three novel agents in a month in myelomaazmyelomanetwork.org/wp-content/uploads/2016/03/3...mar 03,...

Three Novel Agents in a Month in Myeloma:A Wealth of Choice!

AZMN

March 2016

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Joseph Mikhael, MD, MEd, FRCPC

Staff Hematologist, Mayo Clinic Arizona

Joseph Mikhael, MD, MEd, FRCPC, FACP

Associate Dean, Mayo School of Graduate Medical Education

Professor of Medicine, Mayo Clinic Arizona

Objectives

1. Review the recently approved agents by the FDA for relapsed multiple myeloma

2. Discuss the overall strategy in deciding which agents to select in relapsed myeloma

3. Provide a practical algorithm for relapsed myeloma based on disease based and patient based factors

4. Engender optimism for the future of Myeloma!

Managing myeloma: the components

Supportive Care

Initial

Therapy

Consolidation Maintenance

Treatment

of Relapsed

disease

Transplant

Eligible

Patients

Transplant

Ineligible

patientsConsolidation/ Maintenance/

Continued therapy

Three New Agents in One Month!

Daratumumab Darzalex©–

Anti CD38 Monoclonal Antibody (11/16)

Ixazomib – Ninlaro©

Oral Proteasome Inhibitor (11/20)

Elotuzumab – Emplicity©

Anti SLAMF7 Monoclonal Antibody (12/1)

Panobinostat – Farydak©

HDAC inhibitor (February 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.

Study Design

• Open-label, international, multicenter study

of Simon-2-stage design

• Initially, patients randomized 1:1 to receive

DARA

– 8 mg/kg every 4 weeks (Q4W) or

– 16 mg/kg every week (QW) for 8 weeks,

every 2 weeks (Q2W) for 16 weeks, then

Q4W thereafter

• 16 mg/kg DARA was established as the

recommended dose for further study

• Results are reported for all patients who

were treated with 16 mg/kg DARA (n = 106)

16 mg/kg

(n = 16)

8 mg/kg

(n = 18)

16 mg/kg

(n = 106)

Response evaluated

Randomization

Additional 90

patients enrolled at

16 mg/kg DARA

Patient Disposition

• Patients were enrolled between October 2013 and May 2014

• Data cutoff January 9th 2015

• Of 106 patients treated with 16 mg/kg DARA, 16 (15%) patients remained on

study at data cutoff

• Discontinuations predominantly due to disease progression

– 82 (77%) due to progressive disease

– 3 (3%) withdrew consent due to symptoms related to disease progression

– 5 (5%) due to adverse events (not related to DARA)

o General physical health deterioration (n = 2)

o H1N1 influenza (n =1)

o Hypercalcemia (n =1)

o Spinal cord compression (n =1)

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+TH

AL

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%)

ORR by Subgroup

33 3330

21 20

30 29 28 2826

21

0

5

10

15

20

25

30

35

40

OR

R, %

Refractory to

Progression-free and Overall Survival

• 29 of 31 responders are still alive

• The 1-year survival rate was 65% (95% CI, 51.2–75.5)

96106 85 82 64 23 10 2 0Patients at risk

80

100

60

40

20

0

0 42 6 8 16141210

Months from start of treatment

Pa

tie

nts

aliv

e (

%)

Median OS = NE

(95% CI, 13.7–NE)Median PFS = 3.7 months

(95% CI, 2.8–4.6)

63106 38 32 17 5 4 1 0Patients at risk

80

100

60

40

20

0

0 42 6 8 16141210

Months from start of treatment

Pa

tie

nts

pro

gre

ssio

n-f

ree a

nd

aliv

e (

%)

Infusion-related Reactions (IRRs)

• Occurred in 43% of patients

• Predominantly Grade 1 or 2

– Grade 3: 5%; no Grade 4

• >90% of IRRs occurred during the

first infusion

• 7% of patients had an IRR at >1

infusion

• Most common IRRs included nasal

congestion (12%); throat irritation

(7%); cough, dyspnea, chills, and

vomiting (6% each)

• No patients discontinued treatment

due to IRRs

0

5

10

15

20

25

30

35

40

45

Overall 1st infusion 2nd infusion 3rd or laterinfusion

Incid

en

ce o

f IR

R, %

Conclusions

• DARA is a fully human mAb with remarkable single-agent activity in heavily

pretreated and refractory MM patients who exhausted other therapeutic options

• Efficacy was consistent across all subgroups

• Responses were rapid, durable, and deepened over time

– 3 sCRs

– 10 VGPR

– Depth of response may translate to prolonged OS

• DARA was well tolerated

– No patients discontinued treatment due to AEs related to DARA

• IRRs predominantly occurred during the first infusion, were usually Grade 1 or 2,

and were manageable

• DARA represents a new standard of care in this setting

My Take - Daratumumab

• Will have the greatest impact of the drugs approved in 2015

• Ideal partner to combine with PIs or IMiDsdue to lack of overlapping toxicity

• Single agent activity impressive (“rituximab” of myeloma)

• Infusional reactions are real and infusion is LONG

• Watch for the next CD38 MoAb = Isatuximab

Ixazomib, an Oral Proteasome Inhibitor,

in Combination with Lenalidomide and

Dexamethasone (IRd), Significantly Extends

Progression-Free Survival for Patients with

Relapsed and/or Refractory Multiple Myeloma:

The Phase 3 TOURMALINE-MM1 Study

(NCT01564537)

Philippe Moreau,1 Tamás Masszi,2 Norbert Grzasko,3 Nizar J. Bahlis,4

Markus Hansson,5 Ludek Pour,6 Irwindeep Sandhu,7 Peter Ganly,8 Bartrum W. Baker,9

Sharon Jackson,10 Anne-Marie Stoppa,11 David Simpson,12 Peter Gimsing,13

Antonio Palumbo,14 Laurent Garderet,15 Michele Cavo,16 Shaji Kumar,17

Cyrille Touzeau,1 Francis K. Buadi,17 Jacob P. Laubach,18 Deborah Berg,19

Jianchang Lin,19 Alessandra Di Bacco,19 Ai-Min Hui,19 Paul G. Richardson18

1University Hospital Hôtel Dieu, Nantes, France; 2St. István and St. László Hospital of Budapest, Budapest, Hungary; 3Medical

University of Lublin and St. John's Cancer Center, Lublin, Poland; 4Southern Alberta Cancer Research Institute, University of

Calgary, Alberta, Canada; 5Skåne University Hospital, Lund University, Lund, Sweden; 6University Hospital Brno, Brno, Czech

Republic; 7University of Alberta, Edmonton, Canada; 8Christchurch Hospital, Christchurch, New Zealand; 9Palmerston North

Hospital, Palmerston North, New Zealand; 10Middlemore Hospital, Auckland, New Zealand; 11Institut Paoli-Calmettes,

Marseille, France; 12North Shore Hospital, Auckland, New Zealand; 13University Hospital Rigshospitalet, Copenhagen,

Denmark; 14University of Torino, Torino, Italy; 15Hôpital Saint Antoine, Paris, France; 16Bologna University School of Medicine,

Bologna, Italy; 17Mayo Clinic, Rochester, MN; 18Dana-Farber Cancer Institute, Boston, MA; 19Millennium Pharmaceuticals, Inc.,

Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

TOURMALINE-MM1: Phase 3 study of weekly

oral ixazomib plus lenalidomide-dexamethasoneR

an

do

miz

ati

on

Ixazomib + Lenalidomide + Dexamethasone

Ixazomib: 4 mg on days 1, 8, and 15

Lenalidomide: 25 mg* on days 1-21

Dexamethasone: 40 mg on days 1, 8, 15, 22

N=722

1:1

Placebo + Lenalidomide + Dexamethasone

Placebo: on days 1, 8, and 15

Lenalidomide: 25 mg* on days 1-21

Dexamethasone: 40 mg on days 1, 8, 15, 22

Repeat every 28 days until progression, or

unacceptable toxicity

Stratification:

• Prior therapy: 1 vs 2 or 3

• ISS: I or II vs III

• PI exposure: yes vs no

Global, double-blind, randomized, placebo-controlled study design

*10 mg for patients with creatinine clearance ≤60 or ≤50 mL/min, depending on local label/practice

1. Rajkumar S, et al. Blood 2011;117:4691–5.

Response and progression (IMWG 2011

criteria1) assessed by an independent review

committee (IRC) blinded to both treatment and

investigator assessment

Primary endpoint:

• PFS

Key secondary endpoints:

• OS

• OS in patients with del(17p)

722 patients enrolled at 147 study centers in

26 countries from 8/2012–5/2014

IRd (N=360) Placebo-Rd (N=362)

Demographics

Median age, years (range) 66 (38–91) 66 (30–89)

Gender – male, % 58 56

Race – white / Black or African American / Other, % 86 / 2 / 12 83 / 2 / 15

ECOG performance status 0 / 1 / 2, %* 50 / 43 / 5 47 / 45 / 7

Stratification factors

ISS Stage at screening: I or II / III, % 87 / 13 88 / 12

Lines of prior therapy: 1 / 2 or 3, % 59 / 41 59 / 41

Proteasome inhibitor-exposed, % 69 70

*Missing data for 2% and 1% in the IRd and placebo-Rd groups, respectively

Prior therapy and baseline cytogenetics

*97% of cytogenetics results were from a Clinical Laboratory Improvement Amendment (CLIA)-certified central laboratory, 3% from local laboratories. †Defined as patients without high-risk abnormalities. ‡Not able to test as sample was clotted, missing, etc.

IRd (N=360) Placebo-Rd (N=362)

Type of prior regimen

Bortezomib-containing 248 (69) 250 (69)

Thalidomide-containing 157 (44) 170 (47)

Lenalidomide-containing 44 (12) 44 (12)

Carfilzomib-containing 1 (<1) 4 (1)

Melphalan-containing 293 (81) 291 (80)

Stem cell transplant 212 (59) 199 (55)

Patient population categories

Relapsed 275 (76) 280 (77)

Refractory 42 (12) 40 (11)

Refractory and relapsed 41 (11) 42 (12)

Primary refractory (defined as no response to all prior lines of therapy)

24 (7) 22 (6)

Cytogenetics

Standard-risk† 199 (55) 216 (60)

High-risk (defined as del(17p), t(4;14), t(14;16)*

75 (21) 62 (17)

Not available‡ 86 (24) 84 (23)

Final PFS analysis:

A significant, 35% improvement in PFS with

IRd vs placebo-Rd

Number of patients at

risk:

IRd

Placebo-Rd

360 345 332 315 298 283 270 248 233 224 206 182 145 119 111 95 72 58 44 34 26 14 9 1 0

362 340 325 308 288 274 254 237 218 208 188 157 130 101 85 71 58 46 31 22 15 5 3 0 0

1.0

0.8

0.6

0.4

0.2

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Pro

ba

bilit

y o

f p

rog

res

sio

n-f

ree

su

rviv

al

Time from randomization (months)

Log-rank test p=0.012

Hazard ratio (95% CI): 0.742 (0.587, 0.939)

Number of events: IRd 129; placebo-Rd 157

Median PFS:

IRd: 20.6 months

Placebo-Rd: 14.7 months

Median follow-up: ~15 months

Outcomes by cytogenetic risk group

Median OS could not be estimated

In the IRd arm, median PFS in high-risk patients was similar to that in the overall

patient population and in patients with standard-risk cytogenetics

ORR, % ≥VGPR, % ≥CR, % Median PFS, months

IRd Placebo

-Rd

IRd Placebo

-Rd

IRd Placebo

-Rd

IRd Placebo

-Rd HR

All patients 78.3* 71.5 48.1* 39 11.7* 6.6 20.6 14.7 0.742*

Standard-risk

patients

80 73 51 44 12 7 20.6 15.6 0.640*

All high-risk

patients

79* 60 45* 21 12* 2 21.4 9.7 0.543

Patients with

del(17p)†

72 48 39 15 11* 0 21.4 9.7 0.596

Patients with

t(4;14) alone

89 76 53 28 14 4 18.5 12.0 0.645

*p<0.05 for comparison between regimens. †Alone or in combination with t(4;14 or t(14;16).

Data not included on patients with t(14:16) alone due to small numbers (n=7).

Improved response rates, durable responses, and

improved time to progression (TTP) with IRd

Response rates IRd

(N=360)

Placebo-Rd

(N=362)

p-value

Confirmed ORR (≥PR), % 78.3 71.5 p=0.035

CR+VGPR, % 48.1 39.0 p=0.014

Response categories

CR, % 11.7 6.6 p=0.019

PR, % 66.7 64.9 –

VGPR, % 36.4 32.3 –

Median time to response, mos 1.1 1.9 –

Median duration of response, mos 20.5 15.0 –

Median TTP, mos 21.4 15.7 HR 0.712

P=0.007

OS interim analysis at a

median follow-up of 23 months

A subsequent interim analysis for OS was conducted

– Median follow-up was 23.3 and 22.9 months in the IRd and

placebo-Rd groups, respectively

– 171 deaths (only 35% of the required number of deaths for

final OS analysis): 81 and 90 in the ixazomib and placebo

regimens, respectively

– An OS benefit was not demonstrated

At the same time point, a non-inferential analysis of PFS was conducted

– 372 PFS events; HR was 0.82 (95% CI: 0.67, 1.0); median PFS was

20 months in the ixazomib regimen and 15.9 months in the placebo

regimen

Summary of treatment exposure and

treatment-emergent adverse events

Adverse event (AE)IRd

(N=361), %

Placebo-Rd

(N=359), %

Any AE 98 99

Any grade ≥3 AE 74 69

Any serious AE 47 49

AE resulting in discontinuation of study regimen 17 14

On-study death (death within 30 days of last

dose)4 6

Higher frequency of grade ≥3 AE, primarily due to thrombocytopenia

Rates of AEs resulting in discontinuation or on-study death were similar between the

two arms

Median follow-up: 23.3 months for IRd and 22.9 months for placebo-Rd

Median number of treatment cycles: 17 (range 1–34) for IRd, and

15 (1–34) for placebo-Rd

– 48% and 43% of patients had received ≥18 cycles, respectively

– 20% and 19% of patients had received ≥25 cycles, respectively

AEs after median follow-up of 23 months: increased

rates with IRd driven by low-grade events

IRd (N=361), % Placebo-Rd (N=359), %

Preferred terms All-grade Grade 3 Grade 4 All-grade Grade 3 Grade 4

AEs overlapping with lenalidomide

Diarrhea 45 6 0 39 3 0

Constipation 35 <1 0 26 <1 0

Nausea 29 2 0 22 0 0

Vomiting 23 1 0 12 <1 0

Rash* 36 5 0 23 2 0

Back pain 24 <1 0 17 3 0

Upper respiratory tract

infection23 <1 0 19 0 0

Thrombocytopenia 31 12 7 16 5 4

AEs with proteasome inhibitors

Peripheral neuropathies* 27 2 0 22 2 0

Peripheral edema 28 1 0 20 1 0

AEs with lenalidomide

Thromboembolism* 8 2 <1 11 3 <1

Neutropenia* 33 18 5 31 18 6

*Represents multiple MedDRA preferred terms.

Conclusions

IRd was associated with a significant and clinically meaningful

improvement in PFS versus Rd in patients with relapsed and/or

refractory MM

The clinical benefit of IRd is further supported by significantly improved

TTP and improved confirmed response rates

Median overall survival was not yet reached

In the IRd arm, median PFS in high-risk patients was similar to that in

the overall patient population and in standard-risk patients

Patient-reported quality of life was maintained with IRd vs placebo-Rd

Addition of ixazomib to Rd was associated with limited additional

toxicity to that seen with placebo-Rd therapy

The all-oral regimen of IRd may become a new standard-of-care for

relapsed and/or refractory MM

Ixazomib was approved by the US FDA on November 20 under the

name NINLARO®

My Take - Ixazomib

• Appears to be slightly less potent than bortezomib, but unique molecule with significant single agent activity

• Very attractive in older or less fit patients

• All oral regimen very convenient

• Lack of neuropathy is encouraging

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

of lenalidomide/dexamethasone with/without elotuzumab

in patients with relapsed/refractory multiple myeloma

Sagar Lonial,1 Meletios Dimopoulos,2 Antonio Palumbo,3 Darrell White,4

Sebastian Grosicki,5 Ivan Spicka,6 Adam Walter-Croneck,7 Philippe Moreau,8

Maria‐Victoria Mateos,9 Hila Magen,10 Andrew Belch,11 Donna Reece,12 Meral Beksac,13

Masafumi Taniwaki,14 Christoph Röllig,15 Anil Singhal,16 Jessica Katz,17 Eric Bleickardt,18

Valerie Poulart,19 and Paul Richardson,20 on behalf of the ELOQUENT-2 Investigators

1Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA; 2National and Kapodistrian University of Athens, Athens, Greece; 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; 6Prague General Hospital, Prague, Czech Republic; 7Medical University of Lublin, Lublin, Poland;

8University Hospital, Nantes, France; 9University Hospital of Salamanca–IBSAL, Salamanca, Spain; 10Tel Aviv University, Ramat Aviv, Israel; 11Cross Cancer Institute and University of Alberta, Edmonton, Canada; 12Princess Margaret Hospital, Toronto, Canada; 13Ankara University, Ankara, Turkey; 14Kyoto Prefectural University of Medicine, Kyoto, Japan; 15Universitatsklinikum der TU, Dresden, Germany; 16AbbVie Biotherapeutics

Inc. (ABR), Redwood City, CA; 17Bristol‐Myers Squibb, Princeton, NJ; 18Bristol-Myers Squibb, Wallingford, CT; 19Bristol-Myers Squibb, Braine-l'Alleud, Belgium; 20Dana-Farber Cancer Institute, Boston, MA

Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting; Chicago, Illinois; May 29–June 2, 2015

8508

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

• Direct activation: Binding to SLAMF7

directly activates natural killer cells,2

but not myeloma cells3

• 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

Direct activationA

B

Myeloma

cell death

EAT-2

Downstream

activating

signaling

cascade

Degranulation

Perforin,

granzyme B

release

Tagging for

recognition

Elotuzumab

SLAMF7

Natural killer cell

Granule synthesis

Polarization

Elotuzumab

SLAMF7

Myeloma cell

SLAMF7 = Signaling Lymphocyte Activation Molecule-F7

ELOQUENT-2 Study Design

• Open-label, international, randomized, multicenter, phase 3 trial (168 global sites)

• 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 Elo administration

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 1–21

Dex: 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 wks until progressive disease

• Survival: every 12 wks after disease progression

CharacteristicE-Ld

(n=321)Ld (n=325)

Age (years), median (range) 67 (37–88) 66(38–91)

≥65 years 187 (58) 183 (56)

Region, n (%)

Europe 196 (61) 194 (60)

North America 66 (21) 68 (21)

Rest of the world 59 (18) 63 (19)

International Staging System disease stage, n (%)

I 141 (44) 138 (43)

II 102 (32) 105 (32)

III 66 (21) 68 (21)

Not reported 12 (4) 14 (4)

Cytogenetics (FISH)del(17p)

Yes 102 (32) 104 (32)

No 213 (66) 218 (67)


t(4;14)

Yes 30 (9) 31 (10)

No 285 (89) 290 (89)


1q21

Yes 147 (46) 163 (50)

No 169 (53) 159 (49)


Baseline Demographics and Disease Characteristics

Treatment Summary

*At the time of the data cut-off for the interim analysis

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

Number of treatment cycles,

median (range)19 (1–42) 14 (1–40)

Patients on treatment, n (%)* 113 (35) 66 (21)

Relative dose intensity (≥90%), n (%)

Elotuzumab 264 (83) -

Lenalidomide 163 (51) 161 (51)

Dexamethasone 146 (46) 148 (47)

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

Ld321

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

bilit

y p

rog

res

sio

n f

ree

E-Ld

Ld

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

0

0

1

0

E-Ld Ld

Hazard ratio = 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)

Co-Primary Endpoint: Overall Response Rate

P=0.0002‡

*Defined as partial response or better; †Complete response rates in the E-Ld group may be underestimated due to

interference from therapeutic antibody in immunofixation and serum protein electrophoresis assay

P=0.0002‡

0

20

40

60

80

100

Re

sp

on

se

ra

te (

%)

E-Ld Ld

p=0.0002

79

66

Overall

response rate*

Complete response

(sCR + CR)†

Very good

partial response

Combined response

(sCR + CR + VGPR)Partial response

47

21

2833

28

38

46

Progression-Free Survival According to Age

100

Pro

gre

ss

ion

-fre

e p

ati

en

ts (

%)

Time (months)

Pro

gre

ss

ion

-fre

e p

ati

en

ts (

%)

Time (months)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

<65 years ≥65 years

Hazard ratio: 0.75

(95% CI: 0.55, 1.02)Hazard ratio: 0.65

(95% CI: 0.50, 0.85)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

2-year

PFS

2-year

PFS

40%

30%

42%

25%

Ld

ELd

Ld

ELd

Key Adverse Events Reported in ≥30% of Patients

Adverse event, n (%)

E-Ld (n=318) Ld (n=317)

Any

grade

Grade

3/4

Any

grade

Grade

3/4

Common non-hematologic adverse events

Fatigue 149 (47) 27 (9) 123 (39) 26 (8)

Pyrexia 119 (37) 8 (3) 78 (25) 9 (3)

Diarrhea 149 (47) 16 (5) 114 (36) 13 (4)

Constipation 113 (36) 4 (1) 86 (27) 1 (0.3)

Muscle spasms 95 (30) 1 (0.3) 84 (27) 3 (1)

Cough 100 (31) 1 (0.3) 57 (18) 0

Common hematologic toxicities

Lymphopenia 316 (99) 244 (77) 311 (98) 154 (49)

Neutropenia 260 (82) 107 (34) 281 (89) 138 (44)

Infections 259 (81) 89 (28) 236 (74) 77 (24)

• Exposure-adjusted infection rate was 197 (incidence rate per 100 person–years of exposure) in both arms

• There was no detriment to overall health-related quality of life with the addition of Elo to Ld

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

1/2Grade 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

Summary and Conclusions

• Elotuzumab is a novel immunostimulatory monoclonal antibody (mAb) with a dual

mechanism of action elicited via natural killer cells

• In relapsed and refractory patients, in combination with Len/Dex, elotuzumab

demonstrated a significant and clinically meaningful increase in PFS and ORR

– 30% reduction in the risk of progression or death compared with Len/Dex alone

– Difference in PFS was greater at 2 years for E-Ld compared with Ld

– Benefit for PFS in elotuzumab group was consistent across key subgroups, including

elderly and high risk patients

– Absolute difference in overall response rate favored elotuzumab group

• Elotuzumab in combination with Len/Dex did not increase the incidence of adverse events

compared to Len/Dex alone

• Elotuzumab is the first mAb demonstrating PFS benefit in combination with Len/Dex in a

large randomized phase 3 study in RRMM

My Take - Elotuzumab

• No single agent activity, but unique mechanism of action

• True “immune effect” of tail of durable response yet to be fully proven

• Limited now by need of lenalidomide –future use with pomalidomide could be important

• Results with bortezomib less impressive

Treatment sequence in Myeloma

Induction Consolidation

Front line treatment

Post

consolidation

Maintenance

Rescue

Relapsed

NewCarfilzomib Combos

“more” induction

Lenalidomide 2 mths? Ixazomib

Oprozomib

Isatuximab

Bendamustine

PD/PDL-1 Inhibition

++++++++

Now

VD

Rev/Dex

CyBorD

VTD

VRD

SCTNothing

Thalidomide?

Bortezomib

Lenalidomide

Bortezomib

Lenalidomide

Thalidomide

Carfilzomib

Pomalidomide

Panobinostat

Daratumumab

Ixazomib

Elotuzumab

The Future of Myeloma

• Other Conventional Chemo (Bendamustine, DPACE)

• Others?

• Steroids• Doxorubicin, Panobinostat, Steroids

Proteasome Inhibitors

(Bortezomib, Carfilzomib, Ixazomib…)

Immuno-modulatory

Agents (Thalidomide, Lenalidomide, Pomalidomide)

Alkylators(melphalan,

cyclophospha-mide)

Monoclonal Antibodies

(Elotuzumab, Daratumumab,

Isatuximab)

Mayo Stratification for Myeloma And Risk-adapted Therapy

Relapsed Myeloma

mSMART

v3 //last reviewed Dec 2015

mSMART 2.0: Classification of Relapsed MM

Relapse <12 months from transplant or progression within first year of diagnosis

FISH Del 17p t(14;16) t(14;20)

High risk GEP

All others including:

Trisomies

t(11;14)

t(6;14)

FISH t(4;14)

1q gain

High PC S-phase

High-Risk Intermediate-Risk Standard-Risk

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin

Proc 2013;88:360-376.


• KRd, carfilzomib, lenalidomide, dexamethasone

• KPd, carfilzomib, pomalidomide, dexamethasone

• CyBorD, cyclophosphamide, bortezomib, dexamethasone

• IRd, ixazomib, lenalidomide, dexamethasone

• ICd, ixazomib, cyclophosphamide, dexamethasone

• Rd-Elo, lenalidomide, dexamethasone, elotuzumab

• Pom-dex, pomalidomide, dexamethasone

• PVd, pomalidomide, bortezomib, dexamethasone

• Dara, daratumumab

Abbreviations for Major Regimens


ICd if Rev

maintenance*

IRd or Rd-Elo if Vel

maintenance*

KPd or CyBord if

Rev maintenance*

KRd or KPd if Vel

maintenance*

Indolent Relapse

or Frail patients

Fit PatientsFit Patients

On maintenance

Indolent Relapse

or Frail patients

Off-therapy/ Unmaintained

*Consider salvage auto SCT in patients eligible for ASCT who have not

had transplant before; Consider 2nd auto SCT if eligible and >18 months

unmaintained or >36 months maintained response to first auto;

First Relapse Off-Study


IRd or Rd-Elo*KRd*

Not Plasma Cell Leukemia (PCL) or Similar extramedullary disease (EMD)

Second or later Relapse* Off-Study

Dual-Refractory

(Bortezomib and

Lenalidomide)**

Triple-Refractory

(Bortezomib, Lenalidomide

and Carfilzomib)**

Triple-Refractory

(Bortezomib, Len, and

Pomalidomide)**

Pom-Dex plus daratumumab Dara-based regimen; or

Alkylator-based regimen if

alkylator naïve; or

Proteasome inhibitor plus

panobinostat

* If single refractory, refer to First Relapse algorithm; **Auto transplant is an option, if transplant

candidate and feasible


Second or later Relapse – Off-Study

Quadruple-refractory (Lenalidomide, Pomalidomide, Bortezomib,

and Carfilzomib)

VDT-PACE* x 2 cycles if possible.*

Auto transplant if transplant candidate; if not, treat with regimens that the patient is not

known to be refractory to (eg., daratumumab-containing regimen; KRd, KPd, IRd, or PVd -

plus moAB; panobinostat-containing regimen; bendamustine; alkylator-containing

combination if not alkylator refractory; or anthracycline containing regimen such as RAD,

VDD, PAD, or CHOP)

*CVAD or similar regimen can be used in place of VDT-PACE in older patients or patients with poor functional status


Secondary PCL or extensive EMD

VDT-PACE x 2 cycles;*

Auto transplant if transplant candidate; if not maintain with one of the regimens listed

that the patient is not known to be refractory to (eg., daratumumab-containing

regimen; KRd, KPd, IRd, or PVd - plus moAB; alkylator-containing combination if not

alkylator refractory; or anthracycline containing regimen such as RAD, VDD, PAD, or

CHOP)

Second or later Relapse – Off-Study

*CVAD or similar regimen can be used in place of VDT-PACE in older patients or patients with poor functional status


Conclusions

• Therapy for myeloma has radically changed in the last year with more options

• Monoclonal antibody therapy has become a critical aspect of relapsed therapy but likely across the spectrum of therapy soon

• Oral proteasome inhibition can now be delivered orally with reduced toxicity

• Optimal combinations and sequencing of therapy have yet to be determined but the ability to individualize therapy is truly here

Mayo Clinic Myeloma Consultants

Rochester

• V. Rajkumar, MD

• Francis Buadi, MD

• David Dingli, MD

• Angela Dispenzieri, MD

• Morie Gertz, MD

• Suzanne Hayman, MD

• Shaji Kumar, MD

• Robert Kyle, MD

• Nelson Leung, MD

• John Lust, MD

• Steve Russell, MD

• Steven Zeldenrust, MD

• Prashant Kapoor, MD

• Wilson Gonsalves, MD

• Yi Lin, MD, PhD

• Martha Lacy, MD

Arizona

•Joseph Mikhael, MD

•Leif Bergsagel, MD

•Rafael Fonseca, MD

•Craig Reeder, MD

•Keith Stewart, MD

Florida

•Vivek Roy, MD

•Asher Chanan Khan, MD

•Taimur Sher, MD

•Sikander Ailawadhi, MD

MSMART.org

three novel agents in a month in myelomaazmyelomanetwork.org/wp-content/uploads/2016/03/3...mar 03,...

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