title of module/lecture - ematologialasapienza.it settembre...phase 2 study of daratumumab (dara) in...

$: Title of Module/Lecture - Ematologialasapienza.it Settembre...Phase 2 Study of Daratumumab (DARA) in Patients with ≥3 Lines of Prior Therapy or Double Refractory Multiple Myeloma:$
Mieloma MultiploMichele Cavo18 SETTEMBRE 2015

Phase 2 Study of Daratumumab (DARA) in

Patients with ≥3 Lines of Prior Therapy or

Double Refractory Multiple Myeloma:

54767414MMY2002 (Sirius)*

Sagar Lonial,1 Brendan Weiss,2 Saad Usmani,3 Seema Singhal,4 Ajai Chari,5 Nizar Bahlis,6 Andrew Belch,7 Amrita Krishnan,8 Robert Vescio,9 Maria Victoria Mateos,10 Amitabha Mazumder,11 Robert Z. Orlowski,12 Heather Sutherland,13 Joan Blade,14 Emma C. Scott,15 Huaibao Feng,16 Clarissa Uhlar,17

Imran Khan,16 Tahamtan Ahmadi,17 Peter Voorhees,18.

1Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA; 2Division of Hematology & Oncology, Department of Medicine, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 3Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC; 4Robert H. Lurie Comprehensive Cancer Center, Division of Hem./Onc.,

Northwestern University Feinberg School of Medicine, Chicago, IL; 5Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY; 6Tom Baker Cancer Center - University of Calgary, Calgary, AB, Canada; 7Cross Cancer Institute, Edmonton, AB, Canada; 8Department Hematology and Hematopoietic Stem Cell Transplant, City of Hope, Duarte, CA; 9Cedars-Sinai Outpatient Cancer Center at the Samuel

Oschin Comprehensive Cancer Institute, Los Angeles, CA; 10University Hospital of Salamanca/IBSAL, Salamanca, Spain; 11NYU PerlmutterCancer Center, New York, NY; 12Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX;

13Leukemia/Bone Marrow Transplant Program, University of British Columbia, Vancouver, BC, Canada; 14IDIBAPS, Hospital Clinic de Barcelona, Barcelona, Spain; 15Knight Cancer Institute, Oregon Health and Science University, Portland, OR; 16Janssen Research & Development, Raritan, NJ; 17Janssen Research & Development, Spring House, PA; 18Division of Hematology/Oncology, Lineberger

Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC

*NCT01985126

Background• CD38 is highly and ubiquitously

expressed on myeloma cells and at

low levels on normal lymphoid and

myeloid cells, making it a promising

therapeutic target in multiple

myeloma (MM)1,2

• Daratumumab (DARA) is a human

monoclonal antibody (mAb) that

binds to CD38-expressing malignant

cells, inducing cell death through

multiple pathways including CDC,3

ADCC,3 ADCP4 and apoptosis5

1. Lin P, et al. Am J Clin Pathol. 2004;121:482-88.

2. Laubach JP, et al. Expert Opin Investig Drugs. 2014;23:445-52.

3. de Weers M, et al. J Immunol. 2011;186:1840-48.

4. Overdijk MB, et al. MAbs. 2015;7:311-21.

5. Jansen JH, et al. Blood.2012; 120. 2974.

DARA Mechanism of Action

CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cell-mediated

cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; NK, natural killer cell; NAD,

nicotinamide adenine dinucleotide; cADPR, cyclic adenosine diphosphate-ribose; NAADP,

nicotinic acid adenine dinucleotide phosphate.

Adapted from Laubach JP, et al. Expert Opin Investig Drugs. 2014;23:445-52.

GEN501: First in Human Study

Cohort A 8 mg/kg

Cohort B 8 mg/kg

Cohort C 8 mg/kg

Cohort D 16 mg/kg

Change in Paraprotein From Baseline

100

–100

80

60

40

20

0

–20

–40

–60

–80

4

• During ASCO 2014, data from a

first-in-human, Phase 1/2 study

were presented that demonstrated

single-agent DARA activity in

relapsed/refractory MM patients1

– No maximum tolerated dose was

reached (up to 24 mg/kg DARA)

– Overall response rate (ORR) was

35% in the 16 mg/kg DARA cohort

• FDA Breakthrough Therapy

designation in May 2013M

axim

um

ch

an

ge

fro

m b

ase

line

(%

)

1. Lokhorst HM, et al. J Clin Oncol. 2014;32(suppl):5s. Abstract 8513.

MMY2002 SIRIUS: Objectives and Eligibility

Primary objective

•Overall response rate of DARA monotherapy in patients with MM who had received ≥3 prior lines of therapy or had disease refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD)

•Responses assessed by an independent review committee (IRC)

Secondary objectives

•Progression-free survival (PFS), overall survival (OS), duration of and time to response, and clinical benefit rate (ORR + minimal response [MR])

•Safety

Eligibility

•Documented MM with disease progression on the most recent treatment regimen

•Received ≥3 prior lines of therapy including a PI and an IMiD, or refractory to their most recent PI and IMiD irrespective of number of prior lines of therapy

•Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

•Absolute neutrophil count >1 x 109/L

•Hemoglobin >7.5 g/dL

•Platelet count ≥50 x 109/L

•Creatinine clearance >20 mL/min/1.73 m2

Baseline Refractory Status

Refractory to, n (%) n = 106

Last prior therapy 103 (97)

PI and IMiD 101 (95)

BORT 95 (90)

CARF 51 (48)

LEN 93 (88)

POM 67 (63)

Alkylating agent 82 (77)

BORT+LEN 87 (82)

BORT+LEN+CARF 42 (40)

BORT+LEN+POM 57 (54)

BORT+LEN+CARF+POM 33 (31)

BORT+LEN+CARF+POM+THAL 12 (11)

• Patients were heavily pretreated, and

most patients were refractory to multiple

lines of PI and IMiD treatment

– 97% were refractory to their last

line of therapy

– 77% were refractory to alkylating

agents

– 95% were double refractory

– 66% were refractory to 3 of 4

therapies (BORT, LEN, CARF, and

POM)

– 63% were refractory to POM

– 48% were refractory to CARF

Overall Response Rate

• ORR was 29% (95% CI, 21–39) in

patients receiving 16 mg/kg DARA

• Stringent complete response (sCR) in 3%

of patients (95% CI, 0.6–8.0)

• VGPR or better achieved in 12% (95% CI,

7–20) of patients

• Clinical benefit rate (ORR + MR) was 34%

(95% CI, 25–44)

0

5

10

15

20

25

30

35

16 mg/kg

Ove

rall

re

sp

on

se

ra

te, %

ORR = 29%

sCR

n = 3 (3%)

VGPR

n = 10 (9%)

PR

n = 18 (17%)

Treatment-emergent AEs >20%

Term Any Grade

n (%)

Grade 3

n (%)

Grade 4

n (%)

Fatigue 42 (40) 3 (3) -

Anemia 35 (33) 25 (24) -

Nausea 31 (29) - -

Thrombocytopenia 27 (26) 18 (17) 8 (8)

Neutropenia 24 (23) 12 (11) 3 (3)

Back pain 23 (22) 3 (3) -

Cough 22 (21) - -

• Serious treatment-emergent AEs

(TEAEs) in 32 (30%) patients and 24

(23%) had Grade 3/4 serious TEAEs

• No discontinuations due to DARA-

related AEs

• No febrile neutropenia reported

• Few required additional supportive care

‒ Red blood cell transfusion (38%)

‒ Platelet transfusion (13%)

‒ Granulocyte colony stimulating

factor (8%)• Grade 3 or higher anemia and thrombocytopenia occurred

more frequently in nonresponders (32% and 24%,

respectively) than responders (3% and 7%, respectively)

• Grade 3 or higher neutropenia rates were similar in

nonresponders (12%) and responders (13%)

9

ELOQUENT-2: a phase 3, randomized, open-

label study of lenalidomide/dexamethasone

with/without elotuzumab in patients with

relapsed/refractory multiple myeloma

Meletios Dimopoulos*†1, Sagar Lonial†2, Antonio Palumbo3, Darrell White4, Sebastian Grosicki5,

Ivan Spicka6, Adam Walter-Croneck7, Philippe Moreau8, Maria-Victoria Mateos9, Hila Magen10,

Andrew Belch11, Donna Reece12, Meral Beksac13, Andrew Spencer14, Heather Oakervee15, Masafumi

Taniwaki16, Christoph Röllig17, Ka Lung Wu18, Anil Singhal19, Jesus San Miguel20, Morio

Matsumoto21, Jessica Katz22, Eric Bleickardt23, Valerie Poulart24 and Paul Richardson25 on behalf of

the ELOQUENT-2 Investigators

1National and Kapodistrian University of Athens, Athens, Greece; 2Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA; 3A.O.U. San Giovanni Battista di Torino - Ospedale Molinette, Torino, Italy; 4QEII Health Science Center and Dalhousie University, Halifax, Canada; 5Silesian Medical University, Katowice, Poland; 6Charles University Hospital, Prague, Czech Republic; 7Medical University of Lublin, Lublin, Poland;

8University Hospital, Nantes, France; 9University Hospital of Salamanca-IBSAL, Salamanca, Spain; 10Davidoff Cancer Center, Rabin Medical Center,

Petah Tikva, and Tel Aviv University, Ramat Aviv, Israel; 11Cross Cancer Institute and University of Alberta, Edmonton, Canada; 12Princess Margaret

Hospital, Toronto, Canada; 13Ankara University, Ankara, Turkey; 14Alfred Health-Monash University, Melbourne, Australia; 15Barts and the London

NHS Trust, London, UK; 16Kyoto Prefectural University of Medicine, Kyoto, Japan; 17Universitatsklinikum der TU, Dresden, Germany; 18ZNA

Stuivenberg, Antwerp, Belgium; 19AbbVie Biotherapeutics Inc. (ABR), Redwood City, USA; 20Clinical Universidad de Navarra, Pamplona, Spain; 21Nishigunma National Hospital, Shibukawa, Japan; 22Bristol-Myers Squibb, Princeton, USA; 23Bristol-Myers Squibb, Wallingford, USA; 24Bristol-

Myers Squibb, Braine-l'Alleud, Belgium; 25Dana-Farber Cancer Institute, Boston, USA

Presented at the European Hematology Association (EHA) 20th Congress; Vienna, Austria; June 11–14, 2015

S471

Dual Mechanism of Action of Elotuzumab

Humanized IgG1 immunostimulatory monoclonal antibody targeted

against SLAMF7, a glycoprotein highly expressed on myeloma and natural

killer cells but not on normal tissues1

A: Direct activation

Binding to SLAMF7 directly

activates natural killer cells,2

but not myeloma cells3

B: Tagging for recognition

Elotuzumab activates

natural killer cells via CD16,

enabling selective killing of

myeloma cells via antibody-

dependent cellular

cytotoxicity (ADCC) with

minimal effects on normal

tissue2

1. Hsi ED et al. Clin Cancer Res 2008;14:2775–84

2. Collins SM et al. Cancer Immunol Immunother 2013;62:1841–9

3. Guo H et al. Mol Cell Biol 2015;35:41–51

SLAMF7 = Signaling Lymphocyte Activation Molecule-F7

Direct activationA

B Tagging for

recognition

Elotuzumab

SLAMF7

Elotuzumab

SLAMF7

Myeloma

cell

Myeloma

cell death

Degranulation

Perforin,

granzyme B

release

Downstream

activating

signaling

cascade

Natural killer cell

Granule synthesis

Polarization

EAT-2

ELOQUENT-2 Study Design

Open-label, international, randomized, multicenter, phase 3 trial

(168 global sites)

Key inclusion criteria

RRMM

1–3 prior lines of therapy

Prior Len exposure permitted in 10% of study population (patients not refractory to Len)

Elo plus Len/Dex (E-Ld) schedule (n=321)

Elo (10 mg/kg IV): Cycle 1 and 2: weekly; Cycles 3+: every other week

Len (25 mg PO): Days 1–21Dex: weekly equivalent, 40 mg

Len/Dex (Ld) schedule (n=325)

Len (25 mg PO): Days 1–21;

Dex: 40 mg PO Days 1, 8, 15, 22

Repeat every 28 days

Assessment

Tumor response: every 4 weeks until progressive disease

Survival: every 12 weeks after disease progression

Endpoints:

– Co-primary: PFS and ORR

– Other: overall survival (data not yet mature), duration of response,

quality of life, safety

All patients received premedication to mitigate infusion reactions prior to

elotuzumab administration

Elotuzumab IV infusion administered ~ 2–3 hours

Baseline Demographics and

Disease Characteristics

Characteristic E-Ld (n=321) Ld (n=325)

Prior regimens, median (range) 2 (1–4) 2 (1–4)

Prior therapies, %

Bortezomib 68 71

Melphalan* 69 61

Thalidomide 48 48

Lenalidomide† 5 7

Response to most recent line of therapy, %‡

Refractory 35 35

Bortezomib refractory 22 21

Thalidomide refractory 9 11

Relapsed 65 65

Prior stem cell transplantation, % 52 57

*Oral or intravenous. †Prior lenalidomide was permitted if best response was ≥partial response and patients were not refractory to prior lenalidomide

treatment; patients could not receive more than 9 cycles of lenalidomide and had at least 9 months between the last dose of lenalidomide and

progression. ‡One patient in the elotuzumab group had an unknown response to the most recent line of therapy

Co-primary Endpoint:

Progression-Free Survival

PFS analysis used the primary definition of PFS

E-Ld−treated patients had a 30% reduction in the risk of disease progression or

death; treatment difference at 1 and 2 years was 11% and 14%, respectively

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

380 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

No. of patients at risk:

E-Ld

Ld

321

325

303

295

279

249

259

216

232

192

215

173

195

158

178

141

157

123

143

106

128

89

117

72

85

48

59

36

42

21

32

13

12

7

7

2

57%

68%

27%

41%

1-year PFS 2-year PFS

PFS (months)

Pro

ba

bil

ity p

rog

res

sio

n f

ree

From N Engl J Med, Lonial S et al, Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. Copyright © (2015) Massachusetts Medical Society. Reprinted with

permission

E-Ld Ld

HR 0.70 (95% CI 0.57, 0.85);

p=0.0004

Median PFS

(95% CI)

19.4 mo

(16.6, 22.2)

14.9 mo

(12.1, 17.2)

E-Ld

Ld

1

0

0

0

Subgroup Hazard ratio (95% CI)

Age (<75 years) 0.73 (0.59–0.92)

Age (≥75 years) 0.56 (0.35–0.89)

Age (<65 years) 0.75 (0.55–1.02)

Age (≥65 years) 0.65 (0.50–0.85)

ISS stage (I) 0.63 (0.46–0.87)

ISS stage (II) 0.86 (0.61–1.22)

ISS stage (III) 0.70 (0.47–1.04)

Response to most recent therapy (refractory) 0.56 (0.40–0.78)

Response to most recent therapy (relapsed) 0.77 (0.60–1.00)

Lines of prior therapy (1) 0.75 (0.56–1.00)

Lines prior therapy (2 or 3) 0.65 (0.49–0.87)

Prior IMiD (prior thalidomide only) 0.64 (0.48–0.85)

Prior IMiD (other) 0.59 (0.25–1.40)

Prior bortezomib (yes) 0.68 (0.54–0.86)

Prior bortezomib (no) 0.72 (0.49–1.07)

Prior SCT (yes) 0.75 (0.58–0.99)

Prior SCT (no) 0.63 (0.46–0.86)

del(17p) (yes) 0.65 (0.45–0.94)

1q21 (yes) 0.75 (0.56–0.99)

t(4;14) (yes) 0.53 (0.29–0.95)

Progression-Free Survival: Subgroup Analysis

IMiD = immunomodulatory drug; ISS = International Staging System

0.25 0.5 0.8 1.251 2 4

E-Ld better Ld alone better

From N Engl J Med, Lonial S et al, Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. Copyright © (2015) Massachusetts Medical Society. Reprinted with permission

PFS benefit in E-Ld group was consistently better across key subgroups

Infusion Reactions

Infusion reactions occurred in 10% of patients

70% of infusion reactions occurred with the first dose

No Grade 4 or 5 infusion reactions

Elotuzumab infusion was interrupted in 15 (5%) patients due to an

infusion reaction (median interruption duration 25 minutes)

2 (1%) patients discontinued the study due to an infusion reaction

Events, n (%)E-Ld (n=318)

Grade 1/2 Grade 3 Grade 4/5

Infusion reaction 29 (9) 4 (1) 0

Pyrexia 10 (3) 0 0

Chills 4 (1) 0 0

Hypertension 3 (1) 1 (<1) 0

Subgroup Analysis by Prior Treatment Among Patients With Relapsed or Relapsed and

Refractory Multiple Myeloma in the PANORAMA 1 Study of Panobinostat or

Placebo Plus Bortezomib and Dexamethasone

Hermann Einsele, Paul G. Richardson, Vânia T.M. Hungria,

Sung-Soo Yoon, Meral Beksac, Meletios Athanasios

Dimopoulos, Ashraf Elghandour, Wieslaw W. Jedrzejczak,

Andreas Guenther, Thanyaphong Na Nakorn, Noppadol

Siritanaratkul, Robert L. Schlossman, Jian Hou, Philippe

Moreau, Sagar Lonial, Jae Hoon Lee, Monika Sopala,

Bourras-Rezki Bengoudifa, Claudia Corrado

and Jesús F. San-Miguel

Pan-DACi, such as panobinostat, inhibit a broad range of deacetylase enzymes that target both histone and nonhistone

proteins involved in oncogenesis1

Pan-DACi inhibit growth and promote death of myeloma cells through inhibition of HDAC enzymes:

• Histone proteins, which are implicated in epigenetic dysregulation, resulting in activation of tumor suppressor genes2-4

• Nonhistone proteins, which promote toxic accumulation of misfolded proteins, leading to cell stress2,5,6

1. Farydak (panobinostat) [package insert]. East Hanover, NJ: Novartis; 2014. 2. Atadja P, et al. Cancer Lett. 2009;280:233-241. 3. Mannava S, et al. Blood.

2012;119:1450-1458. 4. Kalushkova A, et al. PloS One. 2010;5:e11483. 5. Catley L, et al. Blood. 2006;108:3441-3449. 6. Glozak MA and Seto E. Oncogene.

2007;26:5420-5432.

Pan-DAC Inhibitors: Mechanism of Action

3

18

Follow-up

Treatment Phase 1 Treatment Phase 2

Eight 21-Day cycles (24 wks) Four 42-Day cycles (24 wks)

Panobinostat +

bortezomib +

dexamethasone

Placebo + bortezomib + dexamethasone

Panobinostat + bortezomib + dexamethasone

Placebo + bortezomib + dexamethasone

Pts with clinical benefita in Treatment

Phase I, can proceed to Treatment Phase II

• Primary endpoint: PFS (per modified EBMT criteria per investigator)1,2

• Key secondary endpoint: OS

• Other secondary endpoints: ORR, nCR/CR rate, DOR, TTR, TTP, QoL, and safety

Study conducted at 215 centers across 34 countries3

Pts(N = 768)

• Rel or Rel/Ref MM (BTZ-ref excluded)

• 1-3 prior lines of therapy

• Stratification factors

–Prior lines of therapy

–Prior BTZ

a Achieving ≥ no change according to

modified EBMT criteria (NC or better)

1. Blade J, et al. Br J Haematol. 1998;102:1115-11232. Richardson PG, et al. N Engl J Med. 2003; 348:2609-26173. San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206

PANORAMA 1 Study Design Randomized, Double-Blind, Phase 3 Study in

Relapsed or Relapsed and Refractory MM

19

Week 1 Week 2 Week 3

Treatment Phase 1 (Cycles 1-8)

PAN/Pbo

BTZ

Dex


Treatment Phase 2 (Cycle 9-12)

PAN/Pbo

BTZ

Dex


PAN: Panobinostat 20 mg oral

BTZ: Bortezomib 1.3 mg/m2 IV

Dex: Dexamethasone 20 mg oral

PANORAMA 1 Treatment Schedule

20

PANORAMA 1: Primary Endpoint Met (PFS)

Primary endpoint was met (P < .0001), with clinically relevant increase

in median PFS of 3.9 months for PAN-BTZ-Dex arm

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

387 288 241 202 171 143 113 89 69 52 44 35 26 18 13 10 5 3 0

381 296 235 185 143 114 89 64 42 32 24 18 12 5 5 3 2 0 0

MonthsNumber of patients at risk

PAN-BTZ-Dex

Pbo-BTZ-Dex

Pro

gre

ss

ion

-fre

e s

urv

iva

l P

rob

ab

ilit

y (

%)

Events

Median PFS

(95% CI)

months

HR

(95% CI)P value

PAN-BTZ-Dex 207/38712.0

(10.3, 12.9) 0.63 (0.52-0.76)

< .0001Pbo-BTZ-Dex

260/3818.1

(7.6, 9.2)

PAN-BTZ-Dex

Pbo-BTZ-Dex

San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206

Subgroup Analysis by Prior Treatment:PFS ≥ 2 Prior Regimens Including BTZ and an IMiD

• Among the subgroup of patients with ≥ 2 prior regimens including

BTZ and an IMiD the difference in median PFS benefit was 7.8

months

73 57 42 36 32 25 20 15 10 6 4 3 2 2 1

74 54 37 23 11 9 5 4 2 2 2 2 2 0 0

Number of Patients at Risk

PAN-BTZ-Dex

Pbo-BTZ-Dex

PF

S P

rob

ab

ilit

y, %

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Months

Events

Median PFS

(95% CI),

months

HR

(95% CI)

PAN-BTZ-Dex 44/7312.5

(7.3-14.0) 0.47

(0.31-0.72)Pbo-BTZ-Dex 54/74

4.7(3.7-6.1)

Censoring times

PAN-BTZ-Dex (n/N = 44/73)

Pbo-BTZ-Dex (n/N = 54/74)

1National and Kapodistrian University of Athens, Athens, Greece; 2Mayo Clinic, Scottsdale, AZ; 3Division of Hematology, Mayo Clinic, Rochester, MN; 4St István and St Laszlo Hospital, Budapest, Hungary; 5Institut Català

d’Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain; 6University Hospital Brno and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; 7Hospital Clínic de Barcelona, Barcelona, Spain; 8John Theurer

Cancer Center at Hackensack University, Hackensack, New Jersey; 9Queen Joanna University Hospital, Sofia, Bulgaria; 10Hematology Clinic University Multiprofile Hospital for Active Treatment, Plovdiv, Bulgaria; 11Department

of Hematology, Mór Kaposi Teaching Hospital, Kaposvár, Hungary; 12Weill Cornell Medical College, New York, New York; 13University of Chicago Medical Center, Chicago, IL; 14Clinica Universidad de Navarra, Spain;15Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria; 16Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA; 17University of Nantes, Nantes, France; 18University of Torino,

Torino, Italy

Effect of Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and Dexamethasone in Patients With Relapsed Multiple Myeloma by Line of Therapy: Interim Results From the Phase 3 ASPIRE Study

Meletios A. Dimopoulos,1 A. Keith Stewart, 2 S. Vincent Rajkumar,3

Tamás Masszi,4 Albert Oriol,5 Roman Hájek,6 Laura Rosiñol,7 David Siegel,8

Georgi G. Mihaylov,9 Vesselina Goranova-Marinova,10 Péter Rajnics,11

Ruben Niesvizky,12 Andrzej Jakubowiak,13 Jesus San-Miguel,14

Heinz Ludwig,15 Naseem Zojwalla,16 Margaret Tonda,16 Xinqun Yang,16

Philippe Moreau,17 Antonio Palumbo18

ASPIRE Study Design

23 IV, intravenous; KRd, carfilzomib, lenalidomide, and dexamethasone; Rd, lenalidomide and dexamethasone.

Rd

Lenalidomide 25 mg days 1–21

Dexamethasone 40 mg days 1, 8, 15, 22

KRd

Carfilzomib 27 mg/m2 IV (10 min)

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)

Lenalidomide 25 mg days 1–21

Dexamethasone 40 mg days 1, 8, 15, 22

Randomization

(1:1)

N=792

Stratification:

• β2-microglobulin

• Prior bortezomib

• Prior lenalidomide

28-day cycles

After cycle 12, carfilzomib given on days 1, 2, 15, 16After cycle 18, carfilzomib discontinued

Progression-Free Survival (PFS)Intent-to-Treat Population (N=792)

24

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n S

urv

ivin

g

With

out

Pro

gre

ssio

n

KRd

Rd

0 6 12 18 24 30 36 42 48

Months Since Randomization

KRd Rd

(n=396) (n=396)

PFS, median months 26.3 17.6

Hazard ratio (KRd/Rd) (95% CI) 0.69 (0.57–0.83)

P value (one-sided) <.0001

No. at Risk:

KRd

Rd396 332 279 222 179 112 24 1

396 287 206 151 117 72 18 1

CI, confidence interval; KRd, carfilzomib, lenalidomide, and dexamethasone; Rd, lenalidomide and dexamethasone.

PFS by Prior Line of Therapy (1 vs ≥2)

25

1 prior line of therapy ≥2 prior lines of therapy

CI, confidence interval; KRd, carfilzomib, lenalidomide, and dexamethasone; PFS, progression-free survival; Rd,

lenalidomide and dexamethasone.

KRd

(n=184)

Rd

(n=157)

KRd

(n=212)

Rd

(n=239)

PFS, median

months29.6 17.6

PFS, median

months25.8 16.7

Hazard ratio

(95% CI)

0.69

(0.52–0.94)

Hazard ratio

(95% CI)

0.69

(0.54–0.89)

P value

(one-sided).008

P value

(one-sided).002

1.0

0.8

0.6

0.2

0.0Pro

po

rtio

n S

urv

ivin

g W

ith

ou

t P

rog

ressio

n

0 6 12 18 24 30 36 42 48

Months from Randomization

0.4

KRd

Rd

1.0

0.8

0.6

0.2

0.0Pro

po

rtio

n S

urv

ivin

g W

ith

ou

t P

rog

ressio

n

0 6 12 18 24 30 36 42 48

Months from Randomization

0.4

KRd

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Impact of Stable Disease as a Response to

Pomalidomide Plus Low-Dose Dexamethasone on

Survival Outcomes in Patients With Refractory or

Relapsed and Refractory Multiple Myeloma in the

MM-003 Trial

Philippe Moreau, Katja Weisel, Kevin Song,

Craig J. Gibson, Owain Saunders, Lars Sternas,

Kevin Hong, Mohamed H. Zaki, Meletios A. Dimopoulos

EHA 2015_Oral presentation # S788

Abstract S788

MM-003 Study Design

Thromboprophylaxis was required for those receiving POM

or at high risk for DVT

PD or

Unacceptable AE

(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

Companion Trial

MM-003C

POM 21/28 days

PD

AE, adverse event; D, day; DVT, deep vein thrombosis; HiDEX, high-dose dexamethasone; LoDEX, low-dose dexamethasone; OS, overall survival; PD,

progressive disease; PFS, progression-free survival; POM, pomalidomide; SPM, second primary malignancy; Tx, treatment.

Stratification factors: age, number of prior Tx, disease population


Objective

• To determine the survival benefit with POM + LoDEX

Tx in pts with RRMM achieving SD in MM-003

Landmark Analyses

• Median follow-up: 15.4 mos

– Last pt enrolled: August 2012

– Data cutoff: September 1, 2013

• Landmark analyses were performed for the POM +

LoDEX arm on D1 of C3, 5, and 7

– Pts with SD were compared with pts who

achieved an overall response ≥ PR or had PD at

the same landmark point in time

C, cycle; LoDEX, low-dose dexamethasone; PD, progressive disease; POM, pomalidomide; PR, partial response; pt, patient; SD, stable disease.


OS Was Similar for Pts With SD and ≥ PR

in Landmark Analysis

Response n

≥ PR 58

SD 116

PD 44

HR, hazard ratio; OS, overall survival; PD, progressive disease; PR, partial response; pt, patient; SD, stable disease; Tx, treatment.

Response HR (95% CI) P Value

≥ PR vs SD 0.66 (0.40-1.08) .0976

PD vs SD 3.43 (2.23-5.27) < .0001

Cycle 3, Day 1

Time From First Tx, mos

1.00

0.6

0.2

6 12 24

0.8

0.4

0.0

0

Su

rviv

al

Pro

ba

bilit

y

18

+++

+

+

+++

+++++

+ +++ +

+

+

++

++

++++++++++++++++

+ +

+

+

+++++++

++++++

++++

+

+

+++++++++

+++

+

++

++++++

n = 218


Similar OS for Pts With SD and ≥ PR Was

Also Seen at Later Landmark Analyses

Response n

≥ PR 56

SD 57

PD 31

HR, hazard ratio; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease; Tx, treatment.


≥ PR vs SD 0.75 (0.38-1.47) .3997

PD vs SD 2.91 (1.56-5.42) .0008

Cycle 5, Day 1

Time From First Tx, mos

1.00

0.6

0.2

0.8

0.4

0.00

Su

rviv

al

Pro

bab

ilit

y

+

++ ++++ ++ ++++

+++++++

++++++

+++ +++++++++ +

+++

++ ++++ ++++

+++

+++

++++++

+

+

++++

+ +

++

+

+++

+

+ ++

6 12 2418

1.00

0.6

0.2

0.8

0.4

0.00

+

+++++++

++

+++

+

++++++++ +

++

+ ++++ +++

++

++

++

++

++

+

++++++++++

++

+

++++

+++

6 12 2418

Cycle 7, Day 1

Response n

≥ PR 47

SD 40

PD 18


≥ PR vs SD 0.79 (0.34-1.83) .5807

PD vs SD 2.68 (1.11-6.46) .0283

n = 144 n = 105


RANDOMIZATION

INDUCTION (three 21-d cycles)

VEL-THAL-DEX

• Vel 1.3mg/m2 twice weekly

• Thal 100200mg/day

• Dex 320mg/cycle

TRANSPLANTATION

• MEL 200

• Thal 100md/day

• Dex 160mg/cycle

• MEL 200

MAINTENANCE

• DEX

PBSC COLLECTION

• CTX+G-CSF


THAL-DEX

• Thal 100200mg/day

• Dex 320mg/cycle

CONSOLIDATION (two 35-d cycles)

VEL-THAL-DEX

• Vel 1.3mg/m2 once weekly

• Thal 100mg/day

• Dex 320mg/cycle


THAL-DEX

• Thal 100mg/day

• Dex 320mg/cycle

RANDOMIZATION 1


VCD

VMP

4 cycles

TRANSPLANTATION 1 or 2

• MEL 200


VEL-LEN-DEX

NO CONSOLIDATION

MAINTENANCE

• LEN until relapse

HDM/ASCT at relapse

RANDOMIZATION 2

Design of GIMEMA MMY-3006 and EMN-02 phase 3 studies

GIMEMA MMY-3006 EMN-02

PBSC COLLECTION

• CTX+G-CSF

1. Cavo M et al. Lancet. 2010;379:2075 .

2. Cavo M et al. Blood. 2012;120:9.

1 8 15 21

Induction: 3 x 21-day treatment cycles

VEL VEL VEL

Dex Dex Dex

THALIDOMIDE

VEL

Dex

4 112 5 9 12

Schema of VTD and VCD regimens

Bortezomib 1.3 mg/sm i.v. Dexamethasone 40 mg Thalidomide 100 → 200 mg/day

1 8 15 21

Induction: 3 x 21-day treatment cycles

VEL VEL VEL

Dex Dex Dex

CTX

VEL

Dex

4 112 5 9 12

Bortezomib 1.3 mg/sm i.v. Dexamethasone 40 mg Cyclophosphamide 500 mg/sm i.v.

CTX

VTD

(n=236)

VCD

(n=236)

Age (years) 58 (52-62) 57 (52-62)

Male vs Female 58% vs 42% 56% vs 44%

Β2m (mg/L) 3.00 (2.30-4.40) 3.18 (2.32-4.60)

Alb (g/dL) 3.83 (3.40-4.32) 3.81 (3.45-4.20)

ISS I vs II vs III 45% vs 39% vs 16% 45% vs 39% vs 16%

Hb (g/dL) 11.15 (9.60-12.50) 11.20 (9.80-12.60)

Plts (109/L) 231 (187-287) 233 (183-277)

Creat (mg/dL) 0.85 (0.70-0.97) 0.85 (0.70-1.02)

IgG vs IgA vs BJ vs Others 65% vs 17% vs 17% vs 1% 64% vs 19% vs12% vs 5%

Del(17p) and/or t(4;14) 24% 24%

Del(13q) with or without del(17p)

and/or t(4;14)47% 49%

Continuous variables are expressed as median (IQR) and categorical variables are expressed as %

Patient demographics and baseline characteristics

Response to induction therapy (intention-to-treat)

P<0.001 P<0.001 P=0.003 P=0.003

Response to both VTD and VCD were reassessed centrally

CR and ≥ VGPR rates in high risk subgroups of patients

P<0.001 P<0.001 P=0.155 P<0.001

Response to both VTD and VCD were reassessed centrally

IMPROVED OVERALL SURVIVAL WITH

AUTOLOGOUS TRANSPLANT VS

CYCLOPHOSPHAMIDE-LENALIDOMIDE-

DEXAMETHASONE IN NEWLY DIAGNOSED

MYELOMA: A PHASE 3 TRIAL

Gay F,1 Genuardi M, 1 Hajek R,2 Petrucci MT,3 Pour L,4 Falcone AP, 3 Offidani M, 3 Patriarca F,3 Corradini P, 3 Gilestro M,1 Pescosta N, 3 Carella AM, 3 Finsinger P, 3 Liberati AM, 3 Petrò D, 3

Pulini S, 3 Oliva S, 1 Di Raimondo F, 3 Spencer A,5 Boccadoro M, 1 Palumbo A. 1

1 Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy; 2 Faculty of

Medicine, University of Ostrava and Department of Haematooncology, University Hospital

Ostrava, Ostrava, Czech Republic; 3 Italian Multiple Myeloma Network, GIMEMA, Italy; 4

Department of Hematology and Oncology, University Hospital Brno, Brno, Czech Republic;

5 Alfred Health-Monash University, Melbourne, Australia.

l 389 patients (younger than 65 years) randomized from 59 centers

l Patients: Symptomatic disease, organ damage (CRAB),measurable disease

Treatment schedule

Rdfour 28-day courses

R: 25 mg/d, days 1-21

d: 40 mg/d, days

1,8,15,22

CRDsix 28-day courses

C: 300 mg/sqm, days 1,8,15

R: 25 mg/d, days 1-21

D: 40 mg days 1,8,15,22

MEL200-ASCTtwo courses

M: 200 mg/m2 day -2

Stem cell support day 0

RP MAINTENANCE 28-day courses until relapse

R: 10 mg/day, days 1-21

P: 50 mg every other day

R MAINTENANCE28-day courses until relapse

R: 10 mg/day, days 1-21

R

A

N

D

O

M

I

Z

A

T

I

O

N

1°

R

A

N

D

O

M

I

Z

A

T

I

O

N

2°

R, lenalidomide; D, dexamethasone; C, cyclophosphamide; P, prednisone; Rd, lenalidomide-dexamethasone; CRD, cyclophosphamide-lenalidomide-

dexamethasone; MEL200-ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; RP lenalidomide-prednisone,

MEL200-ASCT vs CRD

CRDsix 28-day courses

C: 300 mg/m2/d, days 1,8,15

R: 25 mg/d, days 1-21

D: 40 mg/d days 1,8,15,22

MEL200-ASCTtwo courses

M: 200 mg/m2 day -2

Stem cell support day 0

R

A

N

D

O

M

I

Z

A

T

I

O

N

1°

CRD, cyclophosphamide-lenalidomide-dexamethasone; C, cyclophosphamide; D, dexamethasone; R, lenalidomide; MEL200-ASCT, melphalan 200 mg/m2

followed by autologous stem-cell transplantation

MEL200-ASCT vs CRD

Progression-free survival

Median follow-up : 55 months

Median PFS

MEL200-ASCT 43.3 months

CRD 28.6 months

MEL200–ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD cyclophosphamide lenalidomide dexamethasone; PFS,

progression-free survival.

MEL200-ASCT

CRD

HR 0.40 95% CI 0.25-0.63 P< 0.001

% o

f p

ati

en

ts

Months0 10 20 30 40 50 60 70

0.0

0.2

0.4

0.6

0.8

1.0

MEL200-ASCT vs CRD

Second-line therapy

MEL200 –ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD, chyclophosphamide lenalidomide dexamethasone; IMIDs, immunomodulatory

agents

No Transplant at relapse

8%

39%

68%

49%

15%

7%

9%

5%

0% 20% 40% 60% 80% 100%

MEL200-ASCT

CRD

Transplant at relapse Bortezomib IMIDs Other

MEL200-ASCT vs CRD

Overall survival

Median follow-up : 55 months

MEL200-ASCT

CRD

4-year OS

MEL200-ASCT 86%

CRD 71%

HR 0.42 95% CI 0.23-0.76 P= 0.004

MEL200–ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD cyclophosphamide lenalidomide dexamethasone; OS,

overall survival.

Months

% o

f p

ati

en

ts

0 10 20 30 40 50 60 70

0.0

0.2

0.4

0.6

0.8

1.0

Abstract S105

UPDATED OVERALL SURVIVAL ANALYSIS OF THE

FIRST STUDY: CONTINUOUS LENALIDOMIDE PLUS

LOW-DOSE DEXAMETHASONE VS MELPHALAN,

PREDNISONE, AND THALIDOMIDE IN PATIENTS

WITH NEWLY DIAGNOSED MULTIPLE MYELOMA

Thierry Facon , Meletios A Dimopoulos , Cyrille Hulin , Lotfi Benboubker,

Andrew Belch , Heinz Ludwig , Antonio Pinto , Michel Attal , Michele Cavo ,

Philippe Moreau , Rik Schots , Nathalie Meuleman , Katia Weisel , Mourad

Tiab , Je-Jung Lee , Andrew Butler , Jennifer Marek , Guang Chen , Annette

Ervin-Haynes , Jean Paul Fermand

EHA 2015_Oral presentation #S105

FIRST: Trial Design


FIRST: Updated OS

• Updated 4-year survival: 60% with Rd continuous vs 57% with Rd18 and 51% with

MPT


FIRST: PFS2

• PFS2 benefit is maintained with Rd continuous vs MPT with updated

data

• 58% of pts had a PFS2 event

• PFS2 continues to improve with Rd continuous vs MPT

– May 24, 2013 data cutoff: HR, 0.78; 95% CI, 0.66-0.931

– March 3, 2014 data cutoff: HR, 0.74; 95% CI, 0.63-0.86

• Median PFS2 with Rd continuous, Rd18, and MPT was

42.9, 40.0, and 35.0 months, respectively

• The most common second-line Tx across all study arms was

bortezomib based (55.7%)


title of module/lecture - ematologialasapienza.it settembre...phase 2 study of daratumumab (dara) in...

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