A. Keith Stewart, MBChB, MRCP, FRCPC, MBA. Keith Stewart, MBChB, MRCP, FRCPC, MBA Vasek and Anna Maria Polak Professor of Cancer Research Consultant, Division of Hematology/Oncology

Building on Myeloma Therapy: Emerging Molecular Targets and Immunotherapeutic ApproachesASH 2015

This material serves as an educational resource only. 1

Opening Remarks

A. Keith Stewart, MBChB, MRCP, FRCPC, MBAVasek and Anna Maria Polak Professor of Cancer Research

Consultant, Division of Hematology/OncologyMayo Clinic

Scottsdale, Arizona

Building on Myeloma Therapy: Emerging Molecular Targets and Immunotherapeutic Approaches

8:15 AM – 8:20 AM Community Case Part 1 Saad Z. Usmani, MD

8:20 AM – 8:40 AM Translating Molecular and Cytogenetic Profiles Into Precision MedicineSuzanne Trudel, MD

8:40 AM – 9:00 AM Induction Therapy Options for Transplant Eligible and Ineligible PatientsMaría-Victoria Mateos, MD, PhD

9:00 AM – 9:05 AM Panel Discussion

9:05 AM – 9:10 AM Community Case Part 2Saad Z. Usmani, MD

9:10 AM – 9:30 AM Consolidation and Maintenance Therapy OptionsSergio Giralt, MD

9:30 AM – 9:50 AM Updates on Options for Relapsed/Refractory DiseaseSaad Z. Usmani, MD

9:50 AM – 9:55 AM Panel Discussion9:55 AM – 10:00 AM Community Case Part 3

Saad Z. Usmani, MD10:00 AM – 10:20 AM Immunotherapy

Thomas G. Martin, III, MD

10:20 AM – 10:40 AM New Agents in DevelopmentA. Keith Stewart, MBChB

10:40 AM – 10:50 AM Community Case RevisitedA. Keith Stewart, MBChB

10:50 AM – 11:00 AM Question and Answer Session



Which of the following best represents your professional role?

A. HematologistB. Hematologist-oncologistC. OncologistD. RN/NP/PAE. PharmacistF. Other health care providerG. ResearcherH. PatientI. Other

?

Which of the following best represents the professional setting

in which you currently work?

A. AcademicB. CommunityC. HMOD. HospitalE. PrivateF. OtherG. Does not apply to me

?



Where do you practice?A. Asia and AustraliaB. CanadaC. Central and South AmericaD. Europe and IsraelE. Middle East and AfricaF. United StatesG. Rest of worldH. Texas

?

Community Case Part 1

Saad Usmani, MD, FACPDirector, Plasma Cell Disorders Program

Director, Clinical Research in Hematologic MalignanciesDepartment of Hematologic Oncology & Blood Disorders

Levine Cancer InstituteCharlotte, North Carolina



Disclosures

• Consultant/Advisor: Array BioPharma, Bristol-Myers Squibb, Celgene, Janssen, Onyx, an Amgen subsidiary, Sanofi, Takeda Oncology

• Research Grant: Array BioPharma, Janssen, Onyx, an Amgen subsidiary, Sanofi

• Speakers Bureau: Celgene, Onyx, an Amgen subsidiary, Takeda Oncology

Case Study Part 154-year-old man presents with 6-month history of lower back pain, increasing fatigue, right rib pain.

• Hypertension for 5 years (controlled)

Past medical history

• Right/left arthroscopic surgery

Past surgical history

• Hypertension

• Type 2 diabetes

• No cancers

Familyhistory

• Banker, marathon runner

• Married

• Two kids

Socialhistory

• Pallor, right rib cage tenderness

Physicalexam



Case Study Part 1ActualValue

Normal Range

CBC withdifferential

WBC (103/mL) 5.3 (4–11)

RBC (106/mL) 2.9 (3.8–5.2)

Hemoglobin (g/dL) 8.5 (13–16)

Hematocrit (%) 26 (34–45)

Platelets (103/mL) 160 (150–400)

Neutrophils (103/mL) 2.5 (1.9–7.5)

CMP

BUN (mg/dL) 17 (7–20)

Creatinine (mg/dL) 1.5 (0.7–1.2)

Calcium (mg/dL) 10.4 (8.4–10.2)

Total protein (g/dL) 11.2 (6.3–8.2)

Albumin (g/dL) 3.6 (3.5–5.0)

SPEP


Gamma (g/dL) 3.2 (0.5–1.6)

M protein spike (g/dL) 4.2 –

ActualValue

Normal Range

QuantitativeIgs + serum immuno-fixation

IgG (mg/dL) 5,100 (700–1,600)

IgA (mg/dL) 35 (70–400)

IgM (mg/dL) 20 (40–230)

FLC

Kappa quant FLC (mg/L) 112 (3.30–19.40)

Lambda quant FLC (mg/L) 2.1 (5.71–26.30)

Kappa/lambda quant FLC ratio 53 (0.26–1.65)

24–hr urinecollection and UPEP

Protein random 80 –

Total protein timed (mg/24 hr) 2010 (40–150)

E/P albumin (%) 30 –

1 (%) 2.5 –

2 (%) 8.5 –

(%) 24 –

(%) 35 –

M protein spike (%) 20 –

M protein spike (mg/24 hr) 420 –

Case Study Part 1• Labs

– Normal LDH

– Serum β2 microglobulin 6 mg/dL

• Skeletal survey– Numerous lytic lesions (skull, long bones, right

5th/6th/7th ribs, pelvis)

• Bone marrow biopsy– 70% cellularity, 80% kappa-restricted plasma cells

– Cytogenetics normal in 20 metaphases

– FISH positive for translocation (11;14) in 75% cells



Which one of the methodologies do you currently use most often?

A. Gene expression profilingB. Conventional cytogeneticsC. FISHD. Gene mutation panelE. Flow cytometryF. More than one methodG. None of the above

?

Is this patient considered eligible for stem cell transplantation?

A. YesB. NoC. Not sure

?



Which factors do you use to decide whether to consider aggressive therapy

such as stem cell transplantation?

A. Age, comorbidity scoreB. Social support and insurance

coverageC. Response to induction therapyD. Risk profileE. All of the aboveF. I don’t do transplants up front

?

What would be your recommendation for initial treatment?

A. Melphalan, prednisone, bortezomib (MPV)B. Bortezomib, thalidomide, dexamethasone (VTD)C. Lenalidomide + low-dose dexamethasone (Ld)D. Lenalidomide, bortezomib, dexamethasone

(RVD)E. Cyclophosphamide, bortezomib,

dexamethasone (CyBorD)F. Carfilzomib, lenalidomide, dexamethasone

(KRD)G. Other

?



Does your practice routinely test for minimal residual disease (MRD)

following therapy?

A. YesB. NoC. We soon willD. Not sure

?

Translating Molecular and Cytogenetic Profiles Into Precision Medicine:

Identifying Molecularly Defined Subsets

Suzanne Trudel, MDPrincess Margaret Cancer Centre

University Health NetworkToronto, Ontario, Canada



Disclosures

• Consultancy: Novartis• Honoraria: Celgene, Amgen, BMS,

Novartis• Research funding: GSK, Oncoethix,

Onyx, Trillium, Astellas

Objectives

• Describe oncogenic drivers in MM and their relationship to molecular subsets

• Describe their prognostic implication and integration of cytogenetics and molecular profiles with clinical data as new prognostic tools

• Describe the use of molecular profiling for precision therapeutic strategies in MM



Multiple Myeloma: Molecular PathogenesisIntrinsic Genetic Background

Figure 3, page 3460

Kuehl WM, Bergsagel PL. Molecular pathogenesis of multiple myeloma and its premalignant precursor. J Clin Invest. 2012;122(10):3456-3463.

Figure 1

Chesi M, Bergsagel PL. Molecular pathogenesis of multiple myeloma: basic and clinical updates. Int J Hematol. 2013 Mar;97(3):313-323.

MM Karyotypes Identify Unique Molecular Subsets

Figure 4A, page 300

Bergsagel PL, et al. CyclinD dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005;106:296-303.



t(4;14)1

• Translocation between heavy Ig gene locus and MMSET + FGFR3

• Associated with IgA myeloma • Immature morphology • Tendency for less lytic bone disease, younger

age

t(11:14)2

• Translocation between heavy Ig gene locus and cyclinD1

• Associated with IgD, IgM and nonsecretory MM• Lymphoplasmacytoid morphology and B

lineage–Ag (CD20 and CD79a)

1. Jaksic W et al. J Clin Oncol. 2005;23:7069.2. An G et al. Leuk Res. 2013;37:1251.

Cytogenetics: Biologically Defined Unique Clinical Subsets

Figure 2A & 2B, page 2033

Garand R, et al. t(11;14) and t(4;14) translocations correlated with mature lymphoplasmacytoid and immature morphology, respectively, in multiple myeloma. Leukemia. 2003 Oct;17(10):2032-2035.

Karyotypes and Prognostic Implications

Figure 1, page 885

Bergsagel PL, et al. Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood. 2013 Feb 7;121(6):884-892.



Heterogeneity Within Cytogenetically-Defined Subsets

t(4;14) Subgroup

Figure 3, page 2022

Moreau P, et al. Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials. Leukemia. 2007 Sep;21(9):2020-2024.

Combined Prognostic ModelsRevised International Staging System (R-ISS)

Table 1

Palumbo A, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015 Sep 10;33(26):2863-2869.

Figure 1A




Revised R-ISS and OS by Type of Treatment

Figure 3, page 2867


Gene Expression Profiling (GEP) for Risk Stratification

Zhou Y et al. Leukemia. 2009; 23: 1941.Shaughnessy JD et al. Blood. 2007;109:2276.

Figure 1, page 2279

Shaughnessy JD, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007 Mar 15;109(6):2276-2284.

UMAS GEP70• Defined in patients with poor

outcomes with Total Therapy 2 (TT2)

• Present in 15% of newly diagnosed patients

• High-risk signature found in all molecular subsets

• Commercially available

Considerations:• No standardized high risk

GEP signature (UAMS70, EMC-92 and IFM)

• Perception that they are not reproducible

• Difficult to interpret



Technological Advances in Detecting Biomarkers in MM

Figure 1, page 811

Landgren O, Morgan GJ. Biologic frontiers in multiple myeloma: from biomarker identification to clinical practice. Clin Cancer Res. 2014 Feb 15;20(4):804-813.

NGS Studies Identify Recurrent Mutations in Key Cellular Pathways

Figure 1B, page 93

Lohr JG, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014 Jan 13;25(1):91-101.

Mutations accumulate in key pathways:• MAPK signaling• NFkB signaling• Cell cycle• Chromatin-modifying• RNA processing



NGS Studies Identify Recurrent Mutations in Key Cellular Pathways

Figure 1B, page 93

Lohr JG, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014 Jan 13;25(1):91-101.

What are the clinical implications?

Impact of Mutations on Myeloma SurvivalAnalysis of MRC XI Trial (IMiD-based Phase 3 in NDMM)

Figure 3

Walker BA, et al. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol. 2015 Nov 20;33(33):3911-3920.

Figure 4D & 4F




Impact on Survival of CCND1 Mutations on Whole Cohort and Among t(11;14) Patients

Figure 7B, 7D & 7F

Walker BA, et al. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J ClinOncol. 2015 Nov 20;33(33):3911-3920.

• Significantly mutated genes occur within cytogenetic subgroups

• Mutations and cytogenetic abnormalities interact to define more homogeneous prognostic groups

Survival Analysis and Cumulative Negative Impact of NGS-Defined

Molecular Abnormalities

Figure 5A, 5B, 5C & 5E




Prognostic Implications of Molecular and Cytogenetic Profiles

• MM is a heterogeneous disease even within cytogenetically defined molecular subtypes

• GEP and/or combined prognostic models demonstrate improved prognostic power and identify patients with poor outcome in the era of novel agents

• NGS identifies important prognostic molecular abnormalities

• Question remains on how do we customize treatment?

Subset Analysis of Patients With t(4;14)Improved Results With Integration of BTZ (Induction,

Consolidation or Maintenance) and Use of Tandem Transplant

Study/Year N Induction # ASCT Consolidation Maintenance

PFS(months)

OS(months)

Chang20041 16 VAD

or dex 1 ─ ± Thal 9.9 18.8

Moreau2

2007 100 VAD 2 ± Thal 21 (EFS) 41.4

Avet-Loiseau3

2010106 BD vs

VAD 1 or 2 ± Len ~ 30% ± Len 28 vs 16 (EFS)63% vs 32% (4 yrs), non t(4;14) 73%

Cavo4

2010 55 VTD vs TD 2 VTD vs TD Dex

66 vs 20% (3 yr), non-t(4;14) 61%

NA

Sonneveld5

2015 50 PAD vs VAD 2 ─ BTZ vs Thal 16 vs 8%

(5 yrs)

52% vs 33% (5 yrs), non-

t(4;14) 75%

Avet-Loiseau6

201065 BD vs

VAD 1 or 2 Len Len vs placebo (randomization) 27 vs 15 NA

1. Chang H et al. Bone Marrow Transplant. 2005; 36: 793; 2. Moreau P et al. Leukemia. 2007;21:2020; 3. Avet-Loiseau H et al. J Clin Oncol. 2010;28: 4630; 4. Cavo M et al. Blood. 2012; 120:9; 5. Sonneveld P et al. Presented at: 57th ASH Annual Meeting & Exhibition. Orlando, FL;

December 2015. Abstract 27; 6. Avet-Loiseau H et al. Blood. 2010;116:1944.



Subset Analysis of Patients With del(17p)Improved Outcome With Aggressive Multi-Combination Treatment

That Includes BTZ and Prolonged Therapy

Study/Year N Induction # ASCT Consolidation MaintenancePFS

(months)OS

(months)

Chang20041 10 VAD

or Dex 1 ─ ± Thal 7.9 14.7

Shaughnessy20092

Low-riskgroup GEP

35 VAD ± Thal 2 DPACE × 4 ± Thal ± Thal 31%

(4 yr EFS)55%

(4 yrs)

Shaughnessy20092

Low-risk group GEP

42

VTDPACE× 2

Thal-Dex× 2

2 VTDPACE × 2Thal-Dex × 2

VTD × 1 yrThal-Dex × 2 yrs

81%(4 yr EFS)

81%(4 yrs)

Avet-Loiseau20103 35 BD vs VAD 1 or 2 ± Len ~ 30% ± Len 14 mo P=0.32

(EFS)

50% (4 yrs)P=0.49, non-del(17p) 79%

Sonneveld4

2015 37 PAD vs VAD 2 ─ Bz vs Thal22 vs 5%

(5 yrs), non-del(17p) 27%

65 vs 5% (5 yrs), non-del(17p) 72%

Avet-Loiseau5

2010 32 BD vs VAD 1 or 2 Len Len vs placebo (randomization) 29 vs 14 NA

1. Chang H et al. Bone Marrow Transplant .2005; 36: 739; 2. Shaughnessy J et al. Br J Haematol . 2009;147: 347.3. Avet-Loiseau H et al. J Clin Oncol. 2010;28: 4630; 4. Sonneveld P et al. Presented at: 57th ASH Annual Meeting &

Exhibition. Orlando, FL; December 2015. Abstract 27; 5. Avet-Loiseau H et al. Blood. 2010;116:1944.

Risk Stratification in MyelomaHow do we customize treatment?

• t(4;14) and del(17p) MM– Need to better define the high-risk t(4;14) and 17p

– New treatment approaches required (eg, immune-based approaches, use of epigenetic modulators, targeted therapies)

• Targeted therapies being designed– TKIs, monoclonal antibody, EZH2 inhibitors for

t(4;14)– Nutlins, PRIMA-1, and PARP inhibitors for del 17p



Chapman MA et al. Nature. 2011;471:467. Lohr JG et al. Cancer Cell. 2014;25:91.

CLINICAL VALIDATION:Treatment with vemurafenib, Morgan G, ASH 2012; Andrulis M et al. Cancer Discov2013

Molecular Profiling for Precision Therapeutic Strategies in MM

BRAFi have now been validated clinically in MM

Before treatment Post 1 cycle

MM Genomics Initiative (MMGI) FINDING:BRAF V600E (4%); confirmed in CoMMpassPreclinical validation of BRAFi

The MMRF CoMMpass StudyAccelerating the Path to Precision Medicine

• Clinical parameters collected every 3 months for a minimum of 8 years• Assays

– Flow cytometry– Molecular profiling (whole genome, exome, transcriptome)– NGS MRD

Untreatedmultiple myeloma

n=1,000

Untreatedmultiple myeloma

n=1,000

Clinical trial orphysician’s choice

Clinical trial orphysician’s choice

IMiD-based regimenIMiD-based regimen

Proteasome-basedregimen

Proteasome-basedregimen

IMID + proteasome-based regimen

IMID + proteasome-based regimen

Molecular-informed trialsor physician’s choice

Molecular-informed trialsor physician’s choice

Relapse 1, 2, 3, …n=800

Relapse 1, 2, 3, …n=800

BM + PBcollectedBM + PBcollected

BM + PBcollectedBM + PBcollected



“Actionable” Alterations in MMMMRF CoMMpass and other efforts have identified “actionable”

molecular alterations in about 60% of relapsed myeloma patients.

KRAS and NRAS(40%)

BRAF(8%)

CDKN2C and CCND1(18%)

PI3K-AKT(5%)

FGFR3(5%)

IGF1R and ALK(5%)

IDH1/2(5%)

MyD88(3%)

Others(11%)

Auclair D, unpublished data.

Selected Academic Molecular Screening Programs

Adapted from Bedard PL et al. Nature 2013; 501:355.

Selected Academic Molecular Screening Programs

Number of Genes

Tumor Types Tissue

MSKCC (IMPACT) 347 All Archival

Dana Farber(PROFILE)

305 (OncoPanel) All Archival

EORTC (SPECTA) ~360 Disease

specific Archival

UCSF(Genomic Medicine)

500 (UCSF 500) All Archival

MD Anderson 50–200 All Archival

Princess Margaret(IMPACT/COMPACT) ~550 All Archival or

fresh

Mayo (MM panel)MP3

~88 (including chromosomal abnormalities)

Myeloma Fresh



Diaz LA, Bardelli A. J Clin Oncol. 2014;32:579.

Source of cfDNA

Cell-Free DNA Provides Access to the Tumor Genome

An alternative to bone marrow aspirates?

Trudel S, unpublished data.

Yield cfDNA MM vs advanced solid tumors

Ultra-Deep, Full-Length Sequencing of cfDNA is Feasible and a Powerful Tool for

Molecular Profiling of MM Patients

0%

10%

20%

30%

40%

50%

60%

70%

p.E545Kp.I841Vp.Y207*p.D64Np.H59P

p.E551Kp.C620Wp.C624Yp.A859Sp.E513E

p.V600E (2)p.D594N (2)p.D594G

p.Q61K (6)p.Q61R (3)p.Q61L p.G13R

p.Q61H (4)p.G12D (3)p.G12V (3)p.G13D (3)p.G13C (2)p.G13Rp.A146V (2)p.A146Tp.K117Np.A59L

31/4829/48

18/48

9/48

5/48 5/483/48

Patients with multiple actionable mutations in MAPK pathway:

1: KRAS p.Q61H, KRAS p.G12V, BRAF p.V600E2: KRAS p.A146V, BRAF p.D594G3: KRAS p.G12V, BRAF p.D594N4: KRAS p.Q61H, KRAS p.G12V, KRAS p.G12D5: NRAS p.Q61R, NRAS p.Q61K Trudel S, unpublished data.

Any gene

KRAS,NRAS, or

BRAF

KRAS NRAS BRAF EGFR PIK3CA

Tumor Data

44 171

ctD

NA

D

ata 43 42 1 97.7%

172

2 170 98.8%

95.5% 99.4%

Pat

ien

ts w

ith

so

mat

ic m

uta

tio

ns



Conclusions• Risk stratification should include combination of ISS

(β2M and albumin), LDH, and chromosomal abnormalities: del(17p), t(4;14), t(14;16), and 1q21 by FISH or GEP

• Prognostic implications are now impacting treatment decisions (use of BTZ, tandem transplant, prolonged treatment)

• NGS studies have uncovered novel prognostic biomarkers and actionable mutations and has the potential to replace iFISH

• With the right small-molecule therapeutic tools we should be able to therapeutically manipulate the key deregulated pathways (eg, clinical data now supports the strategy of targeting MAPK signaling)

Induction Therapy Options for Transplant-Eligible and -Ineligible Patients

María-Victoria Mateos, MD, PhDConsultant Physician

Haematology DepartmentUniversity Hospital of Salamanca

Salamanca, Spain



Disclosures• María-Victoria Mateos, MD, PhD, has

disclosed the following relevant financial relationships:

– Janssen, Celgene, Takeda, Amgen, BMS, Novartis

• Dr. Mateos will discuss the unlabeled or investigational use of a commercial product.

Main Objectives for NDMM Patients

A. CureB. Prolong overall survival (OS)C. Prolong progression-free

survival (PFS)D. Maintain quality of lifeE. Prolong PFS, OS, and ensure good

quality of life



Maximal Eradication of Tumor Clone Through Achievement of Best Possible

Response

Figure 2, page 532

Martinez-Lopez J, et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood. 2011 Jul; 21;118:529-534.


A. Cure

B. Prolong OS

C. Prolong PFS

D. Maintain quality of life

E. Prolong PFS, OS, and ensure good quality of life




A. Cure

B. Prolong OS

C. Prolong PFS

D. Maintain quality of life

E. Prolong PFS, OS, and ensure good quality of life

Does quality of the response predict final outcome?

Impact of MRD Detected by Flow Cytometry on Clinical Outcomes


Rawstron AC, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J ClinOncol. 2013 Jul 10;31(20):2540-2547.



Flow-MRD Monitoring in Large Clinical Trials

The GEM/PETHEMA Experience

Figure 1C & 1D, page 688

Paiva B, et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustainedcomplete response after autologous stem cell transplantation in multiple myeloma. Blood. 2012 Jan 19;119(3):687-691.

Flow-MRD negativity in favorable biology MM to predict “operational cure”

Paiva B et al. Leukemia. 2013;27:2056.

Flow-MRD Monitoring in Large Clinical Trials

The GEM/PETHEMA Experience

Time From Diagnosis (months) Time From Diagnosis (months)

Median: 10 y

Median: 6 y

Median: 3y

0

20

40

60

80

100

PF

S (

%)

P<0.001

0 50 100 150 200

0

20

40

60

80

100

OS

(%

)

P<0.001

Median: NR (79%, 10 y)

Median: 9 y

Median: 5.5 y

0 50 100 150 200

MGUS-like + MRD negativeMM-like + MRD negativeMM-like + MRD positive



8 cycles of CRd lenalidomide (2-year)

• MRD testing was clinically feasible in 55 of 56 (98%) patient samples by MFC (1 patient sample was not processed due to equipment breakdown)

• NGS assay at MRD was technically successful in 45 of 56 (80%) patient samples (8 with undetectable clonotypes; 3 without available sample)

Flow and NGS-MRD Monitoring: The NIH Experience

Figure 3B & 3C, page 752

Korde N, et al. Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomideextension in patients with smoldering or newlydiagnosed multiple myeloma. JAMA Oncol. 2015 Sep;1(6):746-754.

Important Aim of Treatment

• CR should be an important objective in this patient

• Achievement of high-quality, sustained CR balanced with acceptable toxicity can translate into an “operational cure”

Does imaging assessment matter in this young patient with bone disease?



Impact of Post-ASCT PET-CT Negativity on Clinical Outcomes

Figure 3, page 5994

Zamagni E, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011 Dec 1;118(23):5989-5995.

Important Aim of Treatment

• CR should be an important objective in this patient

• Achievement of high-quality, sustained CR balanced with acceptable toxicity can translate into an “operational cure”*

What is the best option of therapy for this patient?

*Inside and outside bone marrow



54-Year-Old Man With Newly Diagnosed MM IgGκ: Anemia, Hypercalcemia, and Bone Lesions

What is the option of therapy proposed?

A. Induction + ASCT + consolidation + maintenance

B. Induction + consolidation and maintenance

C. Induction + ASCTD. Induction + ASCT + maintenance

Is there something better than VAD or thalidomide/dexamethasone?

Modified from Figure 2, page 5438

Stewart AK, et al. How I treat multiple myeloma in younger patients. Blood. 2009 Dec 24;114(27):5436-5443.



Bortezomib-Based vs Nonbortezomib-BasedInduction: A Meta-Analysis of Phase 3

Randomized, Controlled Trials (2,086 pts)

Bz-based induction results in significant improvements in PFS/OS compared wih nonbortezomib-based induction.


Sonneveld P et al. Bortezomib-based versus nonbortezomib-based induction treatment beforeautologous stem-cell transplantation in patientswith previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlledtrials. J Clin Oncol. 2013 Sep 10;31(26):3279-3287.

*P value statistically significant

Bortezomib/Thalidomide-Based Induction Regimens

InductionRegimen

Number of

Cycles Phase Study Details

ResponsePostinduction

(%)

CR ≥VGPR

VTD vs TD1 3 3 VTD vs TD as induction and

consolidation19*5

62*28

VTD vs TD2 6 3

VBMCP/VBAD + V vs TD vs VTD induction + α-IFN, thalidomide, or thalidomide/bortezomib maintenance

35*14

60*29

vTD vs VD3 4 3 Comparison of induction regimens 13

1249*36

1. Cavo M et al. Lancet. 2010;376:2075.2. Rosinol L et al. Blood. 2012;120:1589.3. Moreau P et al. Blood. 2011;118:5752.

VTD, bortezomib-thalidomide-dexamethasone; TD, thalidomide- dexamethasone; VBMCP, vincristine-BCNU-melphalan-cyclophosphamide-prednisone; VBAD, vincristine-BCNU-adriamycin- dexamethasone.



Bortezomib/Lenalidomide-Based Induction Regimens

InductionRegimen Cycles Study Details

ResponsePostinduction (%)

CR ≥VGPR

RVD1 Up to 8 Phase 1/2: up to 8 cycles VRD 29 67

RVD2 3 Phase 2: VRD induction and consolidation, len maintenance 23 58

1. Richardson PG et al. Blood. 2010;116:679.2. Roussel M et al. J Clin Oncol. 2014; 32:2712.

What is the value of thealkylator as part of the

induction in young NDMM patients?



Retrospective, Case-Matched Analysis: VTD vs VCD Induction

Patients enrolled in GIMEMA MMY-3006 study and EMN-02 study

VTD (n=236)

VCD (n=236) P

Response to induction therapy

CR 19% 6% <0.001

≥ VGPR 64% 37% <0.001

≥ PR 93% 81% <0.001

Toxicity

Any grade 3–4 hematological AE 2% 8% 0.003

Any grade 3–4 PN 7% 2% 0.009

No difference between regimens in terms of efficiency to mobilize PBSC.

Cavo M et al. Leukemia. 2015;Oct 7 [Epub ahead of print].AE, adverse event; PN, peripheral neuropathy; PBSC, peripheral blood stem cell.

What has been the value of addition a fourth drug for induction in young NDMM

patients so far?



Is the Alkylator Necessary as Part of the Induction?

Phase 2 Randomized European Trial

Ludwig H et al. J Clin Oncol. 2013;31:247.

Response, %VTD

(N=49)VTDCy(N=48)

After induction

CR (%) 27 27

≥VGPR (%) 69 69

ORR (%) 100 96

Post ASCT

CR/nCR (%) 85 77

MRD negative (%) 35 27

3-y OS (%) 80 80

G3–4 AEs/SAEs (%) 47/22 57/41

The addition of the alkylator as fourth drug doesnot add any significant benefit

SAE, serious adverse events.

EVOLUTION Trial: Three- and Four-Drug Combinations for NDMM Patients

Response, n (%)VDCR (n=40)

VDR (n=41)

VDC (n=32)

VDC-mod (n=17)

CR 2 (5) 3 (7) 1 (3) 2 (12)

sCR 1 (3) 1 (2) 0 2 (12)

VGPR 11 (26) 10 (24) 3 (9) 5 (29)

≥ VGPR 13 (33) 13 (32) 4 (13) 7 (41)

≥ nCR 4 (10) 3 (7) 1 (3) 3 (18)

ORR (≥ PR) 32 (80) 30 (73) 20 (63) 14 (82)

Progressive disease 0 0 0 0

Patients categorized as VGPR include those who have no measurable M-protein but have not yet had bone marrow assessments to confirm CR/nCR status.

Kumar S et al. Blood. 2012;119:4375.

No substantial advantage was observed in four- vs three-drug combinations.



What about the second-generation proteasome

inhibitors?

HDM, high-dose melphalan.

Carfilzomib + Thal + Dex (KTd): Responses

3-year PFS was 72%

Sonneveld P et al. Blood. 2015;125:449.

Dosing Level of Carfilzomib

20/27 mg/m2 20/36 mg/m2 20/45 mg/m2 All pts

Pts, n 50 20 21 91

Response induction (%)

CR 20 30 33 25

≥ VGPR 56 85 81 68

HDM (%)

CR 28 40 38 33

≥ VGPR 64 90 90 76

Response consolidation (%)

CR 58 70 67 63

≥ VGPR 86 90 95 89



Phase 2: KRd (Carfilzomib, Lenalidomide, Dexamethasone)

in NDMM Patients

N: 53 patients

Post-Induction

Post-Transplant

Post-Consolidation Post-KRd

≥ PR (%) 98 100 100 100

≥ VGPR (%) 78 97 100 100

≥ nCR (%) 14 44 91 100

sCR (%) 10 25 70 86

• At the end of 8 cycles, 15/17 evaluable pts (88%) MRD-negative• Median follow-up 9.7 months: all pts alive; 52 of 53 progression

free

Zimmerman TM et al. J Clin Oncol. 2015;33. Abstract 8510.

Weekly Oral Ixazomib + Lenalidomide and Dexamethasone in Previously Untreated

MM: Response

• 14 patients were evaluated for MRD– 7 patients achieved CR at the time of assessment

• All 7 were MRD negative– 9 patients achieved VGPR or better at the time of assessment

• 8/9 were MRD negative

Kumar S et al. Lancet Oncol. 2014;15:1503.

Response, n (%)Phase 1 (n=15)

Phase 2 (n=49)

Total (N=64)

ORR (≥PR) 15 (100) 44 (90) 59 (92)

CR 5 (33) 12 (24) 17 (27)

sCR 2 (13) 5 (10) 7 (11)

VGPR 3 (20) 17 (35) 20 (31)

nCR 1 (7) 4 (8) 5 (8)

≥VGPR 8 (53) 29 (59) 37 (58)

PR 7 (47) 15 (31) 22 (34)



What about the addition of “a different fourth drug” in the

near future?

Daratumumab + Bortezomib-Thalidomide-DexElotuzumab + Bortezomib-Lenalidomide-Dex

• Dara-bortezomib (sc)-thalidomide-dexamethasone (VTD)1

– 100% ORR– Daratumumab does not appear to have a negative effect on

stem cell mobilization

• Phase 3 study is ongoing – VTD + daratumumab (induction, MMY3006/IFM-HOVON-

CASSIOPEIA)

• Elo-bortezomib (sc)-lenalidomide-dexamethasone (VRD)*2

– The addition of Elo is feasible with no major additive adverse events

1. Mateos MV et al. Haematologica. 2015;100. Abstract P275.2. Usmani SZ et al. Blood Cancer J. 2015;5:e334.*In high-risk patients



GEM2005MAS65: VMP/VTP→VT/VPImpact of Response in the Whole Series of Patients

(n=260)


Mateos MV et al. GEM2005 trial update comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-1893.

GEM2005MAS65: VMP/VTP→VT/VPImpact of Flow-CR in the Whole Series After Induction

(n=153)

Modified from Figure 3C & 3D, page 1891

Mateos MV et al. GEM2005 trial update comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-1893.



MPT

MP

VMP

Alkylator-based regimens

Alkylator-freeregimens

Len-dex

IMiDs

Six randomized trials:benefit in

PFS & OS...6 m

One randomized trial:benefit in PFS & OS

One randomized trial:benefit in PFS & OS

vs MPT

New Standards of Care for Elderly MM Patients

Figure 1

San Miguel JF et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-917.

Figure 2, page 451

San Miguel JF, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-455.

MP + Bortezomib (VMP) vs MP: VISTABortezomib Twice a Week× 4 Cycles + Weekly× 5 Cycles



Further optimization was done through subcutaneous administration.5

Modified-VISTA Schemes: Weekly Bortezomib

Study Details

Grade 3/4GI

Toxicity (%)

Grade 3/4 Peripheral

Neuropathy (%)

ORR (%)

CR (%)

PFS (mos)

OS (mos)

VISTA1,2: VMP Bortezomib twice weekly (5+4 cycles)

20 14 71 30 21 56

PETHEMA/GEM3: VMP Bortezomib once weekly except 1st cycle (6 cycles)

7 7 80 20 — —

GIMEMA4: VMP Bortezomib once weekly (9 cycles)

— 5 81 24 25 54

1. San Miguel J et al. J Clin Oncol. 2013; 31:448.2. San Miguel J et al. N Engl J Med. 2008;359:906.

3. Mateos MV et al. Lancet Oncol. 2010;11:934.4. Palumbo A et al. J Clin Oncol. 2010;28:5101.

5. Moreau P et al. Lancet Oncol. 2011;12:431.

FIRST Trial: Study Design

1. Benboubker L et al. N Engl J Med. 2014;371:906. 2. Facon T et al. Lancet. 2007;370:1209.

3. Hulin C et al. J Clin Oncol. 2009;27:3664.

Patients >75 yrs: LoDEX 20 mg D1, 8, 15, 22/28; THAL 100 mg D1–42/42; MEL 0.2 mg/kg D1–4.All patients received thromboprophylaxis.

• Stratification: age, country, and ISS stage

RA

ND

OM

IZA

TIO

N 1

:1:1

Arm BRd18

Arm CMPT

LEN + LoDEX 18 Cycles1 (72 wks) LENALIDOMIDE 25 mg D1-21/28LoDEX 40 mg D1,8,15 & 22/28

MEL + PRED + THAL 12 Cycles2,3 (72 wks)MELPHALAN 0.25 mg/kg D1-4/42PREDNISONE 2 mg/kg D1-4/42THALIDOMIDE 200 mg D1-42/42

PD

, OS

, an

d

Su

bse

qu

ent

AM

T

PD

or

Un

acce

pta

ble

To

xici

ty

Active Treatment + PFS Follow-up Phase

LEN + LoDEX Continuously1

LENALIDOMIDE 25 mg D1-21/28LoDEX 40 mg D1,8,15 & 22/28

Arm ARd Continuous

ScreeningLT

Follow-Up

AMT, antimyeloma therapy; ISS, International Staging System; LEN, lenalidomide; LoDEX, low-dose dexamethasone; LT, long-term; MEL, melphalan; PD, progressive disease; PRED, prednisone; THAL, thalidomide.



FIRST Trial: Progression-Free Survival & Overall Survival


Benboubker L, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-917.

Severely frail:Dependent on other

people

Elderly MM Patients Are a Heterogeneous Group

Very fit: Active, exercise

regularly

Moderately fit:Not regularly active but

routinely walking

Vulnerable:Can perform limitedactivities; don’t need

help

Mildly frail:Need help for

household tasks

Moderately frail:Need partial help for

personal care

Palumbo A et al. Blood. 2011;118:4519.



Optimization of the Treatment

Chronological vs

biological age

Fit/independent vs

frail/dependent on help

ComorbiditiesDisability

• We need a simple and time-efficient tool to evaluate the status of patients− Age− Comorbidities− Cognitive condition− Physical condition

Palumbo A et al. Blood. 2015;125:2068.Bonanad S et al. J Geriatric Oncol. 2015;6:353.

Elderly patients with myeloma are a veryheterogenous population.

Activity of Daily Living, Instrumental Activity of Daily Living, Charlson Comorbidity Score, Freiburg Comorb Index, GAH scale...

Gait speed

Mood

ADL/IADL

Nutrition

Options for Elderly Patients

Fit Unfit Frail

Alkylator-based comb

VMPCyBorD

Alkylator-free comb

VTPRVdRd until DP

Bz biweekly the 1st cycle and weekly thereafter; Bz SQThal doses up to 200 mgLen full dosesCy at 500 mg/m2 days 1, 8, 15Melph full dosesDex low doses: 40 mg weekly



VMP × 9 cycles Lendex × 9 cycles

Sequential scheme

Alternating scheme*

Mateos MV et al. Blood. 2015; Oct 23 [Epub ahead of print].

Both schemes were equivalent in terms of efficacy and safety:• ORR of 77% and 80%, respectively• CR rate of 42% and 40%, respectively

VMP/Rd: GEM/Pethema GEM2010 Trial

VMP Rd VMP Rd VMP Rd VMP Rd VMP Rd VMP Rd VMP Rd VMP Rd VMP Rd

231 symptomatic newly diagnosed MM patients >65 years

VMP/RD According to the Age(65–80 vs ≥80 yrs)

Mateos MV et al. Blood. 2015; Oct 23 [Epub ahead of print].

≥80 yrs: 24m

<80 yrs: 33 m

P=0.01

9080706050403020100

1.0

0.8

0.6

0.4

0.2

0.0

Median f/u: 37 m (3 yrs)

PFS

≥80 yrs: 30 m

<80 yrs: 80% at 3 yrs

P<0.0001

50403020100

1.0

0.8

0.6

0.4

0.2

0.0

OS




VMP CyBorD

Alkylator-free comb

VTP/VdRVD x9cLd until DP


Bz weekly since the beginning; Bz SQThal doses not superior to 100 mgLen 25 mg daily in Ld, but 15 mg in RVDCy 300 mg/m2 days 1, 8, 15Melph reduced doses: 6–7 mg/m2

Dex reduced doses: 20 mg weekly

Fit Unfit Frail


Fit Unfit Frail


CyTPCyBorPVMP lite

Alkylator-free comb

VPLd until DP

Bz weekly since the first cycle; Bz SQThal doses not superior 50 mgLen dose of 10–15 mgCy dose of 50 mg dailyMelph reduced dosesPrednisone instead of dex



What about the second-generation proteasome

inhibitors?

Second-Generation Proteasome Inhibitorsin Elderly Newly Diagnosed MM Patients:

Carfilzomib & Ixazomib

1. Moreau P et al. Blood. 2015;125:3100.2. Bringhen S et al. Blood. 2014;124:63.

3. Dytfeld D et al. Haematologica. 2014;99:e163.4. Kumar S et al. Lancet Oncol. 2014;15:1503.

Carf-Cydex has been also evaluated with carfilzomib weekly.

Carf-MP1

Phase 1/2Carf-Cydex2

Phase 2Carf-Rd3

Phase 1/2I-Rd4

Phase 1/2

Patients (N) 50 58 23≥65 years

65(34 ≥65 years)

ORR (%) 90 95 100 88

≥VGPR (%) 58 (12% CR) 71 (49% nCR, 20% sCR)

91 (≥ nCR 87%, sCR 65%)

60 (sCR/CR 24%)

Safety profile G3: PN: 1% No PN G3–4: PN 13% (all grades 1/2)

G3–4: PN 6%Skin rash 17%

Phase 3 KMP vs VMP ─ Carf-Rd vs Rd IRd vs Rd



What will be the addition of “a different fourth drug” in the

near future?

VMP +/- DaratumumabLenalidomide-Dex +/- DaratumumabLenalidomide-Dex +/- Elotuzumab

• Bortezomib (sc)-melphalan and prednisone (VMP) + dara– 100% ORR

• Phase 3 studies are ongoing – VMP +/- Daratumumab (Alcyone trial)– Rd +/- Daratumumab (Maia trial)– Rd +/- Elotuzumab (Eloquent-1 trial):

completed recruitment

Mateos MV et al. Haematologica. 2015;100. Abstract P275.



Conclusions• Highest quality of the response (inside/outside BM)

should be the goal for all MM patients• PI-based combinations plus IMiDs will be the standard of

care as induction for NDMM patients, plus the addition of mAbs

• Number of cycles undecided: – 4–6 for trx-eligible– Fixed vs continuous for non-trx eligible

• Dose adjustments should be considered based on age and comorbidities to enable optimal delivery of effective therapy

• Numerous planned/ongoing studies addressing questions of optimal regimen, schedule, treatment duration...to optimize and individualize induction therapy

Panel Discussion




Case Study Part 2• Induction chemotherapy: RVd × 4 cycles

– Aspirin and acyclovir prophylaxis

• Bone health: bisphosphonates every month

• Best response: VGPR by IMWG criteria

• Relevant events during induction– Grade II peripheral neuropathy after cycle #2

• Started on gabapentin, symptoms controlled

– Increasing lower back pain during cycle #3• L3 compression fracture, undergoes kyphoplasty with

near complete resolution of back pain



Based on the patient’s response to induction therapy, you collect stem cells.

What would you consider next ?

A. Continue current regimen

B. Wait to transplant after relapse

C. Proceed to transplant

D. Provide consolidation therapy

?

Case Study Part 2• Transplant eligible• Collects 13.5 million CD34 cells/kg BW in six bags• Mel-200 ASCT with 4.2 million CD34 cells/kg BW in

two bags• Transplant course: grade 3 diarrhea, resolved by Day

+28• Restaging post-ASCT

– M spike 0– Normal k/l ratio– BM biopsy shows no clonal PCs and normal hematopoiesis– sCR by IMWG criteria

• Patient comes to discuss maintenance



Is now an appropriate time for MRD testing?


?

Do you recommend maintenance?


?



Would the MRD result affect your decision to use maintenance therapy?


?

Which maintenance treatment do you recommend?

A. LenalidomideB. BortezomibC. Lenalidomide, bortezomibD. ThalidomideE. PrednisoneF. Clinical trialG. I don’t use maintenance

?



Would your maintenance choice change if the patient had low-risk cytogenetics?


?

High-Dose Therapy and Hematopoietic Cell

Transplantation: Current Status in Myeloma

Sergio A. Giralt, MDMelvin Berlin Family Chair in Myeloma Research

Professor of MedicineWeill Cornell Medical College

Chief, Adult Bone Marrow Transplant ServiceDivision of Hematologic Oncology

Department of MedicineMemorial Sloan Kettering Cancer Center

New York, New York



Disclosures

• Consultant/Advisor: Celgene, Jazz Pharmaceuticals, Onyx Pharmaceuticals, an Amgen subsidiary, Sanofi, Takeda Oncology

• Research Grant: Celgene, Sanofi, Takeda Oncology

Rationale for High-Dose Therapy

100%

Cures

DoseLethal bone

marrow toxicityLethal toxicity

to other organs



McElwain et alLancet 1983

McElwain TJ, Powles RL. Lancet. 1983;2:822.Barlogie B et al. Blood. 1987;70:869.

Transplant Eligible vs Transplant Ineligible

Transplant ineligible• Poor performance status

– Elderly and frail– Unable to perform activities of daily living– Decompensated comorbidity

• Congestive heart failure (CHF)• Uncontrolled diabetes• Unstable angina

• Socioeconomic factors– Lack of caregiver– Distance from transplant center– Inability to comply with peritransplant

follow-up care• Patient choice• Very low–risk disease

– Asymptomatic myeloma– Solitary plasmacytoma

• AGE PER SE SHOULD NOT BE CONSIDERED AN ABSOLUTE CONTRAINDICATION FOR STEM CELL COLLECTION AND TRANSPLANTATION

Transplant eligible• Good performance status• Adequate organ function

– Compensated comorbidities• No actve CHF• Patients with renal failure stable on dialysis

are appropriate candidates• No active uncontrolled infections• No acute bleeding or recent thromboembolic

events

• Socioeconomic factors– Adequate caregivers– Adequate support for transport to and

from transplant center– Ability to comply with peritransplant

follow-up care• Willing to proceed



100-Day Mortality by HCT-CI After Autologous Hematopoietic Cell Transplantation According to Performance Score and Disease Indication

100-

Day

Mo

rtal

ity

(%)

0

5

10

15

KPS <80 KPS >80 Myeloma Lymphoma

HCT CI 0

HCT CI 1–2

HCT CI >3

Sorror ML et al. Biol Blood Marrow Transplant. 2015;21:1479.Saad A et al. Biol Blood Marrow Transplant. 2014;20:402.

847

3,24

6

4,26

4

957 2,

710 4,

820

2,04

4

9,61

8

22,3

57

1,36

9

6,63

8

17,8

39

0

5,000

10,000

15,000

20,000

25,000

18-49 50-64 65+

Number of newly diagnosed cases Number of first AHPCT

212

616

228

237

592

1651,02

5

4,08

1

1,90

3

643

2,85

0

1,23

9

0

5000

10000

15000

20000

25000

18-49 50-64 65+

0

0.1

0.2

0.3

0.4

0.5

0.6

40 45 50 55 60 65 70 75 80 85 90

AHPCT “utilization rate”

Black men Black women White men White women

Black menBlack womenWhite menWhite women



Case Studies Case 1• 55-year-old woman presents

with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L

• Workup reveals– 30% plasma cells– Cytogenetic diploid– IgA kappa peak of 3.2– β2M of 3.0

• Receives 4 cycles of Bz/Thal/Dex

• Achieves stringent CR

Case 2• 55-year-old woman presents

with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L

• Workup reveals– 30% plasma cells– Cytogenetic t(4;14)– IgA kappa peak of 3.2– β2M of 3.0

• Receives 4 cycles of Bz/Thal/Dex

• Paraprotein peak stays at 2.8 gm/dl

Timing of HCT

• What are the issues?– Early vs late– After fixed number of cycles

• 4–6, 8–10?– After a defined response

• VGPR?• Plateau?• What about the nonresponder?

• NO RANDOMIZED TRIALS BEING PERFORMED



Effect of Pre-transplant Salvage Therapy Prior to Autologous

Transplant (AHCT) in Patients Not Responding to Initial Induction for

Multiple Myeloma (MM)

CIBMTR Study MM06-04

Vij R et al. Biol Blood Marrow Transplant. 2015;21:335.

Methods

< PR toinduction

Salvage chemotherapy

Autologous transplant

Diagnosis and initial induction

Autologous transplant

12 months from diagnosis to AHCT

Salvage cohort

No salvage cohort

AHCTDiagnosis




Years Years0 2 4 1086

100

0

20

40

60

80

90

10

30

50

70

No salvage(n=251)

Salvage(n=324)

PFS

0 2 4 10860

100

20

40

60

80

90

10

30

50

70

Salvage(n=324)

No salvage(n=251)

OS

P=0.3470 P=0.2622

Outcomes With/Without Pre-AHCT Salvage


Study DesignAge ≤65

• 2 phase 3 trials comparing Mel 200-ASCT vs CC+R

Gay F et al. Blood. 2014;124. Abstract 198.

GIMEMA MM-RV-209Rd induction

(N=402)

EMN-441Rd induction

(N=389)

Eligible for first randomizationN=529

Mel200-ASCTN=268

Rd-Mel200Rd-Mel200-R

Rd-Mel200-RP

CC+RN=261

Rd-MPR-RRd-MPR

Rd-CRD-RRd-CRD-RP

Random




Mel200-ASCT vs CC+R: PFS1Median Follow-Up From Randomization: 4 Years

First line Second line Subsequent lines Death

PFS1: from random to first progression

Median PFS1

Mel200-ASCT 41 months

CC+R 26 months

1.00

0.00

0.50

0.75

0.25

0 10 20 30 40 50 60 70 80Months

HR 0.55 (95% CI 0.45–0.69) P<0.0001

Mel200-ASCT

CC+R

Pat

ien

ts (

%)


Mel200-ASCT vs CC+R:Second-Line Therapy

• Only 57% of patients relapsing from CC+R actually received ASCT• Most of the patients who received ASCT at first relapse were re-

induced with bortezomib (66% in Mel200-ASCT and 84% in CC+R)

Mel200-ASCT

CC+R

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

Transplant at relapse Bortezomib IMIDs Other

No transplant at relapse

57% 34% 6%3%

13% 63% 17% 7%




Mel200-ASCT vs CC+R: OSMedian Follow-Up From Randomization: 4 Years

First line Second line Subsequent lines Death

OS: from random to death

4-year OS

Mel200-ASCT 84%

CC+R 71%1.00

0.00

0.50

0.75

0.25

0 10 20 30 40 50 60 70 80Months

HR 0.59 (95% CI 0.40–0.87) P=0.008

Mel200-ASCT

CC+R

Pat

ien

ts (

%)


Mel200-ASCT vs CC+ROS Subgroup Analysis

HR (95% CI) P value

Age <60 0.67 (0.41–1.11) 0.117

Age ≥60 0.44 (0.23–0.86) 0.015

KPS 60%–70% 0.76 (0.33–1.72) 0.506

KPS 80%–100% 0.54 (0.34–0.85) 0.008

ISS I/II 0.55 (0.34–0.89) 0.016

ISS III 0.75 (0.38–1.45) 0.376

No del17, t(4;14), t(14;16) 0.57 (0.34–0.94) 0.029

Del17, t(4;14), t(14;16) 0.60 (0.31–1.14) 0.118

LDH < ULN 0.62 (0.41–0.95) 0.027

LDH ≥ ULN 0.23 (0.03–1.92) 0.177

0,01 0,1 1

Favors Mel200-ASCT Favors CC+R



Design of EuropeanPhase 3 Studies

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

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

IFM 2005-1[1]

R

PAD ASCT1 ± ASCT2 Bort maintenance

VAD ASCT1 ± ASCT2 Thal maintenance

HOVON-65/GMMG-HD4[2]

VTD ASCT1 + ASCT2 + VTD cons. Dex maintenance

TD ASCT1 + ASCT2 + TD cons. Dex maintenance

GIMEMA MM-BO2005[3]

VTD ASCT1

CHT + Bort ASCT1

PETHEMA GEM05MENOS65[4]

TD ASCT1 Thal

VT

IFN

1. Harousseau JL et al. J Clin Oncol. 2010; 28:4621.2. Sonneveld P et al. J Clin Oncol. 2012;30:2946.

3. Cavo M et al. Lancet. 2010;376:2075.4. Rosinol L et al. Blood. 2012;120:1589.

R

R R R

Multivariate Analysis of Prognostic Factors for PFS

Variable PFS

HR 95% CI p

< CR at induction 1.80 1.29–2.51 0.001

Del(17p) and/or t(4;14) 1.56 1.18–2.05 0.002

ISS >2 1.57 1.14–2.17 0.006

Plts <150 (109/L) 1.48 1.05–2.08 0.025

Hb <10.5 (g/dL) 1.32 1.03–1.70 0.028

Del(13q) 1.20 0.94–1.54 0.145

IgA isotype 1.13 0.85–1.50 0.393

Creat >1.2 (mg/dL) 0.87 0.64–1.19 0.391

1 2Hazard Ratio

Cavo M et al. Blood. 2013;122. Abstract 767.



Score System Definition(Assessable Pts = 606)

Score Group

Prognostic variables

ISSCytogenetic

AbnormalitiesResponse at

Induction # of Pts (%)

0 1–2 Del(17p) – t(4;14)- CR 77 (12.71%)

1 Presence of a single adverse variable 369 (60.88%)

1–2 Del(17p) – t(4;14)- < CR 330 (54.45%)

1–2 Del(17p) ± t(4;14) CR 22 (3.63%)

3 Del(17p) – t(4;14)- CR 17 (2.80%)

2 Presence of 2 out of 3 adverse variables 141 (23.27%)

1–2 Del(17p) ± t(4;14) < CR 70 (11.55%)

3 Del(17p) – t(4;14)- < CR 65 (10.73%)

3 Del(17p) ± t(4;14) CR 6 (0.99%)

3 3 Del(17p) ± t(4;14) < CR 19 (3.14%)


PFS According to Score Groups

Log-rank test: score 0 vs 1 P=0.0546

P<0.0001 score 1 vs 2 P<0.0001

trend P<0.0001 score 2 vs 3 P=0.0103

1.00

0.75

0.00

0.25

0.50

Months0

Kaplan-Meier survival estimates

12 24 36 48 60

61 mo

score 0

score 1

score 2

score 3

56 mo36 mo26 mo




What is the role of consolidation?

PFS According to Preplanned Number of ASCT(s)

Log-rank test: HR 0.72 (0.60–0.87)

P=0.0005 P<0.001

50 mo2 ASCT

38 mo

1 ASCT


Kaplan-Meier survival estimates1.00

0.75

0.00

0.25

0.50

Months0 12 24 36 48 60



PFS According to Preplanned ASCT(s) for Pts With del(17p) and/or t(4;14) and Who Failed CR

After B-based Induction Regimens

Score

Prognostic Factors

ISS Cytogenetic Abnormalities Response at Induction # of Pts (%)2 141 (23.27%)

1–2 Del(17p) ± t(4;14) < CR 70 (11.55%)

3 Del(17p) – t(4;14)- < CR 65 (10.73%)

3 Del(17p) ± t(4;14) CR 6 (0.99%)

Cavo M, et al. Double vs single autologous stemcell transplantation after bortezomib-basedinduction regimens for multiple myeloma: anintegrated analysis of patient-level data from phaseEuropean III studies [abstract]. Blood. 2013;122(21). Abstract 767.

OS According to Preplanned ASCT(s) for Pts With del(17p) and/or t(4;14) and Who Failed CR

After B-based Induction Regimens

Score

Prognostic Factors

ISS Cytogenetic Abnormalities Response at Induction # of Pts (%)2 141 (23.27%)

1–2 Del(17p) ± t(4;14) < CR 70 (11.55%)

3 Del(17p) – t(4;14)- < CR 65 (10.73%)

3 Del(17p) ± t(4;14) CR 6 (0.99%)

Cavo M, et al. Double vs single autologous stemcell transplantation after bortezomib-basedinduction regimens for multiple myeloma: anintegrated analysis of patient-level data from phaseEuropean III studies [abstract]. Blood. 2013;122(21). Abstract 767.



Lenalidomide maintenance†

Lenalidomide maintenance†

BMT CTN 0702: SCHEMA

Register and randomize MEL 200

mg/m2VRD × 4*

Lenalidomide maintenance*

MEL 200 mg/m2

*Bortezomib 1.3 mg /m2 days 1, 4, 8, 11 Lenalidomide 15 mg days 1–15 Dexamethasone 40 mg days 1, 8, 15

†Lenalidomide 15 mg daily × 3 years

https://clinicaltrials.gov/ct2/show/NCT01109004.

IFM/DFCI 2009 StudyNewly Diagnosed MM Pts (SCT Candidates)

VRD × 3

VRD × 2 VRD × 5

Lenalidomide 12 mos

Melphalan200 mg/m2*

+ ASCT

Induction

Consolidation

Maintenance

CY (3g/m2) MOBILIZATION

Goal: 5 ×106 cells/kg

VRD × 3

CY (3g/m2)MOBILIZATION

Goal: 5 ×106 cells/kg

Randomize, stratification ISS & FISH

Collection

Lenalidomide 12 mos

SCT at relapse MEL 200 mg/m2 if <65 yrs,

≥65 yrs 140 mg/m2

http://www.clinicaltrials.gov/ct2/show/NCT01208662?term=nct01208662&rank=1.Attal M et al. Presented at: 57th ASH Annual Meeting & Exhibition. Orlando, FL; December 2015. Abstract 391; Sunday, December 6.



What is the role of maintenance?

Lenalidomide: 10–15 mg/d until relapse

Placebo until relapse

First-line

ASCT<65 years

Lenalidomide: 25 mg/d Days 1–21/month2 months

Primary end point: PFS

≤6 monthsNo PD

N=614

Lenalidomide: 25 mg/d Days 1–21/month2 months

Consolidation

Phase 3 IFM 2005-02: Lenalidomide as Consolidation/Maintenance Post-ASCT

Attal M et al. N Engl J Med. 2012;366:1782.



HR 0.37 (CI 95% 0.25–0.58) HR 0.54 (CI 95% 0.37–0.78)

Phase 3 IFM 2005-02: PFS According to Response Preconsolidation

Attal M et al. Blood. 2009;114. Abstract 529.Attal M et al. J Clin Oncol. 2010;28. Abstract 8018.

Attal M et al. N Engl J Med. 2012;366:1782.

LEN PLA

PR or SD VGPR or CR

P<10-5 P=0.0010.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

LEN PLA

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

Stage 1–3, <70 yearsTherapy at least 2 cycles Stable disease or better≤1 year from Rx initiation2 × 106 CD34 cells/kg

Placebo

Lenalidomide10 mg/d with ↑↓ (5–15 mg)

RestagingDays 90–100

Registration

CRPRSD

Stratification based on diagnostic β2M andIMiD use during induction

Mel 200

ASCT

CALGB 100104 Schema

McCarthy PL et al. N Engl J Med. 2012;366:1770.



CALGB 100104

Figure S2e, supplement to:

McCarthy PL, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1770-1781.


McCarthy PL, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1770-1781.



Impact of Response on Outcome: OS After 1 or 2 Transplants

IFM 99 trials courtesy of JL Harousseau.Harousseau JL et al. Blood. 2006;108:3077.

VGPR

N=849

P=0.0002CR

PR

<PR

0 1 2 3 4 5 6 7 80.00

0.25

0.50

0.75

1.00

Median follow-up

Making Transplant Easier

%



Symptoms, Toxicities, and Cytokines

Wang XS et al. Cancer. 2008;113:2102.

0

6

10

2

Glo

bal

Mea

n S

ymp

tom

Sev

erit

y

8

4

1.1 1.2 1.3 1.4 1.5 1.6 1.7Global Mean (log) Cytokine

0

6

7

2

5

4

1

3

Mea

n M

DA

SI

Sev

erit

y

0

1.5

2

1

0.5

IL-6

(lo

g)IL-6

Symptoms

Does high-dose therapy and transplant cure myeloma?

Long-term disease control is possible, and some patients may never have to

deal with their disease again…Are they cured?



>4 years (44)

<2 years (56)

2–4 years (42)NR→CR (12)

CR→CR (31)Median 16 yrs

PR→CR (79)

Primary→CR (24)

Natural History of CR on Myeloma OutcomesRole for HDT in CR Patients

Years of Treatment

20

40

60

80

100

5 10 15

Per

cen

t L

ivin

g

0

Years of Treatment

20

40

60

80

100

5 10 15

Per

cen

t L

ivin

g

0200200

Median 14 yrs

AHCT as Initial Therapy

Raghavendra M. et al. Blood. 2013;122. Abstract 760.

0%

40%

20%

80%

100%

60%

10%

50%

30%

90%

70%

Yes No

Cohort 1 Cohort 1 Cohort 1 Cohort 1



CR Definition Does Matter With Regards to Depth of Remission

Figure 1

Poon ML, Chng WJ. Is complete remission an important therapeutic aim in multiple myeloma? Cancer Ther. 2008;6:275-284.

In My Humble Opinion• High-dose melphalan is one of the most active agents in

myeloma today– 30%–40% CR– 24 months median remission duration without maintenance– Name another agent with similar single-agent activity– It is also cost-effective

• With stem cell support it can be given safely to older patients with comorbidities

• Thus, not planning for its use up front is similar to telling a patient, “I am never going to use bortezomib or lenalidomide during your disease course because I don’t like it or I don’t believe in it”

• Early or late or once, twice, or more times, it remains an active agent that can be extremely effective in all stages of the patient’s disease journey

• Continued exploration in clinical trials is essential



Updates on Options for Relapsed/Refractory Disease

Saad Usmani, MD, FACPDirector, Plasma Cell Disorders Program

Director, Clinical Research in Hematologic MalignanciesDepartment of Hematologic Oncology & Blood Disorders

Levine Cancer InstituteCharlotte, North Carolina

Outline

• Practical considerations in choosing therapy for relapsed and/or refractory MM

• New options for relapsed MM (1–3 prior therapies)

• Role of transplant in relapsed and/or refractory MM



When to Consider Retreatment in Relapsed/Refractory MM

• Nature of relapse/progression– Slow/biochemical vs rapid/high burden– Renal failure, sPCL, EMD, bone fractures, cytogenetic

abnormalities

• Host factors– Age, comorbidities, performance status, organ failure

• Prior therapies/treatment-related factors– Tolerability, dose reductions, adverse events (AEs)/serious

adverse events (SAEs)– Duration of therapy and durability of previous response

• Socioeconomic aspects– Insurance issues, access to care, adequate social support

• Availability of clinical trials

Treatment Approaches in Relapsed/Refractory MM

Figure 1, page S72

Usmani SZ, Lonial S. Novel drug combinations for the management of relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2014 Sep;14 Suppl:S71-S77.



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

RdLenalidomide 25 mg Days 1–21


ASPIRE Study Design

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

28-day cycles

Stewart AK et al. N Engl J Med. 2015;372:142.

Randomization N=792

Stratification:

• β2 microglobulin

• Prior bortezomib

• Prior lenalidomide

LEN NAÏVE OR LEN SENSITIVE

ASPIRE ResultsKRd

(n=396)Rd

(n=396) HR P Value

Median PFS, mos 26.3 17.6 0.69 0.0001

24-mo OS, % 73.3 65 0.79 0.04

≥CR, % 31.8 9.3 ─ <0.001

Discontinuation 15.3 17.7 ─ ─

AEs, %

≥G3 cardiac failure 3.8 1.8 ─ ─

≥G3 ischemic heart disease 3.3 2.1 ─ ─

≥G3 hypertension 4.3 1.8 ─ ─

≥G3 acute renal failure 3.3 3.1 ─ ─

Stewart AK et al. N Engl J Med. 2015;372:142.

No benefit observed in patients who were previously non-responsive to bortezomib and refractory to immunomodulatory agent.



ELOQUENT-2 Study Design Open-label, international, randomized, multicenter phase 3 trial (168 global sites)

Lonial S et al. N Engl J Med. 2015;373:621.


Elo + Len/Dex (E-Rd) schedule (n=321)Elo (10 mg/kg IV): Cycle 1 and 2: weekly;

Cycles 3+: every other weekLen (25 mg PO): days 1–21

Dex: weekly equivalent, 40 mg

Len/Dex (Rd) schedule (n=325)Len (25 mg PO): days 1–21;

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

Key inclusion criteria

• RRMM

• 1–3 prior lines of therapy

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

Assessment• Tumor response:

every 4 weeks until progressive disease

• Survival: every 12 weeks after disease progression

• End points:– Co-primary: PFS and overall response rate (ORR)– Other: OS (data not yet mature); duration of response, quality of life, safety

• All patients received premedication to mitigate infusion reactions prior to Eloadministration

Repeat every 28 days

ELOQUENT-2 ResultsE-Rd

(n=321)Rd

(n=325) HR P Value

Median PFS, mos 19.4 14.9 0.70 <0.001

ORR, % 79 66 ─ <0.001

≥VGPR, % 33 28 ─ ─

AEs, %

≥G3 cardiac failure 4 6 ─ ─

≥G3 acute renal failure 4 4 ─ ─

Lonial S et al. N Engl J Med. 2015;373:621.

Patients with del17p, 1q21 amplifications, and t(4;14) fared as well as standard risk.

No benefit observed in patients who were previously exposed to immunomodulatory agent.



TOURMALINE-MM1 Study Design

Moreau P et al. Presented at: 57th ASH Annual Meeting & Exhibition. Orlando, FL; December 2015. Abstract 727.

IRdIxazomib 4 mg Days 1, 8, 15

Lenalidomide 25 mg Days 1–21Dexamethasone 40 mg Days 1, 8, 15, 22

RdLenalidomide 25 mg Days 1–21


28-day cycles


Randomization N=722

Stratification:

• Number of prior therapies

• PI exposure

• ISS stage

TOURMALINE-MM1 ResultsI-Rd

(n=360)Rd

(n=362) HR P Value

Median PFS, mos 20.6 14.7 0.742 0.012

ORR, % 78.3 71.5 ─ 0.035

≥VGPR, % 48.1 39.0 ─ 0.014

AEs, %

≥G3 Diarrhea 6 2 ─ ─

≥G3 PN 2 2 ─ ─

Benefit with IRd was also noted in pts with high-risk cytogenetics.

Moreau P et al. Presented at: 57th ASH Annual Meeting & Exhibition. Orlando, FL; December 2015. Abstract 727.



ENDEAVOR Study Design

Dimopoulos MA et al. J Clin Oncol. 2015;33. Abstract 8509.

KdCarfilzomib 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 disease progression or unacceptable toxicity

VdBortezomib 1.3 mg/m2 (3–5 second IV bolus

or subcutaneous injection)Days 1, 4, 8, 11


21-day cycles until disease progression or unacceptable toxicity

BOR NAÏVE OR BOR SENSITIVE

Randomization 1:1 N=929

Stratification:

• Prior proteasome inhibitor therapy

• Prior lines of treatment

• ISS stage

• Route of administration

ISS, International Staging System

ENDEAVOR ResultsKd

(n=464)Vd

(n=465) HR P Value

Median PFS, mos 18.7 9.4 0.53 <0.0001

≥CR, % 12.5 6.2 ─ ─

≥VGPR, % 54.3 28.6 ─ ─

Discontinuation 14.0 15.7 ─ ─

AEs, %

≥G3 Hypertension 8.9 2.6 ─ ─

≥G3 Dyspnea 5.6 2.2 ─ ─

≥G3 Cardiac failure 4.8 1.8 ─ ─

≥G3 Acute renal failure 4.1 2.6 ─ ─

≥G2 PN 6.3 32.0 ─ <0.0001

Dimopoulos MA et al. J Clin Oncol. 2015;33. Abstract 8509.

No benefit observed in patients refractory to lenalidomide



Pano-VdPanobinostat 20 mg Days 1, 3, 5, 8, 10, 12

Bortezomib 1.3 mg/m2 Days 1, 4, 8, 11Dexamethasone 20 mg Days 1, 2, 4, 5, 8, 9, 11, 12

VdBortezomib 1.3 mg/m2mg Days 1, 4, 8, 11


RandomizationN=768

Stratification:

• Number of previous treatment lines

• Prior bortezomib

PANORAMA1 Study Design21-day cycles

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

LEN AND BZ EXPOSED

PANORAMA1 ResultsPano-Vd(n=387)

Vd(n=381) HR P Value

Median PFS, mos 12 8.1 0.63 <0.0001

ORR, % 60.7 54.6 ─ 0.09

≥nCR, % 27.6 15.7 ─ <0.001

IMiD + bortezomib, mos 10.6 5.8 -- --

IMiD + bortezomib + ≥2 prior lines, mos

12.5 4.7 -- --

AEs, %

≥G3 Diarrhea 25 7 ─ ─

≥G3 Asthenia 24 12 ─ ─

≥G3 PN 17 15 ─ ─

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

Benefit less pronounced in women and patients > 65 years BUT more evident in patients who with previous exposure to bortezomib and immunomodulatory agent.




Figure 1, page S72



Figure 1, page S72




Summary of PI Combination Therapy

Regimen Phase N

Outcomes, %

NotesORR CR VGPR PR

Carfilzomib + lenalidomide + LoDex1

2 84 69 4.8 35.7 28.6ORR similar

in bor- or len-refractory pts

Bortezomib+ pomalidomide + LoDex2

1 28 70 7 37 26

Carfilzomib + pomalidomide + dexamethasone3

2 79 70 – 27 43 PFS: 9.7 mos

Carfilzomib + cyclophosphamide + thalidomide + dexamethasone4

1b/2 64* 91 5 51 22 PFS 76% (24 mos)

1. Wang M et al. Blood. 2013;122:3122. 2. Richardson PG et al. J Clin Oncol. 2014;32. Abstract 8589.

3. Shah JJ et al. Blood. 2013;122. Abstract 690.4. Mikhael JR et al. Br J Haematol. 2015;169:219.

CR, complete response; MTD, maximum tolerated dose; ORR, overall response rate; PFS, progression-free survival; PR, partial response; SD, stable disease; VGPR, very good partial response.

*In newly diagnosed MM

1. Berdeja JG et al. J Clin Oncol. 2015;33. Abstract 8513. 2. Plesner T et al. Presented at: 57th ASH Annual Meeting & Exhibition. Orlando, FL; December 2015. Abstract 507.

3. Chari A et al. Presented at: 57th ASH Annual Meeting & Exhibition. Orlando, FL; December 2015. Abstract 508.4. Raje N et al. Blood. 2013;122. Abstract 759.

5. Raje N et al. EHA 2014. Abstract P358.

Summary of Other Notable Combination Therapy

Regimen Phase (N)

Outcomes

ORR CBR

Panobinostat + carfilzomib + dexamtheasone1

1 (36) 77%88%

(1 pt CR, 10 pts VGPR, 16 pts PR, 4 pts MR, 4 pts SD)

Daratumumab + lenalidomide + dexamtheasone2

1/2 (32) 88% ─

Daratumumab + pomalidomide + dexamtheasone3

1b (77) 58.5% ─

Ricolinostat ±bortezomib + dexamethasone4

1 (20) 25% (heavily pretreated)

60% (2 pts VGPR, 3 pts PR,

2 pts MR, 5 pts SD)

Ricolinostat + lenalidomide + dexamethasone5

1 (22) 64%100%

(1 pt CR, 5 pts VGPR, 8 pts PR, 3 pts MR, 5 pts SD)



100

2 4 53

80

60

40

20

0

Summary of Combination Therapy

Median Lines of Tx:

1. Dimopoulos M et al. N Engl J Med. 2007;357:2123. 2. Stewart AK et al. N Engl J Med. 2015;372:142. 3. Richardson PG et al. Blood. 2014;123:1461. 4. Lacy MQ et al. Blood. 2014. Abstract 304.

5. Mikhael JR et al. Br J Haematol. 2009;144:169. 6. Monge J et al. J Clin Oncol. 2014. Abstract 8586. 7. Morgan GJ et al. Br J Haematol. 2007;137:268. 8. Baz R et al. Blood. 2014. Abstract 303.

9. San Miguel J et al. Lancet Oncol. 2013;14:1055. 10. Lendvai N et al. Blood. 2014;124:899. 11. Shah JJ et al. Blood. 2013. Abstract 690.

RD

*1

CR

D7

Pd

*9

CP

d8

Kd

10

KR

d*2

KP

d11

Vd

*5

RV

D*3

PV

d4

CyB

orD

6

RD

*1

Pd

*9

CP

d8

Kd

10

KR

d*2

KP

d11

RV

D*3

PV

d4

CyB

orD

6

OR

R (

%)

Su

rviv

al (

Mo

s)*Data from phase 3 trials, all others from phase 1 or 2 trials

6065

31

6555

87

706764

85

71

35

30

25

20

15

10

5

0

11

NR

4

1310

NR

4

20

NR

26

10

NR

30

10

29

911

NR

2 3 4 5Median Lines of Tx:

ORR OSPFS/TTP

Salvage Autologous Stem Cell Transplant

• Option for:– Patients who deferred autologous stem

cell transplant for first relapse

– ≥18 month PFS benefit from first autologous stem cell transplant

– Special considerations: improve cytopenias and bridge to clinical trial or allogeneic stem cell transplant

Giralt S et al. Biol Blood Marrow Transplant. 2015;21:2039.



Salvage Allogeneic Stem Cell Transplant

• Nonrandomized experience showing long-term disease control in some patients

• Randomized tandem auto-SCT vs auto-SCT/allo-SCT: nonrelapse mortality higher, survival similar

• Option for young, fit MM patients, BMT-CTN 1302 phase 2 trial accruing for high-risk patients

Monoclonal Antibody–Based Therapeutic Targeting of MM

Apoptosis/growtharrest via targetingsignaling pathways

Complement-dependentcytotoxicity

(CDC)

Antibody-dependentcellular cytotoxicity

(ADCC)

• Lucatumumab or Dacetuzumab (CD40)

• Elotuzumab (CS1)• Daratumumab (CD38)• XmAb5592 (HM1.24)

• Daratumumab (CD38) • huN901-DM1 (CD56)• nBT062-maytansinoid (CD138)• 1339 (IL-6)• BHQ880 (DKK1)• RAP-011 (activin A)• Daratumumab (CD38)

Tai YT, Anderson KC. Bone Marrow Res. 2011;2011:924058.



AnMed

Blue Ridge

Cleveland Regional

CMC

LCI-Lincoln

LCI-Mercy

LCI-NortheastLCI-Pineville

LCI-Union

Roper St. FrancisStanly Regional

Thank you for your attention!

LCI-University

LCI-Main

Panel Discussion




Case Study Part 3• Patient deferred Len maintenance and prefers

close observation

• Traveling for new job, starts to train for half-marathon 6 months post ASCT

• Monthly CBC, CMP, SPEP, FLC; doctor visits every 2–3 months

• Successfully runs half marathon for MMRF and raises $26K 1 year after ASCT

• Returns 2 years post-ASCT with increasing shoulder pain while working out in the gym, increasing fatigue, and urinary frequency with frothiness



Case Study Part 3ActualValue

Normal Range

CBC withdifferential

WBC (103/mL) 4.5 (4–11)

RBC (106/mL) 3.3 (3.8–5.2)

Hemoglobin (g/dL) 10 (13–16)

Hematocrit (%) 31 (34–45)

Platelets (103/mL) 175 (150–400)

Neutrophils (103/mL) 3 (1.9–7.5)

CMP

BUN (mg/dL) 27 (7–20)

Creatinine (mg/dL) 1.8 (0.7–1.2)

Calcium (mg/dL) 9.4 (8.4–10.2)


Albumin (g/dL) 3.7 (3.5–5.0)

SPEP


Gamma (g/dL) 2.8 (0.5–1.6)

M protein spike (g/dL) 2.1 –

ActualValue

Normal Range

QuantitativeIgs + serum immuno-fixation

IgG (mg/dL) 2,400 (700–1,600)

IgA (mg/dL) 75 (70–400)

IgM (mg/dL) 45 (40–230)

FLC

Kappa quant FLC (mg/L) 300 (3.30–19.40)

Lambda quant FLC (mg/L) 0.5 (5.71–26.30)

Kappa/lambda quant FLC ratio 600 (0.26–1.65)

24–hr urinecollection and UPEP

Protein random 120 –

Total protein timed (mg/24 hr) 3,200 (40–150)

E/P albumin (%) 30 –

1 (%) 2.5 –

2 (%) 3.5 –

(%) 2 –

(%) 62 –

M protein spike (%) 58 –

M protein spike (mg/24 hr) 1,856 –

Case Study Part 3

• BM biopsy:– 60% cellularity, 50% kappa-restricted

plasma cells– FISH positive for translocation (11;14) in

50% cells, del17p in 20%

• He is here to discuss treatment options



What would you use for treatment of MM in first relapse?

A. Bortezomib + dexamethasone ±cyclophosphamide

B. Lenalidomide + dexamethasoneC. Pomalidomide + dexamethasoneD. Bortezomib, lenalidomide, and

dexamethasoneE. Carfilzomib + dexamethasoneF. Carfilzomib + lenalidomide + dexamethasoneG. Elotuzumab + lenalidomide + dexamethasoneH. Daratumumab

?

2015: Immunotherapy for the Treatment of Multiple Myeloma

Thomas Martin, MDUniversity of California, San Francisco

Medical CenterSan Francisco, California



Disclosures

• Speakers Bureau: Millennium

What Is Immunotherapyin Myeloma?

• Passive immunity – Monoclonal antibodies (mAbs)/

aptamers– Targeting a receptor

• MM cell• Immune cell

• Adjuvant therapy – Vaccines– Whole-cell vaccine

• Active therapy– Allogeneic transplantation– CAR T cells– NK cell infusions

CD38SLAMF-7 CD138-ADCBCMA

CD38SLAMF-7 CD138-ADCBCMA

Dendritic cell–MM-DC fusionsDendritic cell–MM-DC fusions

MILSGVAX Oncolytic viruses

Peptide vaccines

PD-1PDL-1KIR

AlloSCTAlloSCT

CAR T cells T, NK cell



mAb-Based Therapeutic Targeting of Tumor

Apoptosis/growth arrest via targetingsignaling pathways

Complement-dependent

cytotoxicity (CDC)

Antibody-dependentcellular cytotoxicity

(ADCC)Antibody-delivery oftoxic payload (ADC)

• Elotuzumab (SLAMF7)

• Daratumumab/isatuximab (CD38)

• Lucatumumab or dacetuzumab (CD40)

• Daratumumab/ Isatuximab (CD38)

• 1339 (IL-6)• BHQ880 (DKK1)• RAP-011 (activin A)• Daratumumab/

Isatuximab (CD38)

• huN901-DM1 (CD56)• nBT062-maytansinoid

(CD138)

Tai YT, Anderson KC. Bone Marrow Res. 2011;2011:924058.

Excitement of Monoclonal Antibodies

• Novel mechanism of action− Additive or synergistic effects

with current anti-MM drugs• Generally well tolerated− Toxicity profile nonoverlapping

with approved anti-MM drugs• Can be combined with other

immune therapies• May be ideally suited to eliminate

MRD• May be beneficial in all patient

groups (SMM, ND, RR, MRD)• Many targets possible − MM cell− Microenvironment− Immune signals

Advantages

• Infusion reactions can limit therapy in some

• No biomarkers for response to predict who may most benefit

• Few long-term survivors

• Cost: very expensive to produce

Disadvantages



Targets for mAbs in MM

FDA Approved• Elotuzumab• Daratumumab

IL-6

CD

38

CD

40

CD

56

CX

CR

4

CD74

PD-1

CD138

β2M

MM cell

SL

AM

F7

Milatuzumab

PembrolizumabNivolumab

Atezolizumab

Indatuximab

Siltuximab

In clinical development

Preclinical activity

BC

MA

CD

70

CD

317

Elotuzumab in Relapsed/Refractory Multiple Myeloma:

Potential Synergy With Lenalidomide

Balasa B et al. Cancer Immunol Immunother. 2015;64:61.

Direct NK cell activation

NK cell

Elotuzumab

SLAMF7

ADCC

CD16a +Myeloma cell

Elotuzumab• Humanized IgG1 mAb, binds SLAMF7• Induces myeloma cell killing through

NK cell–mediated ADCC• Directly activates NK cells through

binding to SLAMF7 on NK cells

Lenalidomide• Enhances immune system

through production of IL-2 to increase NK cell activity

• Direct anti-MM effects



Elotuzumab in Relapsed/Refractory Multiple Myeloma:

Clinical Synergy With Lenalidomide• Elotuzumab in combination with lenalidomide and dexamethasone (E-Ld)

demonstrated a high response rate and progression-free survival (PFS) benefits in an open-label phase 1b/2 study1 in patients with MM

• Elotuzumab has FDA breakthrough therapy designation in MM

1. Richardson PG et al. Blood. 2014;124. Abstract 302.

6050403020100

-10-20-30-40-50-60-70-80-90

-100

10 mg/kg elotuzumab (n=36)

Per

cen

tag

e C

han

ge

Fro

m B

asel

ine

Maximum Percent Reduction in Serum M Protein in Multiple Myeloma – Study 17036050403020100

-10-20-30-40-50-60-70-80-90

-100

20 mg/kg elotuzumab (n=29)*

Per

cen

tag

e C

han

ge

Fro

m B

asel

ine

*Eight patients without measurable disease (baseline and all on-study M-protein levels <0.5 g/dL) were not included.

Repeat every 28 days

ELOQUENT-2 Study Design • Open-label, international, randomized, multicenter, phase 3 trial

(168 global sites)

Of note: ELOQUENT-1 Study: similar design in newly diagnosed MM; ongoing Lonial S et al. N Engl J Med. 2015;373:621.

• End points:– Co-primary: PFS and overall response rate (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 + Len/Dex (E-Ld) schedule (n=321)Elo (10 mg/kg IV): cycle 1 and 2: weekly;

cycles 3+: every other weekLen (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

Assessment• Tumor response:

every 4 weeks until progressive disease

• Survival: every 12 weeks after disease progression



ELOQUENT-2 StudyBaseline Demographics and Disease Characteristics

Table 1, page 625

Lonial S, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-631.

ELOQUENT-2 Study Results

Co-Primary End Point: Overall Response Rate

Lonial S et al. J Clin Oncol. 2015;33. Abstract 8508.

*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

100

80

60

40

20

0

Res

po

nse

Rat

e (%

)

ORR* CombinedResponse

(sCR + CR + VGPR)

CompleteResponse

(sCR + CR)†

Very GoodPartial Response

PartialResponse

E-Ld Ld79

66

3328

4 7

2821

4638

P=0.0002




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.

Figure 1A, page 626

Lonial S, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-631.

ELOQUENT-2 Study ResultsProgression-Free Survival by Tumor Response

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

Patients achieving ≥PR showed improved PFS with E-Ld vs Ld alone.

1.0

0.8

0.6

0.4

0.2

0.0

Pro

bab

ilit

y P

rog

ress

ion

Fre

e 0.9

0.7

0.5

0.3

0.1

1-year PFS 2-year PFSsCR + CR + VGPR (E-Ld)sCR + CR + VGPR (Ld)PR (E-Ld)PR (Ld)

Lonial S et al. J Clin Oncol. 2015;33. Abstract 8508.Lonial S et al. N Engl J Med. 2015;373:621.



24

ELOQUENT-2 Study ResultsProgression-Free Survival According to Age


100

80

60

40

20

0

Pro

gre

ssio

n-F

ree

Pat

ien

ts (

%)

90

70

50

30

10

0 2 4 6 8 101214161820222426283032343638

Time (months)

100

80

60

40

20

0

Pro

gre

ssio

n-F

ree

Pat

ien

ts (

%)

90

70

50

30

10

0 2 4 6 8 10121416182022 26283032343638

Time (months)

2-year PFS2-year PFS

≥65 years<65 years

Hazard ratio: 0.75(95% CI, 0.551.02)

Hazard ratio: 0.65(95% CI, 0.500.85)

40%

30%

E-Ld

Ld

42%

25%

E-Ld

Ld

1.0

0.8

0.6

0.4

0.2

0.0

Pro

bab

ilit

y P

rog

ress

ion

Fre

e

0.9

0.7

0.5

0.3

0.1

0 2 4 6 8 10 121416 18 20 2224 2628 3032 3436 38

PFS (months)



Progression-Free Survival of Patients With del(17p) and t(4;14) Translocation

1.0

0.8

0.6

0.4

0.2

0.0

Pro

bab

ilit

y P

rog

ress

ion

Fre

e

0.9

0.7

0.5

0.3

0.1

0 2 4 6 8 10 121416 18 20 2224 26 28 3032 3436 38

PFS (months)

t(4;14)+del(17p)+

Hazard ratio: 0.65(95% CI, 0.450.94)

Hazard ratio: 0.53(95% CI, 0.290.95)

E-Ld

Ld E-Ld

Ld



Maximal Reduction of Serum M-Component

RRMM:Dose 4–24 mg/kg QW ORR ~42%

Plesner T et al. Blood. 2012;120. Abstract 73.

Daratumumab: A Novel Anti-CD38 Monoclonal Antibody

504540353025201510

50

-5-10-15-20-25-30-35-40-45-50-55-60-65-70-75-80-85-90-95

-100-105-110

Max

imu

m %

Ch

ang

e In

Ser

um

M-C

om

po

nen

t M

on

ocl

on

al P

eak

1 (g

/L)

005

001 020

009

019 010

029

012

002 006 007 008 013 016 018 028

004 026

003 011017

014

015027 030

021

023031

022

0.005 mg/kg

2 mg/kg

0.05 mg/kg

4 mg/kg

0.1 mg/kg

8 mg/kg

0.5 mg/kg

16 mg/kg1 mg/kg

BM, bone marrow; SD, stable disease; MR, minimal response; FLC, free light chain

Daratumumab Phase 2 StudySingle Agent in RRMM

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)

Lonial S et al. J Clin Oncol. 2015;33. Abstract LBA8512.

Randomization

16 mg/kg(n=16)

8 mg/kg(n=18)

Response evaluated

16 mg/kg(n=106)

Additional 90 patients enrolled at 16 mg/kg DARA




97% refractory to last therapy, 95% double refractory, 63% Pom refractory Lonial S et al. J Clin Oncol. 2015;33. Abstract LBA8512.

Baseline CharacteristicsDemographic (n=106)

Median (range) age, yAge ≥75 y, n (%)

63.5 (31–84)12 (11)

Renal function (CrCl), n (%)≥60 mL/min<60 mL/min

60 (57)46 (43)

ISS staging, n (%)IIIIII

26(25)40 (38)40 (38)

ECOG score012

29 (27)69 (65)8 (8)

Median (range) time since diagnosis, y 4.8 (1–24) High-risk cytogenetics, n (%) 20 (19)

Prior therapies (n=106)

Median (range) number of prior therapies 5 (2–14) >3 lines of prior therapy, n (%) 87 (82)

Prior chemotherapy, n (%)Alkylating agentsAnthracyclines

106 (100)106 (100)55 (52)

Prior IMiD, n (%)LENPOMTHAL

106 (100)105 (99)67 (63)47 (44)

Prior ASCT, n (%) 85 (80)Prior PI, n (%)

BORTCARF

106 (100)105 (99)53 (50)

CrCl, creatinine clearance; ISS, International Staging System; LEN, lenalidomide; POM, pomalidomide; THAL, thalidomide; ASCT,autologous stem cell transplantation; BORT, bortezomib; CARF, carfilzomib.


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)


35

25

15

5

0

Ove

rall

Res

po

nse

Rat

e (%

)

30

20

10

16 mg/kg

ORR = 29%

sCRn=3 (3%)

VGPRn=10 (9%)

PRn=18 (17%)




Change in Paraprotein From Baseline


100

50

0

-75

-100

Max

imu

m C

han

ge

Fro

m

Bas

elin

e (%

)

75

25

-25

-50

-90

• The majority of patients had reductions in paraprotein from baseline– 40 patients (38%) had reductions >50%– 17 patients (16%) had reductions >90%

20

35

5

OR

R, %

10

25

15

0


40

30


33 3330

21 20

30 29 28 2826

21

ORR by Subgroup

Refractory to





Progression-Free and Overall Survival

20

80

Pat

ien

ts P

rog

ress

ion

-Fre

e an

d A

live

(%

)

40

0

100

60

0 2 4 6 8 10 12 14 16

Months From Start of Treatment

Median PFS = 3.7 months(95% CI, 2.8–4.6)

20

80

Pat

ien

ts A

live

(%)

40

0

100

60

0 2 4 6 8 10 12 14 16

Months From Start of Treatment

Median OS = NE(95% CI, 13.7–NE)

• 29 of 31 responders are still alive• The 1-year survival rate was 65% (95% CI, 51.2–75.5)

Phase 1 Isatuximab Monotherapy Study: Results High-Risk Cohort

Key eligibility criteria• 17 p del, t(4;14), t(14;16), t(14;20), or

>3 copies of 1q21• Relapsed <6 months of autologous

transplantation• A high-risk GEP signature Patient characteristics• Median prior lines of treatment: 4.5

(range 2–8)• All patients received IMiD and

proteasome inhibitor• Majority (72.2%) received

pomalidomide or carfilzomib

Overall response rate

# Responder features1 t(4;14)2 17p and 1q gains3 t(4;14)4 HR GEP

22.2

0

10

20

30

40

50

60

10mg/kg Q2W (HR)(N=18)

ORR = 22% (4/18)

Presented by Tom Martin at IMW Rome, Italy 2015

High-risk criteria N=1817p 4 (22.2%)

17p and 1q gains 4 (22.2%)

1q 4 (22.2%)

1q and t(4;14) 2 (11.1%)

t(4;14) 2 (11.1%)

HR GEP 1 (5.6%)

Transplant relapse 1 (5.6%)



Antibody Treatment in Combination With Lenalidomide/Dex

Antibody Target No. ORR (≥PR), % PFS (mos)

BT062[1] CD138 41 78 Too early

SAR650984 (Isatuximab)2 CD38 31 58 6.2

Daratumumab3 CD38 32 88 Too early

Elotuzumab4,5 SLAMF773 84 28

321 79 19.4

Nonrandomized, historical comparison from ASCO/ASH 2013–2015 reports

1. Kelly KR et al. Blood. 2014;124. Abstract 4736.2. Martin TG et al. Blood. 2014;124. Abstract 83.

3. Lokhorst HM et al. J Clin Oncol. 2013;31. Abstract 8512.4. Lonial S et al. J Clin Oncol. 2013;31. Abstract 8542.

5. Lonial S et al. N Engl J Med. 2015;373:621.

Factors Impacting mAb Activity• CDC

– CDC inhibitors• ADCC

– FcγRIIIa variant – PDL-1/PD-1

interaction– TGFβ – C3b deposition– HLA-KIR match

• ADCP– FcγRII variants– CD47

C3a

C5aC3

C4

C1q

Tumor cell

C3b

Factor 1

CDC

C9

CD55CD46

CD59

Membranepores

ADCC

ADCP

FcγRIIb

FcγRIIa

Porins/granzymes

Cytokines

Cytokines(IL8, IL10,

TNFα, IFN)

NK cellMΦ



Target

HLA

HLA-A3 and A11

HLA-Bw4 (80lle, 80 thr)

HLA-C1B46, B73, some C2

HLA-C2

HLA-CHLA-B HLA-A

1,786 938 1,264

MHC class I genes (chromosome 6)

Number of proteinvariants

KIRligands

Bw4+Bw4-

C1/C2C1/C1C2/C2

A3/11+A3/11-

Bw4

C1

C1C2 Bw4

A11

A3

N80

K80

NK cell

KIR3DL2

KIR3DL1

KIR3DS1

KIR2DS5

KIR2DS4

KIR2DS3

KIR2DS2

KIR2DS1

KIR2DL2/3

KIR3DL3

KIR2DL5

KIR2DL4

KIR2DL1

KIR

KIR-HLA interactions that effect NK cell activation1. Licensing: iKIR binds to ligand2. Missing ligand: KIR-ligand not present on target cell3. Activating KIRs: present on NK cells

Hypothesis: KIR-HLA Interactions Impact Response to ISA/LEN/DEX

Marra J et al. Blood. 2014;124. Abstract 2126.Presented by Tom Martin at IMW Rome, Italy 2015

UCSF Biomarker Study: NK Cell ResultsIsatuximab, Lenalidomide, and Dexamethasone in RRMM

Months Since C1D1

PF

S(%

)

3 12 15

20

0 copies of HLA-B Bw4-I80 or KIR3DL1- (n=19) 1 copy of HLA-B Bw4-I80, KIR3DL1+ (n=8)2 copies of HLA-B Bw4-I80, KIR3DL1+ (n=4)

P=0.01

Conclusions: 1. ISA provides NK activation signal through Fc2. Lenalidomide activates NK cells through IL-2 3. The licensed NK cell then kills the target4. Provocative: needs confirmation in a larger trial

Hypothesis

NK i-KIR

a-KIR

FcR

HLA

CD38

?

MMtarget

ISA → + SIGNAL

+ LEN → + IL-2

80

60

40

100

06 9

Gene dosage effects: HLA-B Bw4-I80 and KIR3DL1

Inhibitory KIR: KIR3DL1Ligand: HLA-B Bw4-I80

Marra J et al. Blood. 2014;124. Abstract 2126.Presented by Tom Martin at IMW Rome, Italy 2015



When and How Should We Incorporate These Antibodies Into Practice?

• Are all patients candidates for mAb therapy?

• Which mAb therapy do we use first?

• Can we combine these with any/all direct anti-MM based approaches (rituximab approach)?

• For a patient progressing on maintenance lenalidomide →which mAb should we choose?

• If a patient does not respond to 1 mAb → will they be resistant to all mAbs?

• What do we need to know to better answer these questions?– DATA, DATA, DATA!

• For now → follow the label– Early relapse → elotuzumab + lenalidomide + dexamethsone– Late relapse/double refractory → daratumumab

• Future trials will interrogate sequence, biomarkers, and combos

The Practical Part: Infusion Info

Agent Dose Pre-Meds IARsInfusion

Rate/Time

Rapid Infusion

( ≤90 min)

ELO1 10 mg/kg Q wk × 8, then Q 2 wks

Dex 8 mg IV (28 mg PO)Acetaminophen 650–1,000 mgDiphenhydramine 25–50 mgRanitidine 50 mg IV

~ 10%• G1–2• 1st inf

~ 1% DC

Start 0.5 ml/min, increase to 2 ml/min(~2-3 hours)

Yes

DARA2 16mg/kg Q wk × 8, Q 2wk × 16, Q 4wk

Methylprednisolone 100 mgAcetaminophen 1,000 mgCetirizine 10 mg or equivDex 4 mg give on Day 2 + 3

~ 4971%• G1–2• 1st−2nd inf

(8%)• <1% DC

1,000 mls -@50→200/hr1st: 7h2nd: 3.25–4 h

TBD

ISA3 TBD Dex 20–40 mgAcetaminophen 650–1,000 mgDiphenhydramine 25–50 mgFamotidine 20 mg

~ 50%• G1–2• 1st inf• 2% DC

10 mg/kg• 1st: 3.5 h• 2nd: 2.5 h

20 mg/kg• 1st : 5.5 h• 2nd: 4 h

TBD

1. Lonial S et al. N Engl J Med. 2015;373:621. 2. Lokhorst HM et al. N Engl J Med. 2015;373:1207.

3. Martin TG et al. Blood. 2014;124. Abstract 83.



The Practical Part: Infusion Reactions

A. Common symptomsAnti-CD38 mAb1. Sinus/nasal congestion2. Throat irritation3. Cough, dyspnea, wheezing4. Rare: anaphylaxis, severe

HTN, CP, arrhythmias

B. Treatment1. Recognize early and stop infusion (37% Dara, 5% Elo)2. Give additional premedications3. Restart at ½ the rate (discontinue if Gr 4 or recurs)

Be prepared: • Start infusions early• Pre-med everyone → additional meds likely to be needed

Lonial S et al. N Engl J Med. 2015;373:621. Lokhorst HM et al. N Engl J Med. 2015;373:1207.

Martin TG et al. Blood. 2014;124. Abstract 83.

Elotuzumab1. Fever, chills2. Hypertension3. Less: bradycardia, hypoTN

The Practical Part:Response and Blood Typing

A. Assessing response• mAb may be detectable on SPEP/IFE• Can obscure CR assessment

B. Infection: VZV prophylaxis

C. Blood banking1,2

• Anti-CD38 may interfere with blood bank tests− CD38 on reagent RBCs

• Positive DAT• Positive antibody screen

• Approaches to resolve anti-CD38 interference*Send type and screen BEFORE first dose-DARA− Genotype/phenotype recipient’s RBCs− DTT-treating reagent RBCs (+/- available, give Kell- cells)− Neutralize anti-CD38 in plasma (anti-idiotype, sCD38)

1. Chapuy CI et al. Transfusion. 2015;55:1545.2. Oostendorp M et al. Transfusion. 2015;55:1555.

IgG k MMIgG k agent

ELP G A M K L1



FUTURE: Where do we go from here?

• Novel antibodies– More specific targets– Checkpoint inhibitors (PD-1, PDL-1)– Stromal compartment/ cell-cell interactions

• Antibody-drug conjugates– BT-062 (anti-CD138)– GSK2857916 (anti-BCMA)

• Can we combine mAbs with ?– Novel drugs– ELO + anti-KIR, ELO + CD137– Vaccines + antibodies

Conclusions• Antibody therapy has “come of age”

– ELO with Len/Dex for early relapse in Len sensitive– DARA for double refractory

• Combinations actively be tested– Frontline, early relapse, and refractory – Proteasome inhibitors, pomalidomide, other mAbs

• Future efforts need to focus on:– Identifying biomarkers for response/relapse– Optimizing the combinations and dosing strategies– Potentially using genomic data to help select patients

• All patients are appropriate for clinical trials



Novel Therapeutics in Myeloma: Update

A. Keith Stewart, MBChB, MRCP, FRCPC, MBAVasek and Anna Maria Polak Professor of Cancer Research

Consultant, Division of Hematology/OncologyMayo Clinic

Scottsdale, Arizona

Disclosures

• Consultant/Advisor: Bristol-Myers Squibb, Celgene, Janssen, MedImmune, Novartis, Takeda Oncology



Progression-Free Survival in Late-Stage Disease

Figure 2A, page 1059

San Miguel J, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-1066.

What’s New in MM Therapeutics?

• Ixazomib

• Oprozomib

Oral proteasome

inhibitors

• Elotuzumab

• Daratumumab

• Isatuximab

Monoclonal antibodies

• Afuresertib

• Dinaciclib

• PIM (LGH447)

• Trametinib

Kinase inhibitors

• Panobinostat

• Ricolinostat

HDACs

• ABT-199

• Selinexor

Novel mechanisms

• CAR-T

• BITE

• PDL-1/PD-1

Immuno-therapies

HDAC, histone deacetylase.



Profile of Single-Agent Oprozomib in Patients With Multiple Myeloma:

Updated Results From a Multicenter, Open-Label, Dose-

Escalation Phase 1b/2 Study

Ravi Vij,1 Michael Savona,2 David Siegel,3 Jonathan Kaufman,4Ashraf Badros,5 Irene Ghobrial,6 Agne Paner,7

Sundar Jagannath,8 Andrzej Jakubowiak,9 Joseph Mikhael,10

Prashant Kapoor,11 Linda Neuman,12 Jesus Berdeja13

1Washington University, St. Louis, MO; 2Vanderbilt University, Nashville, TN; 3John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ; 4Winship Cancer Institute, Emory University, Atlanta, GA; 5University of Maryland, Baltimore, MD; 6Dana-Farber Cancer Institute, Boston, MA; 7Rush University, Chicago, IL;

8Mt. Sinai Hospital, New York, NY; 9University of Chicago Medical Center, Chicago, IL; 10Mayo Clinic, Scottsdale, AZ; 11Mayo Clinic, Rochester, MN; 12Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA;

13Sarah Cannon Research Institute, Nashville, TN

Phase 1b/2 Study of Single-Agent Oprozomib in MM: Efficacy

9 42

44

9

19

9

19

12

13

2

0 20 40 60 80 100

Phase 1b + 2 150–270 mg/d

(n=43)

Phase 1b 150–330 mg/d

(n=16)

PD

SD

MR

PR

VGPR

CR

5/14

Sch

edu

le2

2/7

Sch

edu

le1

Patients, %

CBR 50%

CBR 32.6%

ORR 31.3%

ORR 23.3%3

1 2/7 schedule: 1 patient (6%) was not evaluable.2 5/14 schedule: 5 patients (12%) were not evaluable and 2 patients (5%) were off study before response assessment.

3 ORR in 11 CFZ-refractory patients (phase 2): 18.2%. Vij R et al. Blood. 2014;124. Abstract 34.



Phase 1b/2 Study of Single-Agent Oprozomib in MM

Vij R et al. Blood. 2014;124. Abstract 34.

Authors’ Conclusions

The most common grade ≥3 nonhematologic AEs were diarrhea, nausea, and vomiting; rates of treatment-emergent PN and rash were low.

Recommended phase 2 dose and schedule: 240/300 mg/day in the 2/7 step-up schedule and 150/180 mg/day in the 5/14 step-up schedule.

Preliminary data suggest that step-up dosing is associated with improved tolerability.

Enrollment of patients with MM continues both schedules in the phase 2 study with a target of 94 patients; all patients are now receiving a new (extended-release) formulation of oprozomib.

Single-agent oprozomib has promising antitumor activity, with responses observed in patients who had carfilzomib-refractory MM.

Phase 1b Study of Ricolinostat (ACY-1215) + LEN-DEX in Patients With RRMM: Efficacy

and Authors’ Conclusions

1625

32

42

24

88

0

25

50

75

100

All Evaluable(n=25)

LEN Refractory(n=12)

Pat

ien

ts (

%)

MR PR VGPR sCR

ORR: 64%ORR: 50%

Yee AJ et al. Blood. 2014;124. Abstract 4772.

Ricolinostat is well tolerated when combined with LenDex at doses up to 160 mg bid; most AEs were low-grade and manageable.

Continuous bid treatment for 21 days is ongoing.

ORR was 64% and CBR was 80%; response rate was 85% in LEN-sensitive and -naive patients, and 50% in LEN-refractory patients.



Phase 1b Study of Ricolinostat (ACY-1215) and BTZ-DEX in Patients With RRMM

Vogl DT et al. Blood. 2014;124. Abstract 4764.

Ricolinostat is tolerable with clinical benefit in combination with bortezomib/dexamethasone.

No differences in PK were observed for the strength formulations.

Toxicities were generally manageable.

Responses were observed in this heavily pretreated population.

An expansion cohort at 160 mg QD is ongoing to better define a recommended phase 2 dose.

Authors’ Conclusions

A Phase 1/2 Trial of Dinaciclib, a Small Molecule Inhibitor of Cyclin-Dependent

Kinase 5 (CDK5)

• 29 patients were accrued (19 phase 1, 9 phase 2)

• Median time from diagnosis to registration was 3.5 years

• Median follow-up for patients still alive is 3.2 months (range: 0.7–20.8)

• Toxicity profile was hematological, fatigue, nausea, and mucositis

• Preclinical work indicates high synergy with bortezomib phase 1b trials now under way

Kumar SK et al. Blood. 2015;125:443.



Table 3, page 447

Kumar SK, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015 Jan 15;125(3):443-448.

Figure 2A, page 447

Kumar SK, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015 Jan 15;125(3):443-448.

Dinaciclib: CDK Inhibitor

Afuresertib (AKT Inhibitor)• ATP-competitive, reversible inhibitor of all 3 AKT kinases• Orally bioavailable• Single-agent activity in heavily pretreated MM patients in FTIH

Voorhees PM et al. Blood. 2013;122. Abstract 283.

Maximum% M Protein Change: Monotherapy FTIH150

50

0

-100

100

-50

-25%

-90%

-50%

100 mg125 mg

FTIH, first time in humans.

Ch

ang

e F

rom

Bas

elin

e (%

)



Afuresertib, Bortezomib, Dex


100

25

0

-50

50

-25

FLC (κ or λ)M protein

Subject

-100-90

Maximum % Change in M Protein or FLC From BaselineC

han

ge

Fro

m B

asel

ine

(%)

Afuresertib, Bortezomib, Dex: Adverse Events

Adverse Event All (%)

≥Grade 3(%)

Nonhematologic (≥20%)Fatigue 51 2

Diarrhea 49 14

Nausea 37 1

Constipation 33 2

Dyspepsia 32 1

Hyperglycemia 28 7

Vomiting 27 2

PN 22 0

Insomnia 20 0

Rash 20 7

HematologicThrombocytopenia 38 27

Anemia 22 10

Neutropenia 11 7

Febrile neutropenia 2 1

• 1 death: septic shock (F, age 61 years)

• 23% discontinuation rate for AEs


Serious adverse eventsrecorded in 31 patients:• Infections • Acute renal injury• Skin disorders• Gastrointestinal• Bone-related events• Vascular events



PIM Inhibition Most Effective in Hematologic Malignancies

Modified from Figure 4A, page 1841

Garcia PD, et al. Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. Clin Cancer Res. 2014 Apr 1;20(7):1834-1845.

Phase 1 Study Of LGH447 in Patients With Relapsed/ Refractory Multiple

Myeloma

• ORR: 10.5%; CBR: 21.1%; DCR: 71.9%• Median duration of response was 23.0 weeks

Raab MS et al. Blood. 2013;122. Abstract 3186.

0%

20%

40%

60%

80%

100%

Res

po

nse

Rat

e

LGH447 Dose, mg

VGPR

PR

MR

SD



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



Selinexor: First-in-Class, Oral Selective Inhibitor of Nuclear Export (XPO1)

• Novel, small molecule selective inhibitor of XPO1

• Oral drug given 2–3 times per week

• No known drug-drug interactions through CYP450s

• Potent antileukemic effects in vitro and in vivo in AML models

• Antitumor activity in ongoing Phase 1 and 2 studies in advanced hematologic and solid tumors

Selinexor


CF3

F3C N

N NO

NH

HNN

N

Best Responses in Evaluable Patients: Single-Agent Selinexor vs 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 low dose: ≤30 mg/m2 15 4 (27%) ─ 4 (27%) 8 (53%) 3 (20%)

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


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%)



Selinexor + Dexamethasone: Common Related AEs in >2 Patients

• Sel(45)-Dex shows reduction in nausea grades and very little weight loss compared with selinexor alone

• The MTD/RP2D of Sel-Dex is 45 mg/m2 + 20 mg Dex, twice weekly


45 mg/m2 Selinexor + 20 mg Dex80

60

40

20

0

AE

In

cid

ence

(% o

f p

ts)

N=10Grade 1Grade 2Grade 3Grade 4

Grade 1Grade 2Grade 3

806040200

Nausea

Fatigue

Anorexia

Vomiting

Weight loss N=18

≥35 mg/m2 Selinexor806040200

45 mg/m2 Selinexor + 20 mg Dex

N=10

80604020060 mg/m2 Selinexor + 20 mg Dex

N=10

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)

Patient ID Maximal ∆ Best Response # Prior Tx Study Days

076 -71% PR 7 301+

079 -53% PR 3 52

081 -99% sCR 5 280

084 -84% PR 9 170

090 41% PD 5 31

092 -55% PR 10 121

093 -41% MR 9 114

098 -48% MR 16 79

099 -82% PR 6 201+

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

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



Cell death (apoptosis)

Inhibition 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) MMTherapy started

50

40

30

20mg

/dL

0

10

Generalized normal highGeneralized normal high

Generalized normal lowGeneralized normal low

200

150

100

mg

/dL

0

50

Generalized normal highGeneralized normal high

Generalized normal lowGeneralized normal low

Kappa FLC Kappa FLC

Stewart AK, unpublished



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

Figure 1A-C, page 1042

Garfall AL, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015 Sep 10;373(11):1040-1047.

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.



Pembrolizumab in Combination with Lenalidomideand Low-Dose Dexamethasone for

Relapsed/Refractory Multiple Myeloma (RRMM)

• Pembrolizumab, a highly selective, humanized IgG4 anti–PD-1 monoclonal antibody designed to block interaction of PD-1 with PD-L1 and PD-L2

• RRMM who have failed ≥2 prior therapies including a proteasome inhibitor and an IMiD

• MTD/MAD was defined as pembrolizumab 200 mg fixed dose in combination with lenalidomide25 mg and low-dose dexamethasone 40 mg.

• 17 patients; 76% response rate

Miguel J et al. Presented at: 57th ASH Annual Meeting & Exhibition. Orlando, FL; December 2015. Abstract 505.

A Phase 2 Study of Anti PD-1 Antibody Pembrolizumab, Pomalidomide and Dexamethasone in Patients with

Relapsed/Refractory Multiple Myeloma (RRMM)

• Pembrolizumab, a highly selective, humanized IgG4 anti–PD-1 monoclonal antibody designed to block interaction of PD-1 with PD-L1 and PD-L2

• RRMM who have failed ≥2 prior therapies including a proteasome inhibitor and an IMiD

• Pembrolizumab 200 mg IV every 2 weeks plus pomalidomide (4 mg daily x 21 days) and dexamethasone 40 mg weekly

• 11 of 22 evaluable patients (50% response rate)

Badros AZ et al. Presented at: 57th ASH Annual Meeting & Exhibition. Orlando, FL; December 2015. Abstract 506.



Summary• Oral proteasome inhibitors seem active; likely

approval(s)

• Monoclonal antibodies: likely to be approved elotuzumab, daratumumab, isatuximab

• Kinase inhibitors dinaciclib (CDK5), afuresertib (AKT), PIM kinase have some single-agent activity and now in combination

• HDACs: ricolinostat too soon to say

• Selinexor, ABT-199 t(11;14) also promising

• Checkpoint inhibitors and CAR-T: too soon to say but potential paradigm shift

Community Case Revisited



Case Study Part 1• 54-year-old man presents with 6-month history of

lower back pain, increasing fatigue, right rib pain.

• Labs– Normal LDH

– Serum β2 microglobulin 6 mg/dL

• Skeletal survey– Numerous lytic lesions (skull, long bones, right 5th/6th/7th

ribs, pelvis)

• Bone marrow biopsy:– 70% cellularity, 80% kappa-restricted plasma cells

– Cytogenetics normal in 20 metaphases

– FISH positive for translocation (11;14) in 75% cells

Having completed this program, which one of the methodologies do

you plan to use most often?

A. Gene expression profilingB. Conventional cytogeneticsC. FISHD. Gene mutation panelE. More than one methodF. None of the above

?



Is this patient considered eligible for stem cell transplantation?


?

Having completed this program, which factors do you plan to use to decide whether to consider

aggressive therapy such as stem cell transplantation?

A. Age, comorbidity scoreB. Social support and insurance

coverageC. Response to induction therapyD. Risk profileE. All of the aboveF. I don’t do transplants up front

?



What would be your recommendation for initial treatment?

A. Melphalan, prednisone, bortezomib (MPV)B. Bortezomib, thalidomide, dexamethasone (VTD)C. Lenalidomide + low-dose dexamethasone (Ld)D. Lenalidomide, bortezomib, dexamethasone

(RVD)E. Cyclophosphamide, bortezomib,

dexamethasone (CyBorD)F. Carfilzomib, lenalidomide, dexamethasone

(KRD)G. Other

?

Having completed this program, will your practice plan to routinely test for minimal residual disease (MRD) following therapy?


?



Case Study Part 2• Induction chemotherapy: RVd × 4 cycles

• Bone health: bisphosphonates every month

• Best response: VGPR by IMWG criteria

• Relevant events during induction– Grade II peripheral neuropathy after cycle #2

– Increasing lower back pain during cycle #3

Based on the patient’s response to induction therapy, you collect stem cells.

What would you consider next?

A. Continue current regimen

B. Wait to transplant after relapse

C. Proceed to transplant

D. Provide consolidation therapy

?



Case Study Part 2• Transplant eligible• Restaging post-ASCT: sCR by IMWG criteria

• Patient comes to discuss maintenance

Is now an appropriate time for MRD testing?


?



Do you recommend maintenance?


?

Would the MRD result affect your decision to use maintenance therapy?


?



Which maintenance treatment do you recommend?

A. LenalidomideB. BortezomibC. Lenalidomide, bortezomibD. ThalidomideE. PrednisoneF. Clinical trialG. I don’t use maintenance

?

Would your maintenance choice change if the patient had low-risk cytogenetics?


?



Case Study Part 3• Patient deferred Len maintenance and prefers

close observation

• Returns 2 years post-ASCT with increasing shoulder pain while working out in the gym, increasing fatigue, and urinary frequency with frothiness

• BM biopsy:– 60% cellularity, 50% kappa-restricted plasma cells– FISH positive for translocation (11;14) in 50%

cells, del17p in 20%

• He is here to discuss treatment options

What would you use for treatment of MM in first relapse?

A. Bortezomib + dexamethasone ±cyclophosphamide

B. Lenalidomide + dexamethasoneC. Pomalidomide + dexamethasoneD. Bortezomib, lenalidomide, and

dexamethasoneE. Carfilzomib + dexamethasoneF. Carfilzomib + lenalidomide + dexamethasoneG. Elotuzumab + lenalidomide + dexamethasoneH. Daratumumab

?



Questions and Answers

Active now:YouKnowIt!—Round 2

and Evaluation

Documents

A. Keith Stewart, MBChB, MRCP, FRCPC, MBA. Keith Stewart, MBChB, MRCP, FRCPC, MBA Vasek and Anna Maria Polak Professor of Cancer Research Consultant, Division of Hematology/Oncology