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
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
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 MAINTENANCECYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE
36 36 361 2 15 16 1 2 15 16
36 36 36 3636 36
Response Assessments
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
San Miguel JF, et al. EHA 2013 [abstract S1151].
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
San Miguel JF, et al. EHA 2013 [abstract S1151].
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
San Miguel JF, et al. EHA 2013 [abstract S1151].
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
San Miguel JF, et al. EHA 2013 [abstract S1151].
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)