5th Annual Symposium on Current Strategies in the Management of B-cell Lymphomas, T-cell Lymphomas,

Multiple Myeloma and LeukemiaProgram Director

Fredrick B. Hagemeister, MDProfessor of Medicine,

Department of Lymphoma/ Myeloma, Division of Cancer Medicine,University of Texas MD Anderson Cancer Center, Houston, TX

Jointly provided by

Educational Grants - This activity is supported by education grants from: Amgen, Inc., Novartis Pharmaceutical Corporation, Celgene Corporation

Pfizer and Seattle Genetics, Inc.

To view full slide handouts, visit www.cancernetus.com/june11

Saturday, June 11, 2016Hyatt Regency Houston/Galleria2626 Sage Road • Houston, TX 77056Phone (832) 802-1234

2

Statement of Need/Program OverviewThis symposium is intended to improve care of patients with hematological malignancies by accelerating adoption of new guidelines and evidence-based practice change. The format will include didactic lectures from known opinion leaders, question and answer sessions, and ample opportunity for participant interaction with faculty.

Target AudienceThis symposium is directed primarily to hematologists/oncologists, radiation oncologists, researchers, pharmacists, registered nurses, physician assistants, nurse practitioners and fellows in training interested in new development in hematological malignancies. No specific skill or knowledge other than a basic training in hematology/oncology is required for successful participation in this activity.

Learning ObjectivesAfter completing this activity, the participant should be better able to:• Explain the treatment options for diffuse large B-cell lymphoma (DLBCL) • Explain the treatment options for follicular lymphoma (FL)• Evaluate the treatment options for chronic lymphocytic lymphoma (CLL) • Evaluate the treatment options for mantle cell lymphoma (MCL)• Cite the novel treatment options for peripheral T-cell lymphomas (PTCL)• Describe the role of risk stratification and upfront therapies in multiple myeloma• Appraise novel approaches in the treatment of relapsed and refractory multiple myeloma• Describe the role of maintenance therapy in the management of multiple myeloma • Describe emerging novel therapeutic pathways for multiple myeloma• Identify updates in the treatment of chronic myelogenous leukemia (CML)• Select appropriate treatment options for myelodysplastic syndromes (MDS)

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5th Annual Symposium on Current Strategies in the Management of B-cell Lymphomas, T-Cell Lymphomas, Multiple Myeloma and Leukemia

AgendaSATURDAY – June 11, 2016

7:00 AM Breakfast and Registrations

7:55 AM Welcome and Introductions Fredrick B. Hagemeister, MD

LYMPHOMA (HL, NHL, T-cell Lymphomas)

8:00 AM Overview of Treatment Options for Diffuse Fredrick B. Hagemeister, MD

Large Cell Lymphoma (DLCL)

8:30 AM Overview of Treatment Options for Follicular Lymphoma (FL) Nathan Fowler, MD

9:00 AM Overview of Treatment Options for Chronic Frederick B. Hagemeister, MD

Lymphocytic Leukemia (CLL)

9:30 AM Overview of Treatment Options for Mantle Cell Lymphoma (MCL) Hun Ju Lee, MD

10:00 AM BREAK

10:15 AM Overview of Treatment Options for Peripheral Michelle Fanale, MD

and Cutaneous T-cell Lymphoma

10:45 AM Case Report and Panel Discussion Fredrick B. Hagemeister, MD/

Nathan Fowler, MD/Hun Ju Lee, MD/ Michelle Fanale, MD

MULTIPLE MYELOMA

11:00 AM Updates in the Management of Transplantation-Eligible Robert Orlowski, MD, PhD

Patients With Newly Diagnosed Myeloma

11:30 AM Recent Approaches in the Treatment of Relapsed and Keith Stewart, MD

Refractory Multiple Myeloma

12:00 PM Maintenance Therapy in the Management of Elisabet Manasanch, MD

Multiple Myeloma

12:30 PM LUNCH

1:30 PM New Drugs and Clinical Trials in Multiple Myeloma Keith Stewart, MD

2:00 PM Case Report and Panel Discussion Robert Orlowski, MD, PhD/

Keith Stewart, MD/ Elisabet Manasanch, MD

LEUKEMIA (CML, MDS)

2:15 PM Overview of Therapeutic Options for Guillermo Garcia-Manero, MD

Myeloproliferative Neoplasms (CML)

2:45 PM BREAK

3:00 PM Overview of Therapeutic Options for Guillermo Garcia-Manero, MD

Myelodysplastic Syndromes (MDS)

3:30 PM Case Report and Panel Discussion Guillermo Garcia-Manero, MD/

Fredrick B. Hagemeister, MD

3:45 PM Closing Remarks and Adjourn Fredrick B. Hagemeister, MD

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Faculty

Michelle A. Fanale, MDAssociate Professor, Department of Lymphoma/ Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Nathan H. Fowler, MDAssociate Professor, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX

Guillermo Garcia-Manero, MDProfessor of Medicine, Chief, Section of MDS, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

Fredrick B. Hagemeister, MDProfessor of Medicine, Department of Lymphoma/ Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Hun Ju Lee, MDAssistant Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Elisabet E. Manasanch, MDAssistant Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Robert Orlowski, MD, PhDProfessor of Medicine, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Keith Stewart, MDDean for Research, Polak Professor of Cancer Research, Mayo Clinic in Arizona, Scottsdale, AZ

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5th Annual Symposium on Current Strategies in the Management of B-cell Lymphomas, T-Cell Lymphomas, Multiple Myeloma and Leukemia

Disclosure of Relevant Financial RelationshipsThe A. Webb Roberts Center for Continuing Medical Education of Baylor Health Care System (AWRC) and American Health Resources, Inc, assess conflicts of interest with its instructors, planners, managers and other individuals who are in a position to control the content of CME activities. All relevant financial relationships are identified and conflicts of interest are resolved prior to the activity to ensure fair balance, scientific objectivity of studies utilized in this activity, and validity of patient care recommendations. AWRC is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity:

Name Conflict of Interest DisclosuresMichelle A. Fanale, MD Speaker’s Bureau: Takeda, Celgene, Spectrum, Seattle

Genetics Advisory Board: Celgene, Spectrum, BMS, MERCK, Seattle Genetics

Nathan H. Fowler, MD Consultant: Celgene, Roche, Pharmacyclics, AbbVie

Guillermo Garcia-Manero, MD No relevant financial relationshipsFredrick B. Hagemeister, MD Consultant: Genentech, GileadHun Ju Lee, MD No relevant financial relationshipsElisabet E. Manasanch, MD No relevant financial relationships

Robert Orlowski, MD, PhD Advisory Board: Array Biopharma, BMS, Celgene, FORMA Therapeutics, Janssen, MPI/Takeda, Onyx/AmgenResearch Support: BMS, Celgene, MPI/Takeda, Onyx/Amgen, Spectrum Pharma

Keith Stewart, MD Consultant: Celgene, NovartisAdvisory Board: BMS

Name Conflict of Interest DisclosuresKamatham A. Naidu, PhD No relevant financial relationships

All other individuals in a position to control content have no relevant financial relationships to disclose.

Overview of Treatment Options for Diffuse Large Cell Lymphoma (DLCL)

Fredrick B. Hagemeister, MD

Overview of Treatment Options for Follicular Lymphoma (FL)

Nathan Fowler, MD

Overview of Treatment Options for Chronic Lymphocytic Leukemia (CLL)

Frederick B. Hagemeister, MD

Overview of Treatment Options for Mantle Cell Lymphoma (MCL)

Hun Ju Lee, MD

Overview of Treatment Options for Peripheral and Cutaneous T-cell Lymphoma

Michelle Fanale, MD

Updates in the Management of Transplantation-Eligible Patients With Newly

Diagnosed Myeloma

Robert Orlowski, MD, PhD

Recent Approaches in the Treatment of Relapsed and Refractory Multiple

Myeloma

Keith Stewart, MD

Relapsed Myeloma

A. Keith Stewart Mayo Clinic in Arizona

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Conflict of Interest Disclosure

Consultant: Celgene, Novartis

Advisory Board: Bristol-Myers Squibb

Case

• 69 yo retired nurse with IgG multiple myeloma

• Hgb 92 and lytic lesions, Creatinine and calcium normal

• Albumin 3.8 and 2m 5.8, so ISS stage III

• FISH trisomy 9 with 1q+ amplification

Treatment• Received RVD for 4 months with grade 1 neuropathy the only toxicity

• Autologous stem cell transplant complicated by hypotensive episode of sepsis with renal injury

• Maintenance lenalidomide (10 mg) given for 17 months – mild fatigue and daily diarrhea x 2

• On maintenance, a rising M-protein but asymptomatic. Creatinine is 182

• What would you recommend?

1960-651965-701970-751975-801980-851985-901990-951995-002000-052005-10

Improving Survival in MM

25% of patients live less than 3 years

Factors in Selecting Relapse Therapy

Age

Performance StatusRenal InsufficiencyPoor Marrow Reserve

NeuropathyOther comorbidities - Cardiac- Diabetes

Risk Status

Rapidity of Relapse- Rate of rise- Organ damage

- Extra-medullaryPrevious Therapy- Depth- Duration

Mode of AdministrationDoublet or TripletCost Toxicity

- Myelosuppression- Neuropathy- Thrombosis

Risk of SPM

PATIENT DISEASE TREATMENT

Factors in Selecting Relapse Therapy

Age

Performance StatusRenal InsufficiencyPoor Marrow Reserve

NeuropathyOther comorbidities - Cardiac- Diabetes

Risk Status

Rapidity of Relapse- Rate of rise- Organ damage

- Extra-medullaryPrevious Therapy- Depth- Duration

Mode of Administration

Doublet or TripletCost Toxicity- Myelosuppression

- Neuropathy- ThrombosisRisk of SPM

PATIENT DISEASE TREATMENT

1School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 2University of Nantes, Nantes, France; 3University of Torino, Torino, Italy; 4Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; 5University Hospital Brno, Brno, Czech Republic; 6University Hospital Brno and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; 7CHRU Lille Hôpital Claude Huriez, Lille, France; 8Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria; 9Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain; 10Heidelberg Medical University, Heidelberg, Germany; 11Hospital Clínic de Barcelona, Barcelona, Spain; 12Vseobecna fakultni nemocnice v Praze, Prague, Czech Republic; 13Hematological Department, First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia; 14Department of Hematooncology, University Hospital Olomouc, Olomouc, Czech Republic; 15Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; 16Universitatsklinikum Tubingen, Tubingen, Germany; 17Hematology Clinic University Multiprofile Hospital for Active Treatment, Plovdiv, Bulgaria; 18Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA; 19National University Cancer Institute, National University Health System, Singapore and Cancer Science Institute, National University of Singapore, Singapore

Carfilzomib and Dexamethasone vs Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma: Results From the Phase 3 Study ENDEAVOR

Meletios A. Dimopoulos,1 Philippe Moreau,2 Antonio Palumbo,3 Douglas Joshua,4 Ludek Pour,5 Roman Hájek,6Thierry Facon,7 Heinz Ludwig,8 Albert Oriol,9 Hartmut Goldschmidt,10 Laura Rosiñol,11 Jan Straub,12 Aleksandr Suvorov,13 Tomas Pika,14 Gianluca Gaidano,15 Katja Weisel,16 Vesselina Goranova-Marinova,17 Heidi Gillenwater,18 Wee-Joo Chng,19 on behalf of the ENDEAVOR investigators

ENDEAVOR Study Design

9

Vd

Bortezomib 1.3 mg/m2 (IV bolus or subcutaneous injection)

Days 1, 4, 8, 11

Dexamethasone 20 mg

Days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycles until PD or unacceptable toxicity

Kd

Carfilzomib 56 mg/m2 IV

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

Infusion duration: 30 minutes for all doses

Dexamethasone 20 mg

Days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycles until PD or unacceptable toxicity

Randomization 1:1

N=929

Stratification:

• Prior proteasome inhibitor therapy

• Prior lines of treatment

• ISS stage

• Route of V administration

ISS, International Staging System; IV, intravenous; Kd, carfilzomib and dexamethasone; PD, progressive disease; Vd, bortezomib and dexamethasone; V, bortezomib.

Primary End Point: Progression-Free Survival Intent-to-Treat Population (N=929)

10

1.0

0.8

0.6

0.4

0.2

0

Pro

port

ion

Sur

vivi

ng

With

out

Pro

gres

sion

0

Months Since Randomization

KdVd

Kd(n=464)

171 (37)18.7

Vd(n=465)

243 (52)9.4

0.53 (0.44–0.65)1-sided P<0.0001

Disease progression or death – n (%)Median PFS – months

HR for Kd vs Vd (95% CI)

CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; Kd, carfilzomib and dexamethasone; PFS, progression-free survival; Vd, bortezomib and dexamethasone.

• Median follow-up: 11.2 months

6 12 18 24 30

Less Common AEs of InterestSafety Population (n=919)

AE, %

Kd (n=463) Vd (n=456)

All grade Grade ≥3 All grade Grade ≥3

Acute renal failure* 8 4 5 3

Cardiac failure* 8 5 3 1.8

Ischemic heart disease* 3 1.7 2.0 1.5

Deep vein thrombosis 4 0.9 0.9 0.4

Pulmonary embolism 3 1.7 0.9 0.9

Pulmonary hypertension* 1.3 0.6 0.2 0.2

Conclusions

ENDEAVOR is the first head-to-head study comparing 2 proteasome inhibitors

Kd resulted in a 2-fold decrease in the risk of progression or death compared with Vd

‒Median PFS of 18.7 months (Kd) vs 9.4 months (Vd)

ORR was significantly higher with Kd than Vd (77% vs 63%)

‒Twice as many patients achieved a complete response (13% vs 6%) or a very good partial response or better (54% vs 29%)

Rates of grade ≥3 hypertension (9% vs 3%), dyspnea (5% vs 2.2%), and cardiac failure (5% vs 1.8%) were higher in the Kd group compared with the Vd group

Grade ≥2 PN rates were significantly lower in the Kd group than in the Vdgroup (6% vs 32%)

The evidence

At least five recent randomized Phase 3 trials support triplet therapy

IFM2005-04: VTD vs VDASPIRE: KRd vs RdTOURMALINE-MM1: IRd vs RdELOQUENT-2: ERd vs RdPANORAMA: PanVd vs Vd

Overall Response Rates in Trials of Triplet Regimens

78.371.5

0

20

40

60

80

100

IRd(N = 360)

Rd(N = 362)

TOURMALINE‐MM12

78.5

65.5

0

20

40

60

80

100

ERd(N = 321)

Rd(N = 325)

ELOQUENT‐23

60.754.6

0

20

40

60

80

100

PanVd(N = 387)

Vd(N = 381)

PANORAMA4

87.1

66.7

0

20

40

60

80

100

KRd(N = 396)

Rd(N = 396)

Overall response rate (%

)

ASPIRE1

Relapsed and/or refractory multiple myeloma (1–3 prior treatments)

Best Response Reported PFS in Trials of Triplet Regimens

26.3

17.6

0

10

20

30

KRd(N = 396)

Rd(N = 396)

Median PFS (months)

ASPIRE1

20.6

14.7

0

10

20

30

IRd(N = 360)

Rd(N = 362)

TOURMALINE‐MM12

19.4

14.9

0

10

20

30

ERd(N = 321)

Rd(N = 325)

ELOQUENT‐23

12.0

8.1

0

10

20

30

PanVd(N = 387)

Vd(N = 381)

PANORAMA4

Relapsed and/or refractory multiple myeloma (1–3 prior treatments)

CARF-NP-KR-001-DEC

Overall Survival Triplet vs. Doublet Trials

• Although data are immature - trends in favor of improved OS are seen

0

10

20

30

40

50

60

70

80

Eloquent IFM2005 Aspire Panorama

Triplet %

Doublet %

p=0.026         p=0.093                   p= 0.04*               p=0.54  

Adverse Events and Treatment Discontinuations

ASPIRE1,2 TOURMALINE-MM13 ELOQUENT-24 PANORAMA5

KRd(N = 392)

Rd (N = 389)

IRd(N = 360)

Rd(N = 362)

ERd(N = 318)

Rd (N = 317)

PanVd(N = 381)

Vd(N = 377)

Grade ≥ 3 AEs

83.7% 80.7% 68% 61% NR NR 96% 82%

Serious AEs 59.7% 53.7% 40% 44% 65% 57% 60% 42%

Discontinuation due toAEs

15% 18% 13% 11% 9% 13% 36% 20%

19

Carfilzomib, Lenalidomide, and Dexamethasone vsLenalidomide and Dexamethasone in Patients with

Relapsed Multiple Myeloma: Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter Phase 3 Study

A. Keith Stewart, S. Vincent Rajkumar, Meletios A. Dimopoulos, Tamás Masszi, Ivan Spicka, Albert Oriol, Roman Hájek, Laura Rosiñol, David S. Siegel, Georgi G. Mihaylov, Vesselina

Goranova-Marinova, Péter Rajnics, Aleksandr Suvorov, Ruben Niesvizky, Andrzej Jakubowiak, Jesus F. San Miguel, Heinz Ludwig, Naseem Zojwalla, Margaret E. Tonda, Biao

Xing, Philippe Moreau and Antonio Palumbo

ASPIRE Study Design

20

RdLenalidomide 25 mg Days 1–21

Dexamethasone 40 mg Days 1, 8, 15, 22

KRdCarfilzomib 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

N=792

Stratification:

• β2-microglobulin

• Prior bortezomib

• Prior lenalidomide

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

After cycle 18, carfilzomib discontinued

28-day cycles

Secondary Endpoints: Response

31.8

69.9

87.1

9.3

40.4

66.7

0

10

20

30

40

50

60

70

80

90

100

≥CR ≥VGPR ORR (≥PR)

KRd

Rd

Per

cent

age

of P

atie

nts

21

P<.0001

P<.0001

sCR14.1% vs 4.3%

P<.0001

Median duration of response was 28.6 months in the KRd group and 21.2 months in

the Rd group

Primary Endpoint: Progression-Free SurvivalITT Population (N=792)

22

1.0

0.8

0.6

0.4

0.2

0.0

Pro

port

ion

Sur

vivi

ngW

ithou

t Pro

gres

sion

KRdRd

0 6 12 18 24 30 36 42 48Months Since Randomization

KRd Rd(n=396) (n=396)

Median PFS, mo 26.3 17.6HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83)P value (one-sided) <0.0001

No. at Risk:KRd

Rd396 332 279 222 179 112 24 1396 287 206 151 117 72 18 1

Cycle 1(Baseline)

Cycle 3 Cycle 6 Cycle 12 Cycle 18

Health-related Quality of Life

Carfilzomib is an investigational product and is not licensed in the EU.EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Core Module. Suppl. to Stewart AK, et al. N Engl J Med 2015;372:142–52.

EO

RT

C Q

LQ-C

30 g

loba

l hea

lth s

tatu

s/qu

ality

of

life

scor

e

0

60

20

50

40

30

10

70

Carfilzomib groupControl group

EORTC Global Health Status improved in the

KRd group

vs the Rd group over 18 cycles of treatment (P

= 0.0001)

Adverse Events (AEs), Treatment Discontinuations, and Deaths

24

CategoryKRd

(n=392)

Rd

(n=389)

Any AE, %

Grade ≥3 treatment-emergent AE

96.9

83.7

97.2

80.7

Deaths within 30 days of last dose, %

Deaths due to disease progression

Deaths due to AEs

7.7

0.5

6.9

8.5

1.3

6.9

Serious AE, % 59.7 53.7

Median treatment duration, weeks (range) 88.0 57.0

Treatment discontinuations, %

Discontinuation due to disease progression

Discontinuation due to AE

69.9

39.8

15.3

77.9

50.1

17.7

Other AEs of Interest

25

AE, %

KRd (n=392) Rd (n=389)

All Grade Grade ≥3 All Grade Grade ≥3

Dyspnea 19.4 2.8 14.9 1.8

Peripheral neuropathy* 17.1 2.6 17.0 3.1

Hypertension 14.3 4.3 6.9 1.8

Acute renal failure* 8.4 3.3 7.2 3.1

Elevated creatinine 6.6 1.0 4.6 0.3

Cardiac failure* 6.4 3.8 4.1 1.8

Deep vein thrombosis 6.6 1.8 3.9 1.0

Ischemic heart disease* 5.9 3.3 4.6 2.1

Pulmonary embolism 3.6 3.1 2.3 2.3

Second primary malignancy* 2.8 2.3 3.3 2.8

*Grouped term.

Other AEs of Interest

26

AE, %

KRd (n=392) Rd (n=389)

All Grade Grade ≥3 All Grade Grade ≥3

Dyspnea 19.4 2.8 14.9 1.8

Peripheral neuropathy* 17.1 2.6 17.0 3.1

Hypertension 14.3 4.3 6.9 1.8

Acute renal failure* 8.4 3.3 7.2 3.1

Elevated creatinine 6.6 1.0 4.6 0.3

Cardiac failure* 6.4 3.8 4.1 1.8

Deep vein thrombosis 6.6 1.8 3.9 1.0

Ischemic heart disease* 5.9 3.3 4.6 2.1

Pulmonary embolism 3.6 3.1 2.3 2.3

Second primary malignancy* 2.8 2.3 3.3 2.8

*Grouped term.

Other AEs of Interest

27

AE, %

KRd (n=392) Rd (n=389)

All Grade Grade ≥3 All Grade Grade ≥3

Dyspnea 19.4 2.8 14.9 1.8

Peripheral neuropathy* 17.1 2.6 17.0 3.1

Hypertension 14.3 4.3 6.9 1.8

Acute renal failure* 8.4 3.3 7.2 3.1

Elevated creatinine 6.6 1.0 4.6 0.3

Cardiac failure* 6.4 3.8 4.1 1.8

Deep vein thrombosis 6.6 1.8 3.9 1.0

Ischemic heart disease* 5.9 3.3 4.6 2.1

Pulmonary embolism 3.6 3.1 2.3 2.3

Second primary malignancy* 2.8 2.3 3.3 2.8

*Grouped term.

Other AEs of Interest

28

AE, %

KRd (n=392) Rd (n=389)

All Grade Grade ≥3 All Grade Grade ≥3

Dyspnea 19.4 2.8 14.9 1.8

Peripheral neuropathy* 17.1 2.6 17.0 3.1

Hypertension 14.3 4.3 6.9 1.8

Acute renal failure* 8.4 3.3 7.2 3.1

Elevated creatinine 6.6 1.0 4.6 0.3

Cardiac failure* 6.4 3.8 4.1 1.8

Deep vein thrombosis 6.6 1.8 3.9 1.0

Ischemic heart disease* 5.9 3.3 4.6 2.1

Pulmonary embolism 3.6 3.1 2.3 2.3

Second primary malignancy* 2.8 2.3 3.3 2.8

*Grouped term.

Other AEs of Interest

29

AE, %

KRd (n=392) Rd (n=389)

All Grade Grade ≥3 All Grade Grade ≥3

Dyspnea 19.4 2.8 14.9 1.8

Peripheral neuropathy* 17.1 2.6 17.0 3.1

Hypertension 14.3 4.3 6.9 1.8

Acute renal failure* 8.4 3.3 7.2 3.1

Elevated creatinine 6.6 1.0 4.6 0.3

Cardiac failure* 6.4 3.8 4.1 1.8

Deep vein thrombosis 6.6 1.8 3.9 1.0

Ischemic heart disease* 5.9 3.3 4.6 2.1

Pulmonary embolism 3.6 3.1 2.3 2.3

Second primary malignancy* 2.8 2.3 3.3 2.8

*Grouped term.

Conclusions

30

PFS was significantly improved by 8.7 months with KRd (HR,

0.69; P<0.0001)

‒An unprecedented median PFS of 26.3 months with KRd

Interim OS analysis: trend in OS favoring the KRd group;

Kaplan-Meier 24-month OS rates 73.3% (KRd) versus 65.0%

(Rd)

ORR was higher with KRd (87.1% vs 66.7%); significantly

more patients achieved ≥CR (31.8% vs 9.3%)

QoL Global Health Status improved

Conclusions (continued)

31

Rates of grade ≥3 hypertension (9% vs 3%), dyspnea (5% vs 2.2%), and cardiac failure (5% vs 1.8%) were higher in the Kd group compared with the Vd group

Grade ≥2 PN rates were significantly lower in the Kd group than in the Vd group (6% vs 32%)

Although Kd patients remained on study treatment longer (40 weeks vs 27 weeks), treatment discontinuation due to AEs and on-study deaths due to AEs were comparable between groups

Kd PFS was superior to Vd regardless of age or prior bortezomib exposure

Conclusions

32

PFS was significantly improved by 8.7 months with KRd (HR,

0.69; P<0.0001)

‒An unprecedented median PFS of 26.3 months with KRd

Interim OS analysis: trend in OS favoring the KRd group;

Kaplan-Meier 24-month OS rates 73.3% (KRd) versus 65.0%

(Rd)

ORR was higher with KRd (87.1% vs 66.7%); significantly more

patients achieved ≥CR (31.8% vs 9.3%)

QoL Global Health Status improved

TOURMALINE-MM1: Phase 3 Study of Weekly Oral Ixazomib Plus Lenalidomide-dexamethasone

Ran

do

miz

atio

n

Ixazomib + Lenalidomide + DexamethasoneIxazomib: 4 mg on days 1, 8, and 15Lenalidomide: 25 mg* on days 1-21

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

N=722

1:1

Placebo + Lenalidomide + DexamethasonePlacebo: on days 1, 8, and 15

Lenalidomide: 25 mg* on days 1-21Dexamethasone: 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/practice1. 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: • PFSKey secondary endpoints: • OS • OS in patients with del(17p)

Final PFS analysis: A significant, 35% improvement in PFS withIRd 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

bab

ility

of

pro

gre

ssio

n-f

ree

surv

ival

Time from randomization (months)

Log-rank test p=0.012Hazard ratio (95% CI): 0.742 (0.587, 0.939)Number of events: IRd 129; placebo-Rd 157

Median PFS:IRd: 20.6 monthsPlacebo-Rd: 14.7 months

Median follow-up: ~15 months

Outcomes by Cytogenetic Risk Group

Median OS was not reached in either arm

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-riskpatients

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).

Conclusions: Ixazomib, the First Oral Proteasome Inhibitor, Significantly Extends PFS in a Phase 3 Trial

Ixazomib when combined with Rd for patients with relapsed and/or refractory MM was associated with:

– a significant and clinically meaningful improvement in PFS

– significantly improved TTP and response rates

– improved PFS in high-risk patients, similar to that in the overall patient population and in standard-risk patients

Ixazomib added limited additional toxicity to that seen withplacebo-Rd

– Low rates of PN and no cardiovascular or renal signals

– Patient-reported quality of life was maintained

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 Nov 20 under the name NINLARO®

ELOQUENT Study Design

• ELOQUENT-2 is an open-label, randomized, multicenter, phase 3 trial

• Statistical analysis– Threshold for interim OS significance was 0.014 based on 295/427 events required

for final analysis

Patients

• RRMM

• 1–3 prior lines of therapy

• Prior Len permitted in 10% of patients (if sensitive)

Elotuzumab plus Ld (E‐Ld): n=321

• Elo: Cycles 1 and 2 weekly, then every other week, 10 mg/kg IV

• Len: D1–21, 25 mg PO

• Dex: weekly equivalent, 40 mg

Endpoints

Co‐primary• PFS• ORR

Others• OS• Safety• Duration of response• Quality of life

Database lock: November 2014 (ASCO/EHA 2015)Primary analysis

Database lock: August 2015 (ASH 2015)  

Extended follow‐up

June 2011 start

Premedication administered prior to elotuzumab infusion to mitigate infusion reactions 

Len/Dex (Ld): n=325

• Len: D1–21, 25 mg PO

• Dex: weekly, 40 mg PO

Elotuzumab: ImmunostimulatoryMechanism of Action

• Elotuzumab is an immunostimulatory monoclonal antibody that recognizes SLAMF7, a protein highly expressed by myeloma and natural killer cells1

• Elotuzumab causes myeloma cell death via a dual mechanism of action2

1. Hsi ED et al. Clin Cancer Res 2008;14:2775–84; 2. Collins SM et al. Cancer Immunol Immunother 2013;62:1841–9.ADCC=antibody‐dependent cell‐mediated cytotoxicity; SLAMF7=signaling lymphocytic activation molecule F7

Directly activating natural killer cells

A

Tagging for recognition (ADCC)

B

EAT-2Downstreamactivatingsignalingcascade

Perforin,granzyme Brelease

Elotuzumab

Natural killer cell

SLAMF7

Myeloma cellMyelomacell

Degranulation

Downstreamactivating signalingcascade

EAT‐2SLAMF7

Polarization

Natural killer cell

Granule synthesis

Myelomacell death

Extended Progression-Free Survival

E‐Ld Ld

HR 0.73 (95% CI 0.60, 0.89); p=0.0014

Median PFS (95% CI)

19.4 mos(16.6, 22.2)

14.9 mos(12.1, 17.2)

PFS benefit with E‐Ld was maintained over time (vs Ld):• Overall 27% reduction in the risk of disease progression or death• Relative improvement in PFS of 44% at 3 years

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

480 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

No. of patients at risk:E‐LdLd

321325

293266

259215

227181

171130

144106

12580

10767

9460

8551

5936

3415

197

83

PFS (months)

Probab

ility progression free

30

195157

E‐Ld

Ld0.1

1‐year PFS 2‐year PFS 3‐year PFS

00

68%

41%

26%

57%

27%

18%

ELOQUENT‐2

Interim Overall Survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

510 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

No. of patients at risk:E‐LdLd

321325

314305

303287

291269

283255

266241

250228

239218

224208

217200

196184

190171

152134

9588

4841

1517

1‐year OS 2‐year OS

OS (months)

Probab

ility alive

53

00

E‐Ld

Ld

No. of patients at risk:

3‐year OSE‐Ld Ld

HR 0.77 (95% CI 0.61, 0.97; 98.6% CI 0.58, 1.03); p=0.0257

Median OS (95% CI)

43.7 mos(40.3, NE)

39.6 mos(33.3, NE)

Prespecified interim analysis for overall survival indicates a strong trend (p=0.0257) with early separation sustained over time for E‐Ld vs Ld

ELOQUENT‐2

Summary

• Elotuzumab, a novel immunostimulatory monoclonal antibody, in combination with Ld, demonstrated a durable and clinically relevant improvement in PFS and ORR

– Extended follow-up demonstrated a 27% reduction in the risk of progression or death compared with Ld alone (HR 0.73; p=0.0014)

– 38% fewer patients in the E-Ld vs Ld arm started a subsequent line of therapy during the follow-up period

– PFS benefits with E-Ld were consistent across key subgroups

• Interim overall survival analysis demonstrated a strong trend in favor of E-Ld vs Ld(HR 0.77; p=0.0257)

• Updated safety and tolerability data are consistent with previous findings, confirming that there is minimal incremental toxicity associated with the addition of elotuzumab to Ld

• FDA recently granted approval for the use of elotuzumab in combination with Ld in patients with multiple myeloma who have received one to three prior therapies

Pomalidomide

Pom/Dex1

1-3 reg

Pom/Dex2

Len ref

Pom+/- dex3

MM-002

Pom dose 2 mg x 28d 2 mg x 28d MTD = 4 mg 21 of 28

> PR 63% 32% 28%

> MR 82% 47% 52%

Median 3 prior regimens Median 4-6 prior regimens

Other Pomalidomide Combinations

Pts, n

Median No. Prior

Regimens ORR (%)

POM + BTZ + low-dose DEX (PVD)1 42 2.5 (1–4) 81

POM + CFZ + DEX2 72 6 (2–15) 64

POM + cyclophosphamide + prednisone3 69 3 (1–3) 41

POM + DEX + clarithromycin4 46 NR (≥3) 60

1. Lacy et al. Blood. 2014. Abstract .2. Shah JJ et al. Blood. 2013;122. Abstract 690.

3. Larocca A et al. Blood. 2013;122:2799.4. Mark TM et al. Blood. 2011;118. Abstract 635.

• Biology supports combination therapy, continuous suppressive therapy and eradication of minor clones

• Treatment @ relapse is individualized

• Carfilzomib, Ixazomib, Elotuzumab and Pomalidomide are useful therapies following Bortezomib and Lenalidomide

• Monoclonal antibody Daratumumamb as a single agents is FDA approved but likely to quickly be used in combination earlier in disease

Summary

Thank you

Maintenance Therapy in the Management of Multiple Myeloma

Elisabet Manasanch, MD

Maintenance Therapy in the Management of Multiple Myeloma

Elisabet Manasanch M.D., M.H.Sc.

Assistant Professor, Department of Lymphoma/Myeloma Division of Cancer Medicine

5th Annual Symposium on Current Strategies in the Management ofLymphoma Myeloma and Leukemia

Conflict of Interest Disclosure

Research Funding: Signal Genetics, Merck

Consulting: Novartis

Overview

Therapy options

New agents in maintenance

Question and Answer Session

Outline BackgroundFavorable results both in younger and older patients with multiple myeloma have been observed in recent years

Despite this, there is a high relapse rate after initial response to treatment

Achieving the deepest level of response and maintaining a sustained remission are important to achieve a cure in multiple myeloma

Maintenance strategies are incorporated in most phase II‐III clinical trials. Sequential treatment strategy is the modern paradigm of treatment for patients with myeloma

Long term melphalan or other alkylator agent use wasassociated with higher risk of secondary cancerslike myelodysplastic syndrome and leukemia

Interferon maintenance was first used in multiplerandomized clinical trials but failed to show abenefit for overall survival

Long term steroid use associated with long term effects

Historical PerspectiveMaintenance was first introduced as treatment after autologous stem cell transplantation

First drug to show a benefit for use in maintenance was thalidomide

Once lenalidomide and bortezomib where approved for treatment, these drugs have also been studied in the maintenance setting 

In the future, pomalidomide, ixazomib, carfilzomib and monoclonal antibodies might also be used

Historical Perspective

Overview

Therapy Options

New agents in maintenance

Questions

OutlineThalidomide

Brioli et al. Expert Rev. Anticancer Ther. 2014.

6/7 trials showed a benefit for progression free survival

Patients that were receiving thalidomide after transplantwere in remission longer

2/7 trials also showed a significant increase in benefitfor overall survival

Thalidomide Lenalidomide

4 clinical trials have been completed using lenalidomide in the maintenance setting 

3 of these trials are after autologous transplantation

4/4 trials show that lenalidomide maintenance prolonged remission

2/4 trials show that lenalidomide maintenance also improved overall survival

CALGB 100104

McCarthy et al. NEJM. 2012

CALGB 100104

McCarthy et al. NEJM. 2012

IFM 05‐02

IFM 05‐02Lenalidomide maintenance

Attal et al. NEJM. 2012

Follow up analysis of PFS and OSAfter second relapse shows something different

Attal et al. ASH 2013.

May be lenalidomide maintenanceis associated with chemoresistance

MM‐015

Study of second line therapies was limited due to the type of analysis

Second line time to progression was similar among all arms of the study

Use of MPR‐R did not induce resistant relapses

Lenalidomide Maintenance in MM:Meta‐analysis of Randomized Trials

Singh et al. ASH. 2013

Outcome: HR for death; len vs no maintenance(<1 implies better outcome with len)

HOVON‐65/GMMG‐HD4

Sonneveld et al. ASH. 2013

EVALUATION OF BORTEZOMIB AS MAINTENANCE

Newly diagnosed multiple myeloma

Update with long term follow up

Comparison with thalidomide as maintenance option

HOVON‐65/GMMG‐HD4

In this trial, bortezomib may be a superior maintenance than thalidomide

VMPT‐VT versus VMP

Palumbo et al. ASH 2012 and JCO. 2010

Newly diagnosed non‐transplant eligible patients

Secondary Malignancies

Reported: small increased risk of secondary malignancies with the use of lenalidomide maintenance when compared to patients who did not receive this maintenance

Secondary Malignancies

Landgren et al. Leukemia. 2014

Secondary Malignancies

Landgren et al. Leukemia. 2014

Secondary Malignancies

Palumbo et al. Lancet Oncol. 2014

Risk of hematologic2ary malignancies is associated with prior use of oral melphalan

Duration of Maintenance

Mian et al. ASH. 2014

<4 months ≥ 4 months

Duration of Maintenance

Longer might be better?

Currently, it is not clear IF patients should stop maintenance after2‐3 years of therapy and more long term follow up data is needed,specially from conducted randomized phase III studies

Several meta‐analysis have been done on efficacy. Most meta‐analysis showthat overall there is a statistical improvement in PFS but not in OS*

Evaluation of level of disease (no evidence of disease vs residual disease),patient preference and tolerance to lenalidomide (quality of life, cytopenias,thrombosis) should be taken into account when making a decision of whether to stop maintenance or not

*Wang et al. JNC. 2015.

Overview

Therapy options

New agents in maintenance

Question and Answer Session

Outline Oral Proteasome Inhibitors/Antibodies

•Ixazomib versus placebo following ASCT and after initial therapy without ASCT

Randomized phase III

• Ixazomib/Len/Dex versus Len/Dex (2 years)  post ASCT

Randomized phase III

• Ixazomib/Lenalidomide/dex consolidation following ASCT followed by Len vs Ixa maintenance (3 years)

Randomized phase II

• Ixa+Len following ASCT (continue until progression or toxicity)

Single arm phase II

•Elotuzumab/Lenalidomide post ASCT (until progression or toxicity) 

Single arm phase II

Oral Proteasome InhibitorsTOURMALINE MM3: Phase III randomized study of Ixazomib versus placebo following ASCT

Gupta N et al. Invest New Drugs. 2016.

Primary endpoint PFS

652 patients

Oral Proteasome InhibitorsTOURMALINE MM4: Phase III randomized study of Ixazomib versus placebo afterinitial treatment in patients who have not undergo autoSCT as initial therapy

Gupta N et al. Invest New Drugs. 2016.

Primary endpoint PFS

761 patients

Patients must have completed 6–12 months of initial standard‐of‐care therapy with a response of PR or better, and be randomized no later than 60 days after the last dose of initial therapy.

PATIENTS and their FAMILIES

Community (physicians/support‐patient groups)

Questions

Elisabet Manasanch

eemanasanch@mdanderson.org

Robert Z. Orlowski, Donna Weber, Jatin Shah, Sheeba Thomas, Hans Lee

MDACC Myeloma Center

5th Annual Symposium on Current Strategies in the Management of Lymphoma, Myeloma and Leukemia

Thank you

Elisabet Manasanch M.D., M.H.Sc.

Assistant Professor, Department of Lymphoma/Myeloma Division of Cancer Medicine

5th Annual Symposium on Current Strategies in the Management of, Lymphoma Myeloma and Leukemia

New Drugs and Clinical Trials in Multiple Myeloma

Keith Stewart, MD

New Agents in Multiple Myeloma

A. Keith Stewart Mayo Clinic in Arizona

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Conflict of Interest Disclosure

Consultant: Celgene, Novartis

Advisory Board: Bristol-Myers Squibb

Patient Course

• The patient is treated with carfilzomib and Pomalidomidewith dexamethasone

Patient Course

• The patient is treated with carfilzomib and Pomalidomidewith dexamethasone

• She becomes febrile and dyspneic on day 2 of therapy, her urine output drops she attends the ER and her creatinine is up to 274, BP is 182/102

• Carfilzomib is discontinued and she remains on Pomalidomide and dexamethasone but does not respond

Patient Course

• The patient is intolerant of both carfilzomib and bortezomiband progressed on both lenalidomide and pomalidomide

• A novel agent is sought

Daratumumab: Mechanism of Action

• Human CD38 IgGκmonoclonal antibody

• Direct and indirect anti-myeloma activity1-5

• Depletes CD38+ immunosuppressive regulatory cells5

• Promotes T-cell expansion and activation5

1. Lammerts van Bueren J, et al. Blood. 2014;124:Abstract 3474.2. Jansen JMH, et al. Blood. 2012;120:Abstract 2974.3. de Weers M, et al. J Immunol. 2011;186:1840-8.4. Overdijk MB, et al. MAbs. 2015;7:311-21.5. Krejcik J, et al. Blood. 2016. Epub ahead of print.

6

Daratumumab: Single-agent Activity

• Daratumumab as a single agent

– Approved by FDA and conditionally approved by EMA in relapsed/refractory multiple myeloma1,2

• Patients received a median of 5 prior lines of therapy

– 86.5% of patients were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD)3

• Combined overall response rate (ORR): 31%3

• Median overall survival (OS): 20.1 months3

– 2-year OS was ~75% in responders– Median OS was 18.5 months MR/SD patients

1. Lokhorst HM, et al. N Engl J Med. 2015;373:1207-19.2. Lonial S, et al. Lancet. 2016;387:1551-60. 3. Usmani SZ, et al. Blood. 2016. Epub ahead of print.

RespondersMR/SDPD/NE

Median OS=NE(95% CI, NE-NE)

Median OS=18.5 months (95% CI, 15.1-22.4)

Median OS=3.7 months (95% CI, 1.7-7.6)

Pa

tien

tsA

live

(%

)

100

75

50

25

0

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

MonthsNo. at risk

RespondersMR/SDPD/NE

467725

467416

466712

456311

44577

43537

43485

41454

40384

39344

28203

1282

1241

210

000

MR, minimal response; SD, stable disease; PD, progressive disease; OS, overall survival; CI, confidence interval; NE, not evaluable.

7

CASTOR: Study Design

• Cycles 1-8: repeat every 21 days• Cycles 9+: repeat every 28 days

RRMM, relapsed or refractory multiple myeloma; DVd, daratumumab/bortezomib/dexamethasone; IV, intravenous; Vel, bortezomib; SC, subcutaneous; dex, dexamethasone; PO, oral; Vd, bortezomib/dexamethasone; PFS, progression-free survival; TTP, time to progression; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease.

Multicenter, randomized, open-label, active-controlled phase 3 study

DVd (n = 251)Daratumumab (16 mg/kg IV)

Every week - cycle 1-3Every 3 weeks - cycle 4-8Every 4 weeks - cycles 9+

Vel: 1.3 mg/m2 SC, days 1,4,8,11 - cycle 1-8dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycle 1-8

Vd (n = 247)Vel: 1.3 mg/m2 SC, days 1,4,8,11 - cycle 1-8dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycle 1-8

Primary Endpoint

• PFS

Secondary Endpoints

• TTP• OS

• ORR, VGPR, CR

• MRD

• Time to response

• Duration of response

Key eligibility criteria

• RRMM

• ≥1 prior line of therapy

• Prior bortezomib exposure, but not refractory

Daratumumab IV administered in 1000 mL to 500 mL; gradual escalation from 50 mL to 200 mL/min permitted

1:1

RANDOMIZE

8

Baseline Demographics and Clinical Characteristics

ISS, international staging system; ASCT, autologous stem cell transplant; aISS staging is derived based on the combination of serum β2-microglobulin and albumin; bInvestigator-reported.

Characteristic DVd(n = 251)

Vd(n = 247)

Prior lines of therapy, n (%)

123>3

122 (49)70 (28)37 (15)22 (9)

113 (46)74 (30)32 (13)28 (11)

Prior ASCT, n (%) 156 (62) 149 (60)

Prior PI, n (%) 169 (67) 172 (70)

Prior IMiD, n (%) 179 (71) 198 (80)

Prior PI + IMiD, n (%) 112 (45) 129 (52)

Refractory to IMiD, n (%) 74 (30) 90 (36)

Refractory to last line of therapy, n (%) 76 (30) 85 (34)

9

Characteristic DVd(n = 251)

Vd(n = 247)

Age, yearsMedian (range)≥75, n (%)

64 (30-88)23 (9)

64 (33-85)35 (14)

ISS staging, n (%)a

IIIIII

98 (39)94 (38)59 (24)

96 (39)100 (41)51 (21)

Cytogenetic profile, n (%)b

Del17pt(4;14)

28 (16)14 (8)

21 (12)15 (9)

Time from diagnosis, years

Median (range)

3.87

(0.7-20.7)

3.72

(0.6-18.6)

Patient Disposition• Accrual: September 2014 – September 2015• Clinical cut-off date: January 11, 2016• Median follow-up: 7.4 (range, 0-14.9) months

Patients DVd (n = 251) Vd (n = 247)

Randomized, n 251 247

Treated, n (%) 243 (97) 237 (96)

Discontinued treatment, n (%)Reasons for discontinuation

Progressive diseaseAdverse eventNon-compliance with study drugWithdrawal by patientDeath

74 (31)

47 (19)19 (8)3 (1)

1 (0.4)4 (2)

104 (44)

60 (25)23 (10)

8 (3)9 (4)4 (2)

10

Progression-free Survival

0 3 6 9 12 15

0

0.2

0.4

0.6

0.8

1.0

Months

Pro

po

rtio

n s

urv

ivin

g w

itho

ut

pro

gre

ssio

n

No. at riskVd

DVd 247251

182215

106146

2556

511

00

Median : 7.2 months

Median : not reached

DVd

Vd

11

HR: 0.39 (95% CI, 0.28-0.53); P<0.0001

1-year PFS*

26.9%

60.7%

*KM estimate; HR, hazard ratio.

61% reduction in the risk of disease progression or death for DVd vs Vd

Time to Progression

70% reduction in the risk of disease progression for DVd vs Vd

12

0 3 6 9 12 150

0.2

0.4

0.6

0.8

1.0

Months

Pro

po

rtio

n s

urv

ivin

g w

itho

ut

pro

gre

ssio

n

No. at riskVd

DVd247251

181214

106145

2556

511

00

DVd

Vd

Median: not reached

Median: 7.3 months

HR: 0.30 (95% CI, 0.21-0.43); P<0.0001

1-year TTP*

65.4%

28.8%

*KM estimate

PFS: Subgroup AnalysisHR (95% CI)

Favor DVd Favor VD

1 100.1

Age

<65 years

ISS staging

I

II

III

Prior lines of tx

1

2

3

>3

Prior ASCT

Yes

No

0.44 (0.28, 0.68)

0.35 (0.22, 0.57)

0.25 (0.13, 0.48)

0.37 (0.23, 0.61)

0.55 (0.31, 0.98)

0.31 (0.18, 0.52)

0.50 (0.28, 0.89)

0.66 (0.31, 1.41)

0.48 (0.20, 1.16)

0.38 (0.26, 0.57)

0.34 (0.19, 0.59)

≥65

HR (95% CI)

Prior bortezomib tx

Yes

No

Prior IMiD

Yes

No

Refractory to IMiD

Yes

No

Refractory to last line of prior tx

Yes

No

Renal function (baseline CrCl)

>60 mL/min

0.46 (0.32, 0.66)

0.25 (0.13, 0.47)

0.38 (0.27, 0.55)

0.50 (0.24, 1.04)

0.50 (0.31, 0.80)

0.32 (0.18, 0.59)

0.42 (0.25, 0.70)

0.38 (0.25, 0.59)

0.30 (0.20, 0.44)

0.55 (0.30, 1.02)≤60 mL/min

13CrCl, creatinine clearance.

Favor DVd Favor VD

1 100.1

Tx, treatment; CrCl, creatinine clearance.

PFS: 1 Prior Line of Treatment

69% reduction in the risk of progression or death for DVd vs Vd

Median: not reached

77.5%DVd

VdMedian: 7.5 months

0 3 6 9 12 15

0

0.2

0.4

0.6

0.8

1.0

Months

Pro

po

rtio

n s

urv

ivin

g w

itho

ut

pro

gre

ssio

n

No. at riskVd

DVd113122

91109

5678

1532

24

00

14

HR: 0.31 (95% CI, 0.18-0.52); P<0.0001

1-year PFS*

29.4%

*KM estimate

Overall Response Ratea

P <0.0001

83

63 59

29

199

0

10

20

30

40

50

60

70

80

90

100

Res

pons

e ra

te,

%

ORR ≥VGPR

P <0.0001

P = 0.0012 DVd

Vd

15

14

3

0

2

4

6

8

10

12

14

16

18

20

%

MRD-neg (10-4)

aResponse-evaluable population.

≥CR

Time to Response

16

No. at risk

234240234240

155108215229

8948197220

4922177203

3517161185

2114121163

14991116

444876

122755

011740

01827

01513

0037

0002

0001

0000

0 1 2 3 4 5 76 98 10 11 12 13 14 15

0

100

80

60

20

40

Res

pond

ers,

%

Months

Vd (PR or better)

DVd (PR or better)

Vd (CR or better)

DVd (CR or better)

Vd (PR or better)

DVd (PR or better)

Vd (CR or better)

DVd (CR or better)

Most Common (>5%) Grade 3-4 TEAE

0 20 40 60 80 100

Sensory PN

Hypertension

Pneumonia

Lymphopenia

Neutropenia

Anemia

Thrombocytopenia

Patients, %

Vd Grade 3

Vd Grade 4

DVd Grade 3

DVd Grade 4

Non

-hem

atol

ogic

Hem

atol

ogic

45

33

14

16

13

4

10

3

10

8

7

0.8

5

7

17

Bleeding:• All grades: 7% in DVd vs 4% in Vd• Grade 3-4: 3 pts in DVd vs 2 pts in Vd

Infections:• Grade 3-4 AEs: 21% in DVd vs 19% in Vd• Serious AEs: 20% in DVd vs 18% in Vd

Discontinued for sensory peripheral neuropathy: • All grades: 0.4% in DVd vs 3% in Vd

Discontinued for TEAE:• 7% in DVd vs 9% in Vd

Infusion-related Reactions (IRRs)

• No grade 4 or 5 IRRs observed

• 98% of patients with IRRs experienced the event on the first infusion

• 2 patients discontinued due to IRRs – Bronchospasm in the first patient– Bronchospasm, laryngeal edema, and skin rash in the second patient

Safety Analysis Set (n = 243)All grades Grade 3

Patients with IRRs, % 45 9Most common (>5%) IRRs

Dyspnea 11 2Bronchospasm 9 3Cough 7 0

18

Preinfusion: dexamethasone 20 mg, paracetamol 650-1000 mg, diphenhydramine 25-50 mgStop infusion immediately for mild symptoms; once resolved, resume at half the infusion rate

PI-based Studies

Daratumumab

DVd vs Vd

PFS HR (95% CI)

0.39 (0.28-0.53)

PFS Median mo NE

>VGPR 59%

>CR 19%

Duration of response, mo

NE

OS HR (95% CI)

0.77 (0.47, 1.26)

1. Dimopoulos MA, et al. Lancet Oncol. 2016;17(1):27-38.2. San-Miguel JF, et al. Lancet Oncol. 2014;15(11):1195-1206.3. San-Miguel JF, et al. Blood. 2015;126(23):Abstract 3026.4. Jakubowiak A, et al. Blood. 2016. Epub ahead of print.

CarfilzomibKd vs Vd1

PanobinostatPVd vs Vd2,3

ElotuzumabEVd vs Vd4

0.53 (0.44-0.65)

0.63 (0.52-0.76)

0.72 (0.59-0.88)

18.7 12.0 9.7

54% 28% 36%

13% 11% 4%

21.3 13.1 11.4

0.79 (0.58-1.08)

0.94 (0.78-1.14)

0.61 (0.32-1.15)

19

Conclusions

20

• Daratumumab-Vd significantly improved PFS, TTP, and ORR in comparison with Vd alone

– DVd was associated with a 61% reduction in the risk of progression/death

• Treatment benefit of DVd vs Vd was consistent across subgroups

– Earlier treatment with DVd may be the most beneficial

• Daratumumab-Vd doubled VGPR and CR rates

• Daratumumab-Vd was not associated with any cumulative toxicities

Daratumumab Phase III Pollux DaraRd versus Rd• 569 patients with relapsed or refractory multiple myeloma were enrolled in the study. 

• The study met the primary endpoint of improving progression free survival (PFS); Hazard Ratio (HR) = 0.34, p<0.0001. 

• ORR 93 versus 76%, CR 43 versus 19%

• The median PFS for patients treated with daratumumab has not been reached, compared to median PFS of 18.4 months for patients who did not receive daratumumab.

Daratumumab Phase III Pollux DaraRd versus Rd

A Dose Finding Phase 1/2 Trial of Isatuximab (SAR650984, Anti-CD38 mAb) as a Single Agent in Relapsed/Refractory

Multiple Myeloma

Thomas Martin,1 Joshua Richter,2 Ravi Vij,3 Craig Cole,4 Djordje Atanackovic,5 Jeffrey Zonder,6 Jonathan Kaufman,7 William Bensinger,8 Meletios Dimopoulos,9 Jesús San Miguel,10 Todd Zimmerman,11 Nikoletta Lendvai,12 Parameswaran Hari,13

Enrique Ocio,14 Cristina Gasparetto,15 Shaji Kumar,16 Karl Hsu,17 Eric Charpentier,17 Stephen Strickland,18 Joseph Mikhael19

1University of California at San Francisco, San Francisco, CA, USA; 2Hackensack University Medical Center, Hackensack, NJ, USA; 3Washington University, St. Louis, MO, USA; 4University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA; 5Huntsman Cancer Institute, Salt Lake City, UT, USA; 6Karmanos Cancer Center, Detroit, MI, USA; 7Winship Cancer Institute of Emory University, Atlanta, GA, USA; 8Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 9National and Kapodistrian University of Athens, Athens, Greece; 10University of Navarra, Pamplona, Spain; 11University of Chicago, Chicago, IL, USA; 12Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 13Medical College of Wisconsin, Milwaukee, WI, USA; 14University Hospital of Salamanca, Salamanca, Spain; 15Duke University Medical Center, Durham, NC, USA; 16Mayo Clinic, Rochester, MN, USA; 17Sanofi Oncology, Cambridge, MA, US; 18Vanderbilt-Ingram Cancer Center, Nashville, TN, USA;19Mayo Clinic, Scottsdale, AZ, USA

24

4

4 12.58.7

12

16.7

24

0

10

20

30

40

3 Q2W(n=23)

10 Q2W/Q4W(n=25)

10 Q2W(n=24)

20 QW/Q2W(n=25)

Pat

ient

s (%

)

PR

VGPR

CR

Response Summary (IMWG criteria): All Treated Patients

ORR 9%

ORR 29%

ORR 20%

ORR 24%

Isatuximab dose, mg/kg and schedule

Duration of F/U

25.1 wks 25.1 wks 30.7 wks 15.1 wks

Interim analysis results Data cut-off: July 15, 2015F/U, follow-up; VGPR, very good partial response

Randomized

What Else is New in MM Therapeutics?

• Oral Proteasome Inhibitors : Oprozomib

• Monoclonal Antibodies: Isatuximab, Durvalumab

• Kinase Inhibitors: Afuresertib, Dinaciclib, PIM (LGH447), Trametinib

• HDACs: Ricolinostat

• Novel mechanisms: Venetoclax, Selinexor, Bromodomain

• Immunotherapies: BCMA CAR-T, BITE

Selinexor, Novel Anticancer Agent: Restores Tumor Suppressors

Schmidt J et al. Leukemia. 2013;27:2357.

Selinexor, Novel Anticancer Agent: Restores Tumor Suppressors

Chen C et al. Presented at: EHA Annual Meeting; June 2014; Milan, Italy. Abstract P953.

CYTOPLASM

Best Responses in Evaluable Patients: Single-Agent Selinexorvs Selinexor + Low Dex

Best Responses in Evaluable* (n=29) MM PatientsOral Selinexor Single-Agent (as of 1-December-2014)

Treatment N CBR PR MR SD PD

Selinexor high dose: ≥35 mg/m2 14 3 (21%) 1 (7%) 2 (14%) 8 (57%) 3 (21%)

Chen C et al. Presented at: EHA Annual Meeting; June 2014; Milan, Italy. Abstract P953.

Best Responses in Evaluable (N=9) Group A MM PatientsOral Selinexor (45 mg/m2) + Dexamethasone (as of 1-Dec-2014)

Treatment N CBR ORR sCR PR MR PD

Selinexor (45 mg/m2) + Low Dose Dex (20 mg) 9 8 (89%) 6 (67%) 1 (11%) 5 (55%) 2 (22%) 1 (11%)

Durable Responses After Multiple Prior Therapies in Relapsed/Refractory MM Patients

Patients With RR MM (7 Median Prior Tx)Treated With Twice-Weekly Oral Combination Selinexor + Dexamethasone

(Selinexor 45 mg/m2 + Dexamethasone 20 mg)

Maximal Δ Best Response # Prior Tx Study Days

-71% PR 7 301+

-53% PR 3 52

-99% sCR 5 280

-84% PR 9 170

41% PD 5 31

-55% PR 10 121

-41% MR 9 114

-48% MR 16 79

-82% PR 6 201+

DCR: 88% ORR: 67% Median: 7 DOR: ~7 months

Chen CI et al. Blood. 2014;124: Abstract 4773.

Cell death (apoptosis)

Venetoclax an Inhibitor of Bcl-2 Critical for Apoptosis

DeathBH3‐only

Bim Bid

Puma

Bak

Bax

MultidomainDeath triggers Executioners

Caspase activation

ActivatedBAX/BAK

Mitochondria

Cyt C

Bik

Bmf

Bad

NoxaHrk

Bcl‐2 Bcl‐w

Bcl‐xL Mcl‐1A‐1

Survival

Guardians

Sentinels

Signals ofcellulardamage

Targets Bcl‐2 GDC‐0199

Souers AJ et al. Nature Med. 2013;19:202.

Venetoclax in t(11;14) MM

Therapy started

50

40

30

20mg

/dL

0

10

Generalized normal high

Generalized normal low

200

150

100

mg

/dL

0

50

Generalized normal high

Generalized normal low

Kappa FLC Kappa FLC

A.K. Stewart, unpublished

A Phase II Study of Pembrolizumab, Pomalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

Ashraf Badros, Mehmet Kocoglu, Ning Ma, Aaron Rapoport, Emily Lederer, Sunita Philip, Patricia Lesho, Cameron Dell, Nancy Hardy, 

Jean Yared, Olga Goloubeva and Zeba Singh

University of Maryland, Baltimore MD

Investigator initiated study supported partially by Merck

ClinicalTrials.gov # NCT02289222

Rationale for Targeting Programmed Cell Death Protein 1 (PD‐1) and its Ligand PD‐L1 in MM

We hypothesized that pembrolizumab (blockade of PD1‐PD‐L1 signaling ) will activate MM specific cytotoxic T cells that can be further enhanced by pomalidomide

Plasma cells

PD‐L1 expression on plasma cells  

– Immune evasion 

– Proliferative advantage 

– Resistance 

Modified from Postow et al. JCO 2015;33:1974‐1982Ray a, et al. Leukemia (2015) 29, 1441–1444; Sponaas AM, et al. PLoS One 2015 Oct 7;10(10)

Best Response to Treatment (IMWG Criteria)Evaluable Pts (n=27)

AllN=27

Double refractoryN=20

High risk cytogeneticsN=12

ORR (≥ PR), %sCRCRVGPRPR

10411

0029

0015

Stable Disease 8  (30%) 6  (30%) 5 (42%)

Progressive disease 3  (10%) 3  (15%) 1 (8%)

60% 55% 50%

‐1

‐0.75

‐0.5

‐0.25

0

0.25

0.5

0.75

1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Percentage chan

ge from baseline (%

)

Patients+

+

*

**

*

**

*

+

+

Max. % Change From Baseline M Protein or FLC

* Progressive disease+ Death

300

Chimeric Antigen Receptor (CAR) T Cells Against CD19 for Multiple Myeloma

Garfall AL et al. N Engl J Med. 2015;373:1040.

8000

7000

6000

5000

4000

3000

2000

1000

0

IgA

(m

g/d

L)

-50 0 50 100 150 200Days (ASCT no. 1)

IgA (mg/dL)

MEL200

LEN LEN-BTZ

LEN-BTZDEX-CLR

8000

7000

6000

5000

4000

3000

2000

1000

0-100 -50 0 50 100 150 200 250 300 350 400

8

6

4

2

0

Days (ASCT no. 2)

LEN

CTL019

MEL140CYCY

Ser

um

M S

pik

e (g

/dl)

IgA (mg/dL)M spike (g/dl)

IgA

(m

g/d

L)

600

400

200

00 50 100 150 200

Days After ASCTCTL019

2.0

1.5

1.0

0.0

0.5

CT

L01

9 (c

ells

/mm

3 )

B C

ells

(ce

lls/m

m3 )

CTL019, flow cytometry (cells/mm3)B cells, flow cytometry (cells/mm3)

CTL019, qPCR (copies/μg of DNA)

PeripheralBlood

CTL019, qPCR(copies/μg of DNA)

Bonemarrow

200

100

0

CT

L01

9(c

op

ies/

μg

of

DN

A)

5000

4000

2000

0

3000

1000

0 20 40 60 80Days After ASCT

CTL019

Inte

rfer

on

-γ,

Inte

rleu

kin

-6 (

ng

/ml)30

20

10

0

Fer

riti

n (

ng

/ml)

Ferritin (ng/ml)Interferon-γ (pg/ml)

Interleukin-6 (pg/ml)

Ferritin

Interferon-γ

Interleukin-6

B-Cell Maturation Antigen (BCMA) CAR-T

Remissions of Multiple Myeloma during a First-in-Humans Clinical

Trial of T Cells Expressing an Anti-BCMA Chimeric Antigen

Receptor

BCMA targeted CAR-T cells infused after 3 days of

cyclophosphamide and fludarabine

Highest dose level in 2 patients– severe cytokine release syndrome

90-100% clearance of bone marrow plasma cells

Ali SA et al. Presented at: 57th ASH Annual Meeting & Exhibition. Orlando, FL; December 2015. Late‐breaking abstract 1. 

• Monoclonal antibodies here to stay – Rituxan for Myeloma

• Venetoclax for t(11;14) excellent choice (off label for now)

• Selinexor promising

• Checkpoint inhibitors ?

• CAR-T cells ?

• Kinase Inhibitors ?

Summary

Thank you

Overview of Therapeutic Options for Myeloproliferative Neoplasms (CML)

Guillermo Garcia-Manero, MD

Overview of Therapeutic Options for Myelodysplastic Syndromes (MDS)

Guillermo Garcia-Manero, MD

For online registration and more information visit: www.cancernetus.com/june11