi 2, Oreste Villani 2, Chiara Nozzoli 2, Giulia Benevolo 2, Tommasina Guglielmelli 2, Anna Marina Liberati

2, Daniele Derudas 2, Fortunato Morabito 2, Angelo Michele Carella 2, Patrizia Caraffa 2, Monica Astolfi 1, Carmen Palladino 1, Vittorio Montefusco 2, Federica Cavallo 1, Maria Teresa

Petrucci 2, Mario Boccadoro 1, Pieter Sonneveld 3, Antonio Palumbo 1

1Myeloma Unit, Division of Hematology, University of Turin, Turin, Italy, 2Italian Multiple Myeloma Network, GIMEMA, Italy,

3Erasmus Universal Medical Center, Rotterdam, Netherlands

GIMEMA: Italian Multiple Myeloma Network

Study design

Phase II, 3-cohort, multicenter study designed to evaluate three

Bortezomib-based combinations as up-front treatment in newly

diagnosed elderly Multiple Myeloma patients, usually excluded

from clinical trials

• Velcade-Prednisone (VP)

• Velcade-Cyclophosphamide-Prednisone (VCP)

• Velcade-Melphalan-Prednisone (VMP)

Treatment schema

Induction: nine 28-day cyclesMaintenance: until progression

V: 1.3 mg/m2, sc days 1 and 15every 28 days

VPV: 1.3 mg/m2, sc, days 1,8,15,22P: 50 mg/d, orally, every other day

VCPV: 1.3 mg/m2, sc, days 1,8,15,22C: 50 mg/d, orally, every other day P: 50 mg/d, orally , every other day

VMPV: 1.3 mg/m2, sc, days 1,8,15, 22M: 2 mg/d, orally, every other day P: 50 mg/d, orally, every other day

VP, bortezomib-prednisone; VCP, bortezomib-cyclophosphamide-prednisone; VMP, bortezomib-melphalan-prednisone; V, bortezomib; P, prednisone; C, cyclophosphmide; M, melphalan.

Patient CharacteristicsVP VCP VMP

No. of patients 51 51 50Median age (range) 78 (70-88) 77 (59-88) 78 (62-88)

≥ 80 years 19 (37%) 12 (24%) 15 (30%)ISS stage

I 12 (23.5%) 15 (30%) 14 (28%)II 12 (23.5%) 12 (23%) 20 (40%)III 27 (53%) 24 (47%) 16 (32%)

Chromosome abnormalitiest(4;14) 4/42 (10%) 0 5/42 (12%)Del17p 6/42 (14%) 7/44 (16%) 6/42 (14%)t(14;16) 1/42 (2%) 4/44 (9%) 0Unfavorable profile* 9/42 (21%) 9/44 (20%) 10/42 (24%)

Frailty°Fit 12% 16% 22%Unfit 20% 31% 20%Frail 69% 53% 58%

VP VCP VMPNo. of patients 51 51 50Median age (range) 78 (70-88) 77 (59-88) 78 (62-88)

≥ 80 years 19 (37%) 12 (24%) 15 (30%)ISS stage

I 12 (23.5%) 15 (30%) 14 (28%)II 12 (23.5%) 12 (23%) 20 (40%)III 27 (53%) 24 (47%) 16 (32%)

Chromosome abnormalitiest(4;14) 4/42 (10%) 0 5/42 (12%)Del17p 6/42 (14%) 7/44 (16%) 6/42 (14%)t(14;16) 1/42 (2%) 4/44 (9%) 0Unfavorable profile* 9/42 (21%) 9/44 (20%) 10/42 (24%)

Frailty°Fit 12% 16% 22%Unfit 20% 31% 20%Frail 69% 53% 58%

*Defined as t(4;14) or Del17 or t(14;16) °Fit defined as: ADL 6 or IADL 8 or Charlson 0

Unfit defined as: ADL 5 or IADL 6-7 or Charlson 1 or fit patient >80 yrFrail defined as: ADL <4 or IADL <5 or Charlson >2 or unfit patient >80 yr

Best Response during induction%

of p

atie

nts

67%

ORR : VMP versus VP, p=0.13 ORR: VCP versus VP, p=0.67ORR VMP versus VCP p=0.06

Median number of cycles 9

Percent of patients

Grade 3-5 non-hematologic Adverse Events

Second primary malignancy 2% VMP. Venous thromboembolism 2% VP , 2% VCP. Peripheral Neuropathy 6% VP, 6% CVP, 6% VMP.

Efficacy, Safety, and QoL in MM-003, a Phase 3, Multicenter, Randomized, Open-Label Study of

Pomalidomide (POM) + Low-Dose Dexamethasone (LoDEX) vs. High-Dose Dexamethasone (HiDEX) in RRMM

Jesus San Miguel,1 Katja C. Weisel,2 Philippe Moreau,3 Martha Q. Lacy,4 Kevin W. Song,5 Michel Delforge,6 Lionel Karlin,7 Hartmut Goldschmidt,8

Anne Banos,9 Albert Oriol,10 Adrian Alegre,11 Christine Chen,12 Michele Cavo,13 Laurent Garderet,14 Valentina Ivanova,15 Joaquin Martinez,16 Stacie Hudgens,17

XinYu,18 Lars Sternas,18 Christian Jacques,18 Mohamed H. Zaki,18 Meletios A. Dimopoulos19

1Hematology, Hospital Universitario de Salamanca, Salamanca, Spain; 2Hematology & Oncology, Department of Medicine, University Hospital Tübingen, Tübingen, Germany; 3Hematology, University Hospital Hôtel-Dieu, Nantes, France; 4Division of Hematology, Mayo Clinic, Rochester, MN, USA; 5Vancouver General Hospital, Vancouver, BC, Canada; 6Department of Hematology, University Hospital Leuven, Leuven, Belgium; 7Centre Hospitalier Lyon Sud/Hospices Civils de Lyon, Pierre-

Bénite, France; 8University Hospital Heidelberg and German Cancer Research Center, Heidelberg, Germany; 9Hematology, Centre Hospitalier de la Côte Basque, Bayonne, France; 10Institut Catala d’Oncologia, HGTiP, Barcelona, Spain; 11Hospital

Universitario La Princesa, Madrid, Spain; 12Princess Margaret Hospital, Toronto, Ontario, Canada; 13Bologna University School of Medicine, Institute of Hematology and Medical Oncology, Bologna, Italy; 14Hôpital Saint Antoine, Paris, France;

15GUZ Moscow City Clinical Hospital S.P.Botkin, Moscow, Russia; 16Hospital 12 de Octubre, Madrid, Spain; 17Adelphi Values, Boston, MA; 18Celgene Corporation, Summit, NJ, USA; 19Alexandra Hospital, Athens, Greece

Refractory to BORT & Relapsed/Refractory or Ineligible to Receive an

IMiD2

0

20

40

60

80

100

Patie

nts

(%)

286 Patients

Time

1971–76

1994–00

1989–94

1977–82

1983–88

0 20 40 60 80 100 120 140

Surv

ival

0.0

0.2

0.4

0.6

0.8

1.0

2001–06

•  Despite the benefit observed with novel agents in the last few years, new drugs are still needed for relapsed/refractory patients

Changes in OS From 1970-20061

Months From Time Zero 12 24 36 48 0 60

Outcome of Myeloma Patients

EFS: event-free survival. 1. Kumar SK, et al. Blood. 2008;111:2516-2520. 2. Kumar SK, et al. Leukemia. 2012;26:149-157.

Events/N Median (range) in mos

OS 170/286 9 (7-11) EFS 217/286 5 (4-6)

Design: POM + LoDEX vs. HiDEX

(n = 302) POM: 4 mg/day D1-21 + LoDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22

RA

ND

OM

IZA

TIO

N 2

:1

Follow-Up for OS and SPM Until 5 Years Post Enrollment

(n = 153) HiDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs)

D1-4, 9-12, 17-20

28-day cycles

PD*

PD* Companion trial MM-003C

POM 21/28 days

Stratification • Age (≤ 75 vs. > 75 yrs) • Number of prior Tx ( 2 vs. > 2) • Disease population (primary refractory vs. relapsed/refractory vs. intolerance/failure)

Thromboprophylaxis was indicated for those receiving POM or with DVT history

* Progression of disease was independently adjudicated in real time. San Miguel JF, et al. EHA 2013 [abstract S1151].

Key Eligibility Criteria

•  All pts had to be refractory to last therapy •  All pts must have received at least 2 prior Tx

–  ≥ 2 consecutive cycles of LEN and BORT (alone or in combination) –  Adequate prior alkylator Tx (SCT or ≥ 6 cycles or PD following ≥ 2 cycles)

•  All pts must have failed BORT and LEN –  Pt progressed on or within 60 days –  Pt with PR must have progressed within 6 mos –  Intolerant to BORT after completing ≥ 2 cycles and achieving ≤ MR

•  Refractory or relapsed and refractory disease –  Primary refractory: Never achieved better than PD to any Tx –  Relapsed and refractory: Relapsed after having achieved ≥ SD for ≥ 2 cycles of

Tx to at least 1 prior regimen and then developed PD ≤ 60 days of completing their last Tx

MR, minimal response; PD, progressive disease; SD, stable disease; SCT, stem cell transplant. San Miguel JF, et al. EHA 2013 [abstract S1151].

Endpoints

San Miguel JF, et al. EHA 2013 [abstract S1151].

• Primary –  Progression-free survival (PFS)

• Key secondary –  Overall survival (OS) –  Overall response rate (ORR ≥ PR) by IMWG and EBMT –  Duration of response (DOR) –  Safety

Status Update

•  Accrual closed on Aug 31, 2012 (N = 455 pts)

•  Final PFS Analysis (data cut-off Sept 7 2012) – Median follow up: 4 mos

–  > 242 PFS events, final PFS analysis

–  > 106 OS events, interim OS analysis

–  IDMC indicated that the primary endpoint of PFS was met; O’Brien-Fleming superiority boundary for OS was crossed

•  Updated OS Analysis (data cut-off March 1 2013) – Median follow-up: 10 mos

–  Sufficient OS events occurred triggering the updated OS analysis

IDMC, Independent Data Monitoring Committee. San Miguel JF, et al. EHA 2013 [abstract S1151].

Patient Disposition Updated March 1 2013


POM + LoDEX (N = 302)

HiDEX (N = 153)

PD

Discontinued: n = 142 (93%) PD: 92 (60%) AE: 16 (10%) Death: 17 (11%) Withdrawal: 6 (4%) Lost to follow-up: 1 (1%) Other: 10 (7%)

Ongoing Tx (n = 11)

7%

Discontinued: n = 242 (80%) PD: 163 (54%) AE: 26 (9%) Death: 23 (8%) Withdrawal: 8 (3%) Lost to follow-up: 2 (1%) Other: 20 (7%)

Ongoing Tx

(n = 60) 20%

Received POM after HiDEX

(n = 76) 50%

RANDOMIZATION 2:1

(N = 455)

Prior Therapies Updated March 1 2013

POM + LoDEX (N = 302)

HiDEX (N = 153)

Median number, n (range) 5 (2-14) 5 (2-17) Prior DEX (%) 98 99 Prior THAL (%) 57 61 Prior SCT (%) 71 69

Prior LEN (%) 100 100 Prior BORT (%) 100 100 Prior alkylator (%) 100 100 LEN-refractory (%) 95 92 BORT-refractory (%) 79 79 LEN- and BORT-refractory (%) 75 74


At Risk (N) POM + LoDEX 302 140 63 15 1 HiDEX 153 29 9 0 0

0.0

0.2

0.4

0.6

0.8

1.0

Progression-Free Survival (mos)

Prop

ortio

n of

Pat

ient

s

0 4 8 12 16

Progression-Free Survival – ITT Population Updated March 1 2013 (median follow-up 10 mos)

Median PFS POM + LoDEX (N = 302) 4.0 mos HiDEX (N = 153) 1.9 mos

HR = 0.48 P < .001

Based on IMWG criteria. San Miguel JF, et al. EHA 2013 [abstract S1151].

PFS – Forest Plot of Subgroup Analyses Updated March 1 2013

* Number of events/number of pts. Based on IMWG criteria. San Miguel JF, et al. EHA 2013 [abstract S1151].

0.25 0.5 1 2

Favors POM + LoDEX Favors HiDEX

ITT Population

LEN & BORT Refractory

LEN as Last Prior Tx

BORT as Last Prior Tx

POM + LoDEX*

233/302

176/225

HiDEX* HR (95% CI)

64/85

97/132

133/153

95/113

42/49

56/66

0.48 (0.39-0.60)

0.52 (0.41-0.68)

0.38 (0.26-0.58)

0.52 (0.37-0.73)

0.0

0.2

0.4

0.6

0.8

1.0

0 4 8 12 20 16

Overall Survival (mos)

Prop

ortio

n of

Pat

ient

s

76 pts (50%) in the HiDEX arm received POM

Median OS POM + LoDEX (N = 302) 12.7 mos HiDEX (N = 153) 8.1 mos

HR = 0.74 P = .028


Overall Survival – ITT Population Updated March 1 2013 (median follow-up 10 mos)

At Risk (N) POM + LoDEX 302 231 145 71 24 2 HiDEX 153 100 59 26 7 0

OS – Forest Plot of Subgroup Analyses Updated March 1 2013

ITT Population

LEN and BORT Refractory

LEN as Last Prior Tx

BORT as Last Prior Tx

Subgroup POM + LoDEX*

145/302

113/225

HiDEX* HR (95% CI)

41/85

56/132

82/153

62/113

29/49

30/66

0.74 (0.56-0.97)

0.77 (0.56-1.05)

0.53 (0.33-0.87)

0.87 (0.56-1.36)

0.25 0.5 1 2

*Number of events/number of pts. San Miguel JF, et al. EHA 2013 [abstract S1151].

Favors POM + LoDEX Favors HiDEX

Response POM + LoDEX (N = 302)

HiDEX (N = 153) P Value

ORR (≥ PR), n (%) 95 (31) 15 (10) < .001

≥ VGPR 17 (6) 1 (1) —

sCR/CR 3 (1) 0 (0) —

≥ MR, n (%) 118 (39) 24 (16) —

≥ SD, n (%) 247 (82) 94 (61) —

Median DOR,* mos (95% CI) 7.0 (6.0-9.0) 6.1 (1.4-8.5) .063

Response – ITT Population Updated March 1 2013

•  PFS of ≥ MR in POM + LoDEX: 8 mos •  Response rate consistent among all subgroups, including LEN and BORT as last prior

Response based on investigator assessment and IMWG criteria, except for MR (based on EBMT criteria). * Kaplan-Meier median, patients with ≥ PR only. San Miguel JF, et al. EHA 2013 [abstract S1151].

Safety Profile Updated March 1 2013 POM + LoDEX

(N = 300) HiDEX

(N = 150) Grade 3/4 hematologic AEs (%)

Neutropenia 48 16 Febrile neutropenia 9 0

Anemia 33 37 Thrombocytopenia 22 26

Grade 3/4 non-hematologic AEs (%) Infections 30 24

Pneumonia 13 8 Bone Pain 7 5 Fatigue 5 6 Asthenia 4 6 Glucose intolerance 3 7

Grade 3/4 AEs of interest (%) DVT/PE 1 0 Peripheral neuropathy* 1 1

Discontinuation due to AEs (%) 9 10 * Peripheral neuropathy includes the preferred terms hyperaesthesia, neuropathy peripheral, peripheral sensory neuoropathy, paraesthesia, hypoaesthesia, and polyneuropathy. San Miguel JF, et al. EHA 2013 [abstract S1151].

Conclusions •  Updated analyses reconfirm POM + LoDEX advantage vs. HiDEX despite

50% of pts in the HiDEX arm receiving subsequent POM

•  POM + LoDEX significantly improved PFS and OS vs. HiDEX –  Median PFS: 4.0 vs. 1.9 mos –  Median OS: 12.7 vs. 8.1 mos

•  Benefit of POM + LoDEX was maintained regardless of refractoriness to BORT and LEN, even as last prior Tx

•  Safety profile of POM + LoDEX is predictable, manageable, and generally well tolerated in heavily pre-treated RRMM

•  POM + LoDEX consistently improved HRQoL vs. HiDEX in heavily pre-treated RRMM pts who have fully benefitted from BORT and LEN

•  In light of the OS advantage, POM + LoDEX, an oral treatment option, should be considered a new standard of care in this RRMM population


DARATUMUMAB, a CD38 Monoclonal An2body Study in Advanced Mul2ple Myeloma

– an Open-‐Label, Dose Escala2on Followed by Open-‐Label Extension in a Single-‐Arm Phase I/II Study

Abstract #S576

Henk Lokhorst, Torben Plesner, Peter Gimsing, Hareth Nahi, Steen Lisby, Paul Richardson

University Medical Center Utrecht, Netherlands; Vejle Hospital, Denmark; Rigshospitalet, Copenhagen, Denmark; Karolinska Ins2tutet, Stockholm, Sweden;

Genmab A/S, Copenhagen, Denmark; Dana-‐Farber Cancer Ins2tute, Boston, MA, USA

•  Human IgG1k monoclonal antibody

•  Broad spectrum mechanisms of action including CDC, ADCC, ADCP, apoptosis induction and inhibition of enzymatic activity

•  In development for multiple myeloma

•  Here we present data from the dose-escalation (part 1) of the FIH study in patients with relapsed or relapsed and refractory multiple myeloma

Daratumumab A Human CD38 mAb with Broad-‐Spectrum Killing Ac2vity

Open label, weekly i.v. infusion, 8 weeks Dose-escalation: 3+3 scheme*

0.005 è0.05 è0.1 è0.5 è1.0 è2.0 è4.0 è8.0 è16.0 è24.0 mg/kg

Dose- escalation cohorts

Expansion cohorts

*

PART 1

PART 2

Ongoing Several cohorts and dose schedules are being tested

-  start with pre-dose at 10% of the full dose, max 10 mg -  three weeks’ delay after first full dose -  governed by independent data monitoring committee

Daratumumab Trial Design

9 2

5 1 20

19 10 12 31 16 29 8 13

4 26 15 3 7 11

17 14

33 27

21 6 30 18 34

23

32

22 28 -100

-50

0

50

100

Rel

ativ

e ch

ange

in p

arap

rote

in fr

om b

asel

ine

(%)

Patient number

A AA A AA A

AA

A

AA AA AA AA AAB

B

B B

C

A

C C C

CC C

2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 24 mg/kg < 1 mg/kg

A: serum M-component, B: urine M-component, C: Free Light Chains (FLC)

Daratumumab Response (Part 1) Maximal Change in Paraprotein

Daratumumab (Part 1) Response according to IMWG

Daratumumab Progression-Free Survival

Final results from the phase 1b/2 study (PX-‐171-‐006) of carfilzomib in combina2on

with lenalidomide and low-‐dose dexamethasone (CRd) for pa2ents with

relapsed or progressive mul2ple myeloma

Ruben Niesvizky,1 Thomas Mar2n,2 William Bensinger,3 Melissa Alsina,4 David Siegel,5 Edward Kavalerchik,6

Michael Wang7 1Weill Cornell Medical College, New York, NY, USA; 2University of California San Francisco, San Francisco, CA, USA; 3Fred Hutchinson Cancer Research Center, Sea`le, WA, USA; 4H. Lee Moffi` Cancer

Center, Tampa, FL, USA; 5John Theurer Cancer Center at Hackensack University, Hackensack, NJ, USA; 6Onyx

Pharmaceu2cals, Inc, South San Francisco, CA, USA; 7University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

49

CFZ 15–27 mg/m2 IV*

LEN 10–25 mg

•  MTD not reached in dose-‐escala2on por2on of trial

•  MPD –  CFZ 20 mg/m2 Cycle 1 D1/2 and

27 mg/m2 thereager –  LEN 25 mg D1–21 –  dex 40 mg weekly

D, day; MPD, maximum planned dose; MTD, maximum tolerated dose. *CFZ given on D1/2/15/16 in Cycles 13–18 (maintenance).

dex 40 mg PO

50

Treatment Schema (28-‐day cycle)

Week 1 Week 2 Week 3 Week 4

D1/D2 D8/D9 D15/D16

D1 D8 D15 D22

Cohort CFZ mg/m2

LEN mg

1 (n=6) 15 10 2 (n=6) 15 15 3 (n=8) 15 20 4 (n=6) 20 20 5 (n=6) 20 25

6/7 (MPD) (n=52) 20/27 25

MPD Cohort (N=52) Overall (N=84) Age, y, median (range) 63.0 (44–86) 61.5 (43–86) Male, n (%) 31 (59.6) 48 (57.1) ECOG performance status, n (%) 0–1 48 (92.3) 79 (94.0) 2 4 (7.7) 5 (6.0) Time since diagnosis, y, median (range)* 3.1 (0–16) 3.1 (0–22) Interna2onal Staging System, n (%) I 20 (38.5) 35 (41.7) II/III 30 (57.7) 46 (54.8) Cytogene2cs/FISH

Standard-‐risk 40 (76.9) 57 (67.9) High-‐risk 11 (21.2) 22 (26.2)

Prior lines of therapy, median (range) 3 (1–5) 2 (1–5) Refractory disease, n (%)†

Last regimen 21 (40.4) 34 (40.5) BTZ 14 (26.9) 17 (20.2) LEN 22 (42.3) 29 (34.5) BTZ and LEN 7 (13.5) 8 (9.5)

BTZ, bortezomib; ECOG, Eastern Coopera2ve Oncology Group; FISH, fluorescence in situ hybridiza2on. *Data unavailable for 1 pa2ent; †≤25% response or progression during therapy.

Baseline Characteris2cs

51

Response to Treatment

52

MPD Cohort (N=52) Overall (N=84)

Median TTR* 1.0 mo Median DOR*† 22.1 mo

CR, complete response; DOR, dura2on of response; MR, minimal response; NE, not evaluable; PD, progressive disease; sCR, stringent complete response; SD, stable disease; TTR, 2me to response; VGPR, very good par2al response. *≥PR; †es2mated by the Kaplan-‐Meier method.

Median TTR* 1.0 mo Median DOR*† 18.8 mo

ORR=76.9% ORR=69.0%

Progression-‐free Survival

53 MPD, maximum planned dose. *7 pa2ents overall and 6 in the MPD cohort discon2nued treatment ager achieving ≥PR and prior to PD to pursue alternate therapies (eg, ASCT).

MPD Cohort (N=52)

Overall (N=84)

Median 15.4 months (95% CI 7.9–27.0)

Median 11.8 months (95% CI 7.6–20.7)

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