Multiple Myeloma Patient Management: New Agents, New … · 1 Multiple Myeloma Patient Management: New Agents, New Challenges 8:15 AM – 8:25 AM Community Case 1 Robert M. Rifkin,

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Multiple Myeloma Patient Management: New Agents, New Challenges

8:15 AM – 8:25 AM Community Case 1 Robert M. Rifkin, MD

8:25 AM – 8:40 AM Advances in the Diagnostic Workup: Imaging and GenomicsA. Keith Stewart, MBChB

8:40 AM – 8:55 AM Making Sense of Frontline OptionsThierry Facon, MD

8:55 AM – 9:05 AM Community Case 2Robert M. Rifkin, MD

9:05 AM – 9:20 AM Strategies to Prolong ResponseAmrita Y. Krishnan, MD

9:20 AM – 9:35 AM Panel Discussion9:35 AM – 9:45 AM Community Case 3

Robert M. Rifkin, MD9:45 AM – 10:00 AM New Agents, Classes in the Relapsed Setting

Faith E. Davies MD10:00 AM – 10:15 AM The Way Forward: Immunotherapy

Paul G. Richardson, MD10:15 AM – 10:30 AM Panel Discussion10:30 AM – 11:00 AM Question and Answer Session

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Patient Case 1

Robert M. Rifkin, MDAssociate Chair – US Oncology Research

Disease Lead – Multiple MyelomaAttending Physician

Rocky Mountain Cancer CentersDenver, Colorado

Case Study 1• 75-year-old man referred for workup of back pain

that radiated to ribs and chest. • CT pulmonary Angiogram was negative for

pulmonary embolus (creatinine 1.5).• This showed multifocal lytic bone disease. Felt

well except for pain in his back.

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Case Study 175-year-old man referred for workup of back pain that radiated to ribs and

chest.

• Hypertension• T2DM• Coronary artery disease with 2 stents

Past medical history

• Left rotator cuff repair 7 years ago

Past surgical history

• Brother and five sisters—all healthy

• Four children

Familyhistory

• Married, bilingual instructor for OSHA

• Nonsmoker, rare social alcohol

• No substance use

Socialhistory

• Normal• ROS: negative except for back pain

Physicalexam

Case Study 1: Labs ActualValue

Normal Range

CBC withdifferential

WBC (103/mL) 5.4 (4–11)

Hemoglobin (g/dL) 12.0 (13–16)

Hematocrit (%) 38 (34–45)

Platelets (103/mL) 210 (150–400)

Neutrophils (103/mL) 4.3 (1.9–7.5)

CMP

BUN (mg/dL) 34 (7–20)

Creatinine (mg/dL) 1.5 (0.7–1.2)

Calcium (mg/dL) 9.4 (8.4–10.2)

Total protein (g/dL) 8.7 (6.3–8.2)

Albumin (g/dL) 3.7 (3.5–5.0)

β2M 4.5

SPEP + serum immuno-fixation

IF-IgG

M protein spike (g/dL) 1.7

ActualValue

Normal Range

QuantitativeIgs

IgG (mg/dL) 2,425 (H) (700–1,600)

IgA (mg/dL) 20 (L) (70–400)

IgM (mg/dL) 3 (L) (40–230)

FLC

Kappa quant Free Lite Chain (mg/L)

112 (H) (3.30–19.40)

Lambda quant FLC (mg/L) 1.8 (L) (5.71–26.30)

Kappa/lambda quant FLC ratio

62.2 (H) (0.26–1.65)

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Case Study 1: Imaging and BM Biopsy

Skeletal survey• 1.6 cm lytic lesion

in the parietal bone; severe loss of bone mineralization—osteoporosis

PET scan• Expansile lytic

lesion in right acromion. Multiple areas of uptake in bilateral ribs, and increased uptake in T5

Boneimaging

• Multifocal lesions in spine and ribs

MRI

• 70% cellular with 70%–80% plasma cells

• Aspirate 66% plasma cells

BMbiopsy

• 25.6% events positive for CD38, CD56, CD138, and kappa light chain

Flow cytometry

Cytogenetics• 46, XYFISH (CD138 selected plasma cells)• 74% with gain of

1q21• 5.4% low-level gain

of 11q23• 91% with loss of

13q14• 12.0 % with low-

level loss of TP53• 92.5% positive for

IgH rearrangement variant

Cytogenetics and FISH

Advances in the Diagnostic Workup: Imaging and Genomics

A. Keith Stewart, MBChB, MRCP, FRCPC, MBACarlson and Nelson Endowed Director

Center for Individualized MedicineVasek and Anna Maria Polak Professor of Cancer ResearchConsultant, Division of Hematology/Oncology, Mayo Clinic

Rochester, Minnesota and Scottsdale, Arizona

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

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Improving Survival in MM

0.0

1.0

0.8

0.6

0.4

0.2

Pro

po

rtio

n S

urv

ivin

g

0.9

0.7

0.5

0.3

0.1

0 4Follow Up From Diagnosis (Years)

2 6 8 10 12 14 1816 20

25% of patients live less than 3 years

1960–19651965–19701970–19751975–19801980–19851985–19901990–19951995–20002000–20052005–2010

Adapted from Kumar SK et al. Leukemia. 2014;28:1122.

Prognostic SystemsCombining Genetics and ISS Model

+

Fonseca R et al. Leukemia. 2009;23:2210.Greipp PR et al. J Clin Oncol. 2005;23:3412.

Risk Criteria Median OS

Standard Lack of del(17p), t(4;14), t(14;16) 50.5 mo

HighAt least one of

del(17p), t(4;14) or t(14;16)

24.5 mo(P<0.001)

Table 2, page 3415:

Greipp PR et al.J Clin Oncol. 2005;23:3412.

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Revised International Staging System(R-ISS) for MM

• R-ISS I (n=871)– Including ISS stage I (serum β2M level <3.5

mg/L and serum albumin level ≥3.5 g/dL)– No high-risk CA [del(17p) and/or t(4;14)

and/or t(14;16)]– Normal LDH level (less than the upper limit of

normal range)

• R-ISS III (n=295)– Including ISS stage III (serum β2M level >5.5

mg/L)– High-risk CA or high LDH level

• R-ISS II (n=1,894)– Including all the other possible combinations

5-Year OS* (%)

5-Year PFS* (%)

R-ISS I 82 55

R-ISS II 62 36

R-ISS III 40 24*At a median follow-up of 46 months

Palumbo A et al. J Clin Oncol. 2015;33:2863.

mSMART 2.0 Variable Outcomes in MM

High20%

Intermediate20%

Standard60%

• FISH‒ del 17p‒ t(14;16)‒ t(14;20)

• GEP‒ High-risk signature

• FISH t(4;14)• Amplification

chromosome 1q

• Others‒ Hyperdiploid‒ t(11;14)‒ t(6;14)

3–4 years 5–6 years 8–10 years

Mikhael JR et al. Mayo Clin Proc. 2013;88:360.

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t(4;14)1

• Translocation upregulates MMSET + FGFR3• Found in 15% of patients• Associated with IgA myeloma• Immature morphology • Often associated with del17• Tendency for less lytic bone disease, younger age

t(11:14)2

• Translocation upregulates cyclinD1• Found in 20% of patients• Associated with IgD, IgM, and nonsecretory MM• Lymphoplasmacytoid morphology• Often associated with B lineage–associated Ag• Enriched for amyloid/plasma cell leukemia

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 Subsets

Figure 2, page 2033

Garand R et al. Leukemia. 2003;17:2032.

Risk Stratification in MyelomaHow do we customize treatment?

• t(4;14) MM– Inferior outcomes with traditional ASCT– Results better with integration of novel agents, particularly BTZ

(consolidation or maintenance) and use of tandem transplant• Del17p (p53 deletion) MM

– Improved outcome for low-risk del17p with aggressive multi-combination and prolonged therapy

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

• Hyperdiploid– Myc dependant– Super responders to IMiDs

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Venetoclax in t(11;14) MM

200

150

100

mg

/dL

0

50

Generalized normal highGeneralized normal high

Generalized normal lowGeneralized normal low

Kappa FLC

A.K. Stewart, unpublishedKumar S et al. Blood. 2016;128: Abstract 488.

Pe

rce

nta

ge

of

Pa

tie

nts

ORR 21%

30

10

20

0

50

40ORR 40%

ORR 6%

All Patients(n=6)

t(11;14)(n=30)

Non-t(11;14) orundetermined

(n=36)

sCR CR VGPR PR

ORR by t(11;14) Status

3%3%

9%

6%

3%

7%

17%

13%3%3%

Imaging in Myeloma: IMAJEM (NCT01309334)

RVD × 3

RVD × 2

RVD × 5

Lenalidomide 1 year

Melphalan 200 mg/m2 + ASCT

CY (3g/m2) MOBILIZATIONGoal: 5 ×106 cells/kg

RVD × 3

CY (3g/m2)MOBILIZATIONGoal: 5 ×106 cells/kg

Randomize

Lenalidomide 1 year

ARM A ARM B

ASCT at relapse

PET-CT/MRI at diagnosis

PET-CT/MRI after 3 cycles

PET-CT/MRI before maintenance

N=134Moreau P et al. Blood. 2015;126: Abstract 395.

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• At diagnosis– MRI was positive in 127/134 (94.7%)

– PET-CT in 122/134 (91%) patients (McNemar test = 0.94, P=0.33)

• MRI of the spine and pelvis and whole-body PET-CT are equally effective to detect bone involvement in symptomatic patients at diagnosis

Moreau P et al. Blood. 2015;126: Abstract 395.


• Univariate analysis for PFS/134 patients• Variables tested:

Gender, age, Ca, creatinine, ISS, response after 3 cycles of induction, response pre-maintenance, cytogenetics, MRI after 3 cycles, PET-CT after 3 cycles, MRI pre-maintenance, PET-CT pre-maintenance

• PET-CT after 3 cycles, P=0.04• PET-CT pre-maintenance, P<0.001• Response after 3 cycles (≥VGPR), P=0.04


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PET-CT Normalization Before Maintenance Impact on PFS (62% Normalized)


P< 0.001

69%

51.6%

1.0

0.8

0.6

0.4

0.0

0.2

0 10 20 30

PET-CT -ve correlates with OS• Univariate analysis for OS/134 patients• Variables tested:

Gender, age, Ca, creatinine, ISS, response after 3 cycles of induction, response pre-maintenance, cytogenetics, MRI after 3 cycles, PET-CT after 3 cycles, MRI pre-maintenance, PET-CT pre-maintenance

• PET-CT pre-maintenance, P=0.003


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69.9%

1.0

0.8

0.6

0.4

0.0

0.2

0 10 20 30

PET-CT Normalization Before Maintenance Impact on OS (62% Normalized)

P=0.003

94.6%


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Conclusions• PET-CT and MRI are equally effective to detect bone

involvement in symptomatic patients at diagnosis

• MRI is not a good imaging method during follow-up

• PET-CT after 3 cycles of RVD and pre-maintenance is a powerful prognostic marker for PFS

• PET-CT pre-maintenance is a powerful prognostic marker for OS

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Genomic Landscape in MM

Walker BA et al. J Clin Oncol. 2015;33:3911.Lonial S et al. Blood. 2014;124: Abstract 722.

Keats JJ et al. Blood. 2012;120:1067.

Chapman MA et al. Nature. 2011;471:467.Bolli N et al. Nat Commun. 2014;5:2997.Lohr JG et al. Cancer Cell. 2014;25:91.

• >1000 whole-exome/genome sequences

• A limited set of genes is recurrently mutated in MM: KRAS, NRAS, TP53, DIS3, FAM46C, BRAF, TRAF3 results are predominantly obtained from newly-diagnosed MM

Figure 1, page 93

Lohr JG et al. Cancer Cell. 2014;25:91.

Myeloma Mutation Panel (M3P)• Recurrently mutated putative MM genes: FAM46C, TP53, DIS3• Actionable genes: RAS, BRAF, IDH1• Pathways: MAPK, Cereblon, MYC• Drug resistance: IMiDs, proteasome inhibitors, glucocorticoid• Copy-number changes and common translocations• Biallelic deletions of tumor suppressors• Sample purity measurement: J regions IGH, IGL-K and IGL-L

88 genes, 1,327 amplicons, 373 Kb

51% of genes shared with Foundation Hemepanel, 35% with Foundation ONE

Kortuem KM et al. Blood. 2015;126: Abstract 1795.Hofste op Bruinink D et al. Blood. 2015;126: Abstract 2984.

Kortüm KM et al. Blood. 2016;128:1226.

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Most Mutations Are Subclonal

Figure 1

Kortuem KM et al. Blood Cancer J. 2016;26:e397.

Myeloma-Specific Gene Mutation Panel Tracks Clonal Changes Over Time

Patient One Patient Two Patient Three

26.1 26.2 44.1 44.2 77.1 77.2

FAM46C 24% 92% 88%

FAT1 73%

KRAS 28% 60% 53%

SP140 48% 37% 85% 23%

SPEN 18%

TP53

24% 92% 82% 94%

78%

88%

Kortuem KM et al. Ann Hematol. 2015;94:1205.

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Impact of Mutation on Myeloma Survival

Figure 4, page 3916

Walker BA et al. J Clin Oncol. 2015;33:3911.

Figure 3, page 3913

Walker BA et al. J Clin Oncol. 2015;33:3911.

Mutations in the Cereblon Pathway in at Least 26% of Relapsed/Refractory Patients

• In a patient refractory to Len/Dextherapy we identified mutations in both CRBN and IRF4

• One patient had 4 different CRBNmutations

• Probably higher as we did not look for structural change on chromosome 3

• 4 out of 5 IRF4-mutated patients shared a K123R variant

CRBN 1

CUL4B 1 1

IKZF3 1 1 1

IRF4 1 1 1 1 1

*gene found mutated in cohort

IRF4MYC

MM cytotoxicity

CRBNIMiDs

IKZF1/3

*

*

*

*DDB1

CUL4

ROC1

Kortüm KM et al. Blood. 2016;128:1226.

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CoMMpass Enrollment• 1,000+ patients enrolled from >90 sites worldwide, with

over 850 samples molecularly profiled at baseline and >100 sequentially

CoMMpass: Triplets versus DoubletsEarly data suggests that patients on a triplet regimen (for ex. Bor-Len-Dex) appear to be doing better than those on a doublet (ex. Bor-Dex or Len-Dex)

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CoMMpass: High Risk DiseaseIntegrative analyses using CoMMpass data will help identify patients at

greater risk of progression upfront and optimize their treatment

CoMMpass MMRF2172 CoMMpass MMRF2250

Age 72 71

Ethnicity Caucasian Caucasian

ISS stage II II

Baseline treatment VRD VRD

Cytogenetics t(4;14), del13, del17p t(4;14), del13, del17p

Time to progression (mos) 1 >18

p53 status mutated WT

MM cells in blood (%) 1.7 0

Circulating MM cells 36,648 614

Finding New Treatment OptionsBy looking closely at the molecular changes happening at progression, one can

identify potential new therapeutic options (for ex. a BRAF inhibitor here)

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Summary• Revised ISS can assist therapeutic decision making• PET-CT normalization is also predictive• Clinical mutation panels now available

– Clonal depth of mutation– Actionable mutation– Prognosis– Drug resistance

• CoMMpass study largest genomics cohort in cancer, leading to precision therapy trials

– Additional CoMMpass data to be presented Saturday, 12/3 at 2:00PM

Making Sense of Frontline Options for Transplant Ineligible Patients

Thierry Facon, MDProfessor of Haematology

Department of HaematologyLille University Hospital

Lille, France

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Patient Case• 75-year-old patient• Significant previous medical history• No significant previous surgical history• Physical examination: normal• Lytic bone disease• Impaired renal function• Revised ISS stage II

The patient is an ELDERLY patient with comorbidities, but good performance status.

He needs treatment.

The Transplant Eligibility Discussion (1)

• Patient is considered transplant candidate and so needs induction-ASCT with or without consolidation and maintenance

• Patient is (most likely) not a transplant candidate and needs conventional treatment

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The Transplant Eligibility Discussion (2)• ASCT remains a standard of care for patients ≤65 years

of age in most countries – IFM 2009 and EMN studies1,2

• No large phase 3 randomized study has established the role of ASCT in elderly patients in the era of novel agents

• ASCT (single or even double) is routinely performed in some countries/centers for elderly patients between 65 and 75 years of age

1. Attal M et al. Blood. 2015;126: Abstract 391.2. Gay F et al. Blood. 2015;126: Abstract 392.

IFM 99-06 Study ProtocolNewly Diagnosed MM Patients 65–75 Years

Time From Randomization (month)

Pro

po

rtio

n

Treatment O/NSurvival time

median ± se (month)MP 97/196 32.2 ± 4.2

MP-T 43/125 53.6 ± 5.2

MEL100 66/126 38.6 ± 3.4

Arm MP

MP 1

MP 2

MP 3

MP 12

Arm MEL100

VAD 1

VAD 2

Cyclophosphamide 3g/m2 + lenograstim

+ PBSC harvest

MEL 100 mg/m2

+ PBSC + lenograstim

MEL 100 mg/m2

+ PBSC + lenograstim

Arm MP-T

MP

+

Thalidomide

400 mg/d

Overall Survival According to Treatment

Facon T et al. Lancet. 2007;370:1209.

0

0.2

0.4

0.6

0.8

1

0 12 24 36 48 60 72

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A Phase III Trial Evaluating Conventional Dose Combination Immunochemotherapy With Ixazomib-Lenalidomide-Dexamethasone and Daratumumab (IRD2) to High-Dose Treatment With ASCT in the

Initial Management of Fit MM Patients Aged 65–75.

IRD2 IRD2IRD2 Collection IRD2 IRD2IRD2 IRD2IRD2 DR maintenance

IRD2 IRD2IRD2 Collection ASCT IRD2IRD2 DR maintenance

Arm A

Arm B

IFM 2017 Study

MPT and VMP Become Standards of Care (2008)

Facon T et al. Lancet. 2007;370:1209. Fayers PM et al. Blood. 2011;118:1239.

San Miguel JF et al. N Engl J Med. 2008;359: 906.

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FIRST (IFM2007-01/MM-020): 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.Avet-Loiseau H et al. Blood. 2015;126: Abstract 730.

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

• Stratification: age, country, and ISS stage

Arm BRd18

Arm CMPT

LEN + LoDEX 18 Cycles (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

Active Treatment + PFS Follow-Up Phase

LEN + LoDEX ContinuouslyLENALIDOMIDE 25 mg D1-21/28LoDEX 40 mg D1, 8, 15 & 22/28

Arm ARd Continuous

LT Follow-Up

PD

or

Un

acce

pta

ble

To

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ty

PD

, O

S, a

nd

Su

bse

qu

ent

AM

T

Screening

RA

ND

OM

IZA

TIO

N 1

:1:1

Hazard ratio Rd vs MPT: 0.69; P<0.001Rd vs Rd18: 0.71; P<0.001Rd18 vs MPT: 0.99; P=0.866

IFM 2007-01 FIRST Trial: PFS and OS

1. Lenalidomide European Public Assessment Report. March 2015. 2. Facon T et al. J Clin Oncol. 2015;33: Abstract 8524.

0 6 12 18 24 30 36 42 48 54 60 66 72

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al

Pro

ba

bili

ty

PFS (months)

Data cut-off: 3 March 2014Median follow-up: 45.5 mos

33%

14%

13%

Median PFS

Rd (n = 535) 26.0 mos

Rd18 (n = 541) 21.0 mos

MPT (n = 547) 21.9 mos

PFS as per investigator assessment1

Hazard ratio Rd vs MPT: 0.75; P=0.002Rd vs Rd18: 0.91; P=0.30

OS (months)

OS2

Data cut-off: 3 March 2014Median follow-up: 45.5 mos697 deaths (43% of ITT)

Median OS 4-year OS

Rd (n = 535) 58.9 mos 60%

Rd18 (n = 541) 56.7 mos 57%

MPT (n = 547) 48.5 mos 51%

0 6 12 18 24 30 36 42 48 54 60 66

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al

Pro

ba

bil

ity

72

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IFM 2007-01, FIRST Trial: Age Analysis, OS

MPT, melphalan, prednisone, thalidomide; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles. Hulin C et al. Haematologica. 2015;100: Abstract S429.

RdRd18MPT

186193188

10810694

888372

704954

573137

442326

271520

1277

443

000

136137125

RdRd18MPT

349348359

311309306

295287291

272265262

249246244

231229223

171164161

1109988

554941

12138

329328330

000

Age ≤75 Years Age >75 YearsMedian, months

4-yr, %

Rd continuous 60.9 64

Rd18 60.6 61

MPT 55.3 57

Median follow-up of 45.5 months as of 3 March 2014

Hazard ratio (95% CI)Rd vs MPT: 0.76 (0.60–0.96)Rd vs Rd18: 0.90 (0.71–1.15)Rd18 vs MPT: 0.84 (0.66–1.06)

Pa

tie

nts

(%

)

100

80

60

40

20

0

OS (months)0 6 12 18 24 30 36 42 48 54 60 66

Hazard ratio (95% CI)Rd vs MPT: 0.72 (0.54–0.96)Rd vs Rd18: 0.91 (0.68–1.22) Rd18 vs MPT: 0.79 (0.60–1.04

Pa

tie

nts

(%

)

100

80

60

40

20

0

OS (months)0 6 12 18 24 30 36 42 48 54 60 66

Median, months

4-yr, %

Rd continuous 52.3 52

Rd18 45.7 48

MPT 37.8 39

After induction

After induction

SWOG S0777: Study Design

Durie B et al. Blood. 2015;126: Abstract 25.

RandomizationN = 525

Stratification:• ISS (I, II, III)• Intent to

transplant at progression (yes/no)

RandomizationN = 525

Stratification:• ISS (I, II, III)• Intent to

transplant at progression (yes/no)

Rd maintenance until PD, toxicity,

or withdrawal

• All patients received aspirin 325 mg/day• VRd patients received HSV prophylaxis

Eight 21-day cycles of VRdBortezomib 1.3/mg2 IVDays 1, 4, 8, and 11Lenalidomide 25 mg/day PODays 1–14Dexamethasone 20 mg/day PODays 1, 2, 4, 5, 8, 9, 11, 12

Eight 21-day cycles of VRdBortezomib 1.3/mg2 IVDays 1, 4, 8, and 11Lenalidomide 25 mg/day PODays 1–14Dexamethasone 20 mg/day PODays 1, 2, 4, 5, 8, 9, 11, 12

Six 28-day cycles of RdLenalidomide 25 mg/day PODays 1-21Dexamethasone 40 mg/day PODays 1, 8, 15, 22

Six 28-day cycles of RdLenalidomide 25 mg/day PODays 1-21Dexamethasone 40 mg/day PODays 1, 8, 15, 22

Lenalidomide 25 mg PO days 1–21

Dexamethasone 40 mg PO days 1, 8,15, 22

Lenalidomide 25 mg PO days 1–21

Dexamethasone 40 mg PO days 1, 8,15, 22

a National Cancer Institute program

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SWOG S0777: PFS and OS by Assigned Treatment Arm

HR = 0.712 (0.560, 0.906)*Log-rank P value = 0.0018 (one sided)*

HR = 0.709 (0.516, 0.973)*Log-rank P value = 0.0250 (two sided)*

* Stratified

Months From Registration

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts (

%)

0 24 48 72 96

PFS by assigned treatment arm

Events/NMedian in months

VRd 137/242 43 (39, 52)

Rd 166/229 30 (25, 39)

OS by assigned treatment arm

Rd

VRdRdVRd

Durie B et al. Blood. 2015;126: Abstract 25.

a National Cancer Institute program

Months From Registration

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts (

%)

0 24 48 72 96

Events/NMedian in months

VRd 76/242 75 (66, -)

Rd 100/229 64 (56, -)

Combination Study of Carfilzomib, Lenalidomide, and Dexamethasone in Patients With NDMM: Study Design

Key inclusion criteria

• Age ≥18 years

• NDMM with measurable disease

• Creatinine clearance ≥60 mL/min

• ECOG PS 0–2

• ANC ≥1.0 × 109/L, hemoglobin ≥8.0 g/dL, platelet count ≥75 × 109/L

• Adequate hepatic function

KRdCarfilzomib

20/36 mg/m2 IV, days 1, 2, 8, 9, 15, 16Cycle 1, days 1, 2: carfilzomib dose 20 mg/m2

Lenalidomide25 mg/day PO, days 1–21

Lenalidomide was administered on days 2–21 in cycle 1 alone and on days 1–21 of cycles 2–8

Dexamethasone20/10 mg IV or PO, days 1, 2, 8, 9, 15, 16, 22, 23

Cycles 1–4: dexamethasone dose 20 mg; cycles 5–8: dexamethasone dose 10 mg.

Lenalidomide10 mg/day PO,

days 1–21

If ≥SD

Eight 28-day cyclesStem cell harvest after 4 cycles of KRd

for transplant-eligible patientsExtended dosing

24 cycles

Korde N et al. JAMA Oncol. 2015;1:746.

Primary end point

• Rate of PN grade ≥ 3

Secondary end point

• MRD*

• Response rates

• Progression-free survival

• Duration of response

• Safety

*Assessed at the following time points: baseline, achievement of a CR and/or at the completion of cycles 8, 20, and 32, and at termination of protocol therapy.

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Combination Study of Carfilzomib, Lenalidomide, and Dexamethasone in Patients With NDMM: Efficacy

Table 3, page 50

Korde N et al. JAMA Oncol. 2015;1:746.

What about the evaluation of frailty?

Do we need specific studies for frail patients?

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FIRST (MM-020): Frailty Analysis-Frailty Algorithm

• Patients were categorized into three severity groups (fit, intermediate, frail) as described by a proxy algorithm based on the IMWG frailty scale1

1. Palumbo A et al. Blood. 2015;125:2068.Facon T et al. Blood. 2015;126: Abstract 4239.

IMWG Frailty Scale1 Proxy for MM-020 Analysis ScoreAge

≤75 yrs76−80 yrs>80 yrs

Age≤75 years76−80 yrs>80 yrs

012

Activity of Daily Living score>4≤4

EQ-5D: Self Care score1 (no problem)2−3 (moderate or severe problem)

01

Instrumental Activity of Daily Living score5≤5

EQ-5D: Usual Activities score1 (no problem)2−3 (moderate or severe problem)

01

Charlson Comorbidity Index score≤1≥2

Charlson Comorbidity Index score≤1≥2

01

Total0: Fit1: Intermediate≥2: Frail

FIRST (MM-020): Frailty Analysis PFS and OS by Severity Group With ISS Stage

• No treatment effects seen in these groups, likely due to small patient numbers

Facon T et al. Blood. 2015;126: Abstract 4239.

Severity n Median PFS, mos (95% CI) HR (95% CI)Fit + ISS I 84 34.1 (25.6-43.7)

0.71 (0.50-0.99)Fit + ISS II/III 171 23.3 (21.2-30.2)Int + ISS I/II 298 27.7 (24.6-30.4)

0.63 (0.49-0.80)Int + ISS III 150 19.2 (17.6-21.3)Frail + ISS I/II 437 23.0 (20.5-25.8)

0.69 (0.58-0.82)Frail + ISS III 377 17.1 (14.1-19.0)

Severity n Median OS, mos (95% CI) HR (95% CI)

Fit + ISS I 84 NR0.57 (0.33-1.00)

Fit + ISS II/III 171 NR

Int + ISS I/II 298 63.1 (58.2-NR)0.43 (0.32-0.59)

Int + ISS III 150 44.3 (33.5-56.1)

Frail + ISS I/II 437 58.9 (49.5-NR)0.57 (0.47-0.69)

Frail + ISS III 377 35.6 (32.5-40.6)

00

0.2

0.4

0.6

0.8

1.0

20 40 60 80PFS By Investigator, mos

Su

rviv

al P

rob

abili

ty

00

0.2

0.4

0.6

0.8

1.0

20 40 60 80OS, mos

Su

rviv

al P

rob

abili

ty

26

UKMRA Myeloma XIV: FITNESSFrailty-Adjusted Therapy In Transplant

Non-Eligible PatientS With Symptomatic Myeloma

First-line therapy in the nonintensive setting for myeloma

CI: Prof Graham Jackson & Prof Gordon Cook

Frailty index–adjusted therapy

1:1

1:2 FIT

C – 500 mg D1 & D8 R – 25 mg D1–21 D – 20 mg I – 4 mg weekly

UNFIT FRAIL

1:2

CRDa IRDa

1:2

CRDa IRDa

1:2

CRDa IRDa

TREAT TO MAXIMUM RESPONSE (6–8 cycles)

FIT: C – 500 mg D1 & D8, R – 25 mg D1-21, D – 20 mg/wk, I – 4 mg/wkUNFIT: C – 350 mg D1 & D8, R – 15 mg D1-21, D – 10 mg/wk, I – 3 mg/wkFRAIL: C – 250 mg D1 & D8, R – 10 mg D1-21, D – 10 mg/wk, I – 3 mg/wk

1:1

Lenalidomide Ixazomib/Lenalidomide

MA

INT

EN

AN

CE

IND

UC

TIO

N

Trial designTransplant-ineligible NDMM

Non-adjusted

CRDa IRDa

REACTIVE ADAPTIVE

Frailty indexing (FI) performed in all patients at baseline

27

Treatment of MM in Elderly Patients: Landscape and Perspectives

1. DaraVMP vs. VMP. Available at: https://clinicaltrials.gov/ct2/show/NCT021954792. Durie B et al. Blood. 2015;126: Abstract 25.

3. O’Donnell EK et al. Blood. 2015;126: Abstract 4217. 4. IRD vs RD (Tourmaline 2). Available at: https://clinicaltrials.gov/ct2/show/NCT01850524. 5. EloRD vs RD (Eloquent 1). Available at: https://clinicaltrials.gov/ct2/show/NCT01335399.

6. DaraRD vs. RD. Available at: https://clinicaltrials.gov/ct2/show/NCT02252172. 7. KMP vs. VMP (Clarion). Available at: https://clinicaltrials.gov/ct2/show/NCT01818752.

8. Mateos MV et al. Blood. 2016;127:420.

MP

VMP

MPT

MPR-R

# Vd

MPT-T

<

<

<

Rd

?

<

VMP – Daratumumab1

VRD2,3

Rd – Ixazomib4

Rd – Elotuzumab5

Rd – Daratumumab6

MP – Carfilzomib7

Alternating regimens8 ?

Phase 3 Rd-Based Continuous Studies for Elderly Patients

• Primary end point for all studies is PFS1. EloRD vs RD (Eloquent 1). Available at: https://clinicaltrials.gov/ct2/show/NCT01335399. 2. IRD vs RD (Tourmaline 2). Available at: https://clinicaltrials.gov/ct2/show/NCT01850524.

3. DaraRD vs. RD. Available at: https://clinicaltrials.gov/ct2/show/NCT02252172.

NCT01335399 NCT01850524 NCT02252172

Placebo + RR 10 mgUntil PD

Ixazomib+ RIxazomib: 3 mgR: 10 mg

Until PD

DEX Discontinued

ELO-RdELO: 10 mg/kg; D1, 8, 15 & 22 (cycles 1–2); D1 & 15 (cycles 3–18); 20 mg/kg on D1 (cycles ≥ 19)

R: 25 mg, D1–21

DEX: 40 mg D1, 8, 15 & 22 (cycles 1–2); D1 & 15 (cycles 3–18); D1 (cycles ≥ 19)

28-d cycles, until PD 28-d cycles; Rdfor up to 2 years;

DARA until PD

RdR: 25 mg PO ; D1–21DEX: 40 mg PO ; D1, 8, 15 & 2228-d cycles until PD

DARA-RdDARA: 16 mg/kg q1wk for 8 wks; q2wk for 16 wks; q4wk thereafter

R: 25 mg PO d;D1–21

DEX: 40 mg PO d; D1, 8, 15 & 22

RdR: 25 mg PO ; D1–21DEX: 40 mg PO ; D1, 8, 15 & 2228-d cycles until PD

Ixazomib-Rd Ixazomib: 4 mg R: 25 mg

DEX: 40 mg; D1, 8, 15 & 22

28-d cycles/18 mos

RdR: 25 mg PO ; D1–21DEX: 40 mg PO ; D1, 8, 15 & 2228-d cycles/18 mos

DEX Discontinued

Elotuzumab Ixazomib Daratumumab

28

Patient Case 2




Case Study 2• 52-year-old woman referred for workup of

anemia that proved to be iron deficiency. This was only partly corrected with oral iron supplementation. Due to her incomplete response to iron replacement, further workup was undertaken.

29

Case Study 252-year-old woman referred for workup of anemia.

• None

Past medical history

• Appendectomy and varicose vein stripping

Past surgical history

• Sister-in-law has myeloma and failed two SCTs

Familyhistory

• Married, works at a uniform supply firm

• Nonsmoker, rare social alcohol

• No substance use

Socialhistory

• Normal

• ROS: negative except for mild fatigue

Physicalexam

Case Study 2: LabsActualValue

Normal Range


WBC (103/mL) 3.7 (4–11)


Hematocrit (%) 30.1 (34–45)

Platelets (103/mL)* 278 (150–400)

Neutrophils (103/mL) 5.6 (1.9–7.5)

CMP

BUN (mg/dL) 16 (7–20)


Calcium (mg/dL) 8.6 (8.4–10.2)


Albumin (g/dL) 3.4 (3.5–5.0)

SPEPIF- IgG


ActualValue

Normal Range

QuantitativeIgs + serum immuno-fixation

IgG (mg/dL) 3,431 (H) (700–1,600)

IgA (mg/dL) 158 (H) (70–400)

IgM (mg/dL) 40 (H) (40–230)

FLC

Kappa quant FLC (mg/L) 437.6 (H) (3.30–19.40)

Lambda quant FLC (mg/L) 13.67 (H) (5.71–26.30)


31.9 (H) (0.26–1.65)

*With normal iron studies

30

Case Study 2: Imaging and BM Biopsy

Skeletal survey• Indeterminate

lesions in right intertrochanteric area

DEXA scan• Osteopenia

Boneimaging

• 40% cellular with 30% plasma cells

• Aspirate 24% plasma cells

BMbiopsy

• 2% events positive for CD38, CD56, CD138, and cytoplasmic kappa light chains

Flow cytometry

• 46, XX

Cytogenetics

• Negative for gain of 1q21

• Negative for loss of chromosome 13q

• Negative for loss of TP53 and ATM

• Negative for IgH (14q32) and IGH/CCND1 [t(11;14)] rearrangement

FISH*

*CD138 selected plasma cells

Strategies to Prolong Response

Amrita Y. Krishnan, MDProfessor, Department of Hematology & Hematopoietic Cell

TransplantationDirector, Judy and Bernard Briskin Center for Multiple Myeloma Research

City of Hope Medical CenterDuarte, California

31

Options to Prolong Remission• Increase depth of response

– High dose chemotherapy (single versus tandem)• EMN02,[1] BMT-CTN0702[2]

• Prolong therapy– Consolidation

• RVD: EMN02/HO95,[3] BMTCTN0702 Stamina2

• Zimmerman (KRd)4 Roussel (KRd)5

– Maintenance • Myeloma XI[6]

1. Cavo M et al. Blood. 2016;128: Abstract 991.2. Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1.

3. Sonneveld P et al. Blood. 2016;128: Abstract 242.4. Zimmerman T et al. Blood. 2016;128: Abstract 675.

5. Roussel M et al. Blood. 2016;128: Abstract 1142. 6. Jackson GH et al. Blood. 2016;128: Abstract 1143.

RVD, cycles 2, 3

RVD × 2RVD × 5

Lenalidomide (10–15 m/d) 12 mos

Melphalan 200 mg/m2 + ASCT

Induction

Consolidation

Maintenance

CY (3g/m2) + G-CSF MOBILIZATION

Goal: 5 ×106 cells/kg

RVD, cycles 2, 3

CY (3g/m2) + G-CSFMOBILIZATION

Goal: 5 ×106 cells/kg

Randomize, stratification ISS & FISH

PBSC collection

Lenalidomide (10–15 mg/d) 12 mos

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

≥65 yrs 140 mg/m2

IFM/DFCI 2009 Study Schema

Attal M et al. Blood. 2015;126: Abstract 391.

Registration, newly diagnosed MM pts 65 years (ASCT candidates)

ARM B: Early transplant armARM A: Late transplant arm

US len maintenance till progression

1 cycle RVD

32


IFM 2009: Best ResponseRVD Arm

N=350Transplant Arm

N=350 P Value

CR (%) 49 59

0.02 VGPR (%) 29 29

PR (%) 20 11

<PR (%) 2 1

At least VGPR (%) 78 88 0.001

Neg MRD by FCM, n (%) 228 (65%) 280 (80%) 0.001


IFM 2009: PFS (9/2015)

P<0.001

0102030405060708090

100

Pat

ien

ts (

%)

0 12 24 36 48Months of Follow-Up

HDTno HDT

N at riskHDT 350 309 261 153 27

no HDT 350 296 228 128 24

33

0102030405060708090

100

Pat

ien

ts (

%)


HDTno HDT

N at riskHDT 350 328 309 226 55

no HDT 350 338 320 244 56


IFM 2009: OS (9/2015)

P NS

RVD ArmN=48

TransplantN=54

Myeloma, n (%) 40/48 (83) 35/54 (65)

Toxicity, n (%) 4/48 (8) 9*/54 (16)

SPM, n (%) 1/48 (2) 6/54 (11)

Others, n (%) 3/48 (6) 4/54 (7)

*Including 5 transplant related deaths.


IFM 2009: Cause of Death (9/2015)

34

Intensification Therapy with Bortezomib-Melphalan-Prednisone Versus Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma:

An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial)

VMP (n=497)

HDM (n=695) HR/OD (95% CI) P Value

Median PFS (mos) 44 NR ─ ─3-Yr PFS (%) 57.5 66 HR 0.73 (0.59-0.90) 0.003Probability of achieving ≥VGPR (%) 74 85.5 OD 1.90 (1.42-2.54) <0.001

Cavo M et al. Blood. 2016;128: Abstract 673.

Upfront HDM and ASCT significantly improved PFS and increased the rate of high quality responses.

R2

VMP4, 42-day cycles

CyBorD3-4, 21-day cycles HDM + Double ASCT

HDM + Single ASCTR1

RVD

No RVD

Len

InductionConsolidation Maintenance

High Dose Therapy: Single vs Tandem

Cavo M et al. Blood. 2016;128: Abstract 991.Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1.

VMP4, 42-day cycles


HDM + Single ASCTR1

Register and Randomize

MEL 200mg/m2 VRD x 4

LenalidomideMaintenance



MEL 200mg/m2

ACM

AM

TAM

EMN02/HO95

Stamina

Median PFS (27-mos f/up):• ASCT1, 45 mos• ASCT2, NR

Estimated PFS (38-mos):• TAM, 56%• ACM, 57%• AM, 52%

35

0102030405060708090

100

Pa

tie

nts

(%

)


0102030405060708090

100

Pa

tie

nts

(%

)


RVD Arm Transplant Arm

Attal M et al. Blood. 2015;126: Abstract 391.Avet-Loiseau H et al. Blood. 2015;126: Abstract 191.

Increase Depth of Response: MRD

P<0.001

MRD posMRD neg

P<0.001

N at riskMRD pos 89 75 54 22 2MRD neg 140 135 113 72 14

MRD posMRD neg

N at riskMRD pos 65 57 43 30 4MRD neg 172 166 151 86 17

MRD: Still ??

Flow cytometry• Feasible in 100% of patients• Does not require diagnostic sample• Widely available/low cost

NGS (adaptive)• Sensitivity <10-6

• Frozen samples• Fully standardized

Advantages

Flow cytometry• Fresh sample (<24–48 h)• Sensitivity 10-4–10-5

• Lack of standardization (operator)

NGS (adaptive)• Requires diagnostic sample (clone

ID)• Feasibility

Disadvantages

Paiva B et al. Clin Cancer Res. 2015;21:2001.Nishihori T et al. Curr Hematol Malig Rep. 2016;11:118.

36

Sensitivity Matters

P value (trend): P<0.0001

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pa

tie

nts

Wit

ho

ut

Pro

gre

ss

ion

(%

)

40 40(0) 40(0) 40(0) 33(6) 23(9) 15(6) 4(4) 2(1)23 23(0) 23(0) 23(0) 22(1) 19(3) 14(2) 3(5) 2(0)29 29(0) 29(0) 29(0) 28(0) 22(5) 16(3) 4(4) 1(1)86 86(0) 86(0) 86(0) 86(0) 77(5) 61(3) 36(5) 10(0)

N at risk (events)

0 6 12 18 24 30 36 42 48

Months Since Randomization

MRD at post-maintenance

[10-4; 10-3][10-5; 10-4][10-6; 10-5]

<10-6

≥10-4

[10-5; 10-4][10-6; 10-5]

<10-6

Avet-Loiseau H et al. Blood. 2015;126: Abstract 191.

Association of MRD With Superior Survival Outcomes in Patients With Multiple Myeloma:

A Meta-Analysis

• 14 studies• MRD negativity correlated with PFS/OS• 5 trials included ASCT• PCR > MFC (sensitivity)• Only 1 study showed predictive value in unfavorable cytogenetics• 10 studies maintenance (2 post maintenance)

Munshi NC et al. JAMA Oncol. 2016. Sept 15 [Epub ahead of print].

37

IMWG Criteria for Response and MRD Assessment in MM

• MRD negativity in the marrow (NGF, NGS, or both) and by imaging as defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years)

Sustained MRD-negativeSustained MRD-negative

• Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher

Flow MRD-negativeFlow MRD-negative

• Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher

Sequencing MRD-negativeSequencing MRD-negative

• MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood pool SUV or decrease to less than that of surrounding normal tissue

Imaging plus MRD-negativeImaging plus MRD-negative

Kumar S et al. Lancet Oncol. 2016;17:e328.

Prolong Response: Consolidation

Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1.

Register and Randomize MEL 200mg/m2 VRD x 4 Lenalidomide

Maintenance



MEL 200mg/m2

N=750 pts (250 in each arm)

ACM

AM

TAM

ASCT with Len Maintenance

(AM)

Consolidation with Len Maintenance

(ACM)

Tandem ASCT with Len Maintenance

(TAM)

N 257 254 247

38-mo PFS (%) 52 57 56

BMT CTN 0702

38


Sonneveld P et al. Blood. 2016;128: Abstract 242.

EMN02/HO95

R2

VMP4, 42-day cycles


HDM + Single ASCTR1

RVD

No RVD

Len

InductionConsolidation Maintenance

ConsolidationNo

Consolidation P Value

3-year PFS (%) 65 60 0.045

Not retained in high risk cytogenetics (0.91)


KRd ASCT KRd KRdIndefinite

Maintenance Lenalidomide

Induction (Cycles 1–4)

Consolidation (Cycles 5–8)

Maintenance (Cycles 9–18) Post

SCTPost KRdConsol

Post KRdMaint

MRD (%) MFC/NGS -- 82/66 90/71

sCR (%) 20 69 82

1. Zimmerman T et al. Blood. 2016;128: Abstract 675.2. Roussel M et al. Blood. 2016;128: Abstract 1142.

KRd ASCT KRdLenalidomide,

1 Year

Induction (Cycles 1–4)

Consolidation (Cycles 5–8) Maintenance

Post Induction

(n=46)Post ASCT

(n=42)

Post Consol(n=42)

MRD (%) by flow 63 81 89

CR + sCR (%) 26 45 69

ORR (%) 98 98 98

Phase 2 US Study1

Phase 2 IFM Study2

KRd is now being compared with VRd in a randomized clinical trial.

39

Prolonging Response: Maintenance

• What is the optimal drug?• What is the optimal duration of maintenance?• What is the benefit of maintenance?

• Ultimate goal; prolonged survival

Maintenance Therapy Post SCT: What Is Known

• Bortezomib maintenance; HOVON1

• Lenalidomide maintenance after ASCT reduces the risk of progression or death by approximately 50%2-5

• All phase 3 studies had progression-free survival as the primary end point

1. Sonneveld P et al. J Clin Oncol, 2012;30:2946.2. Palumbo A et al. N Engl J Med. 2014;371:895.

3. McCarthy PL et al. N Engl J Med. 2012;366:1770. 4. Attal M et al. N Engl J Med. 2012;366:1782.

5. Palumbo A et al. N Engl J Med. 2012;366:1759.

40

Randomization

MM Stage II or III, Age 18–65

CAD + GCSF

3 × VAD

CAD + GCSF

3 × PAD

MEL 200 + PBSCT

In GMMG 2nd

MEL 200 + PBSCT

MEL 200 + PBSCT

In GMMG 2nd

MEL 200 + PBSCT

Thalidomide maintenance50 mg/day for

2 years

Allogeneic transplant

Bortezomib maintenance

1.3 mg/m2/2 weeks for 2 years

Bortezomib 1.3 mg/m2

i.v., 2x/w

Doxorubicin 9 mg/m2

Dexameth 40 mg

HOVON Study Schema

Sonneveld P et al. J Clin Oncol, 2012;30:2946.

OS by Treatment Arm

• OS at 96 m: 48% vs 45%

• HR: 0.87, 95% CI0.71–1.04; P=0.22

• RMST8y: 4.8 months (95% CI 0.2–9.5; P=0.04)

Sonneveld P et al. Blood. 2015;126: Abstract 27.

A: VAD

B: PAD

0

25

50

75

100

Cu

mu

lati

ve P

erce

nta

ge

Months0 24 48 72 96

Overall SurvivalRandomization Arm

N D

A: VAD 414 217

B: PAD 413 204

Cox LR Stratified P=0.22

41

Studies Included in Meta-Analysis

Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT

CALGB 100104(accrual 8/2005–11/2009)

INDUCTIONASCT

1:1 RANDOMIZATION“NO EVIDENCE OF PD”

LEN MNTCa

(n=231)PLACEBO

(n=229)

INTERIM ANALYSIS AND UNBLINDING

Dec 2009

CROSSOVER BEFORE PD ALLOWED

CONTINUEDTREATMENT

a Starting dose of 10 mg/day on days 1–28/28 was increased to 15 mg/day if tolerated and continued until PD. b Patients received maintenance 10 mg/day on days 1–21/28 until PD.

GIMEMA (RV-MM-PI-209)(accrual 11/2007–7/2009)

CONTINUEDTREATMENT

LEN MNTCb

(n=67)NO TREATMENT

(n=68)

CONTINUED TREATMENT

LEN MNTCbNO TREATMENT

PRIMARY ANALYSIS

2 × 2 DESIGNLEN + DEX × 4

INDUCTION

ASCT MPR: 6 COURSES

Attal M et al. J Clin Oncol. 2016;34: Abstract 8001.

IFM 2005-02(accrual 6/2006–8/2008)

INTERIM ANALYSIS AND UNBLINDING

Dec 2009 Jan 2010

NO CROSSOVER BEFORE PD ALLOWED

CONTINUED TREATMENT

ALL TREATMENT DISCONTINUED

Jan 2011

LEN MNTCa

(n=307)PLACEBO

(n=307)

LEN: 2 COURSES

INDUCTIONASCT

1:1 RANDOMIZATION“NO EVIDENCE OF PD”

Overall Survival: Median Follow-Up of 80 Months

There is a 26% reduction in risk of death, representing an estimated 2.5-year increase in median survival.a

N=1,209 Lenalidomide Control

Median OS(95% CI), mos

NE(NE–NE)

86.0(79.8–96.0)

HR (95% CI)P value

0.74 (0.62–0.89)0.001

a Median for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74).

0.00 10 20 30 40 50 60 70 80 90 100 110 120

0.2

0.4

0.6

0.8

1.0

605 578 555 509 474 431 385 282 200 95 20 1 0604 569 542 505 458 425 350 271 174 71 10 0

Overall Survival, mos

Su

rviv

al

Pro

bab

ility

Patients at risk

7-yr OS

62%

50%


42

Cumulative Incidence of Second Primary Malignancies

a HR based on Cox proportional hazards model. b P value is based on log-rank test.

586 559 514 465 422 365 251 139 38 1 586 554 508 458 415 360 251 136 35 0602 559 525 468 428 340 248 119 28 0 602 559 520 461 417 328 241 117 28 0

Time to Hematologic SPM Onset, mos Time to Solid Tumor SPM Onset, mos

LenalidomideControl

HR (95% CI): 2.03a (1.14–3.61)P=0.015b

LenalidomideControl

HR (95% CI): 1.71a (1.04–2.79)P=0.032b

Hematologic Solid Tumor

Patients at risk

Patients at risk

0 12 24 36 48 60 72 84 96 1080.0

Cu

mu

lati

ve I

nci

de

nce

0.20

0.40

0.60

0.80

1.00

0 12 24 36 48 60 72 84 96 1080.0

Cu

mu

lati

ve I

nc

ide

nc

e

0.20

0.40

0.60

0.80

1.00


Lenalidomide is Highly Effective Maintenance Therapy in MM: Phase 3 Myeloma XI study

• Lenalidomide continued to disease progression versus no therapy in both newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) populations

• Hematologic second primary malignancy 0.9% with maintenance vs 0.3% with no maintenance

Jackson G et al. Blood. 2016;128: Abstract 1143.

TE (n=828) TNE (n=722)

P ValueMaint No Maint Maint No Maint

Median PFS (mos) 60 28 26 12 <0.0001

43

Ultimate Goal: Prolong Survival• High dose therapy (IFM/DFCI, EMN02, BMTCTN)• Consolidation (EMN02, BMTCTN)• Maintenance

– Lenalidomide: Estimated 2.5-year improvement in median overall survival

– Bortezomib: Estimated 5-month improvement in overall survival

Future: MRD-directed therapy

Panel Discussion

44

Patient Case 3




Case Study 3• 73-year-old man with a 7-year history of IgG kappa MGUS• Experiences evolution of disease to symptomatic myeloma:

– IgG has increased to 7,233 mg/dL– Hgb has fallen to 8.5 gm/dL– Bone marrow is 60% cellular with 50% plasma cells that are

CD138(+) – Marrow cytogenetics shows 46,XY – Myeloma FISH panel is negative

• The patient is placed on lenalidomide and dexamethasone – Achieves VGPR after 2½ years of therapy– Stops this due to diarrhea and asthenia

45

Case Study 3• Patient becomes anemic again after being off of therapy

for 9 months • He then moves to Colorado, where he reports dyspnea

that he feels is due to the altitude– IgG is 8592 mg/dL– Hgb is 8.0 gm/dL– Bone marrow biopsy shows 75% cellularity with 80% plasma

cells, some in sheets – Conventional cytogenetics are normal – FISH panel shows new del17p

Case Study 3• The patient elects to begin therapy with carfilzomib and

dexamethasone; refuses further lenalidomide • After two cycles, the patient presents with dyspnea; a

cardiac echo shows a LVEF of 40%• Patient also notes left tibial pain; a plain x-ray shows a

destructive lesion• Patient undergoes surgery to place an IM rod in his left

femur following treatment of his presumed carfilzomib cardiomyopathy

• Patient now returns to clinic to discuss his next therapy after completion of five fractions of radiation to his tibia

46

Case Study 3: LabsActualValue

Normal Range


WBC (103/mL) 3,400 (4–11)


Hematocrit (%) 31.6 (34–45)

Platelets (103/mL) 164 (150–400)

Neutrophils (103/mL) 2.1 (1.9–7.5)

CMP

BUN (mg/dL) 24 (7–20)


Calcium (mg/dL) 7.6 (8.4–10.2)


Albumin (g/dL) 1.7 (3.5–5.0)

SPEPIF- IgG


ActualValue

Normal Range

QuantitativeIgs + serum immuno-fixation

IgG (mg/dL) 8,431 (H) (700–1,600)

IgA (mg/dL) <30 (L) (70–400)

IgM (mg/dL) <5 (L) (40–230)

FLC

Kappa quant FLC (mg/L) 760.4 (H) (3.30–19.40)

Lambda quant FLC (mg/L) 13.67 (H) (5.71–26.30)


55.62 (H) (0.26–1.65)

New Agents, Classes in the Relapsed Setting

Faith E. Davies, MBBCh, MRCP, MD, FRCPathProfessor of Medicine

Medical Director, Myeloma InstituteUniversity of Arkansas for Medical Sciences

Little Rock, Arkansas

47

Factors Affecting Treatment Decisions in RRMM

*IMiD-based, proteasome-based, alkylators, dexamethasone.

Salvage therapies

Class of prior therapy*; degree of response to prior therapy;

PFS; tolerability of prior therapy

(treatment-related AEs)

Patient-related factors: age, PS, counts, PN, VTE, RI, cytogenetic

profile, extramedullary involvement,

etc

Aggressiveness of disease and

prognostic features

Number and degree of

relapses and refractory disease

Disease progression

First-line therapy

Current Therapies for RRMM 1–3 Lines Can Be Classified by the Drug’s Mechanism of Action

BortezomibProteasome inhibitors Carfilzomib Ixazomib

ThalidomideImmunomodulators Lenalidomide Pomalidomide

PanobinostatHistone deacetylase

DaratumumabMonoclonal antibodies Elotuzumab

High-dose melphalanAlkylators Bendamustine Cyclophosphamide

DexamethasoneSteroids Prednisolone Methyl prednisolone

Critical to understand treatment patterns specific to your own country/region as

drug approval variability exists

48

Two Important Questions• Which drugs do I use in the combination?

– Individualize the drug choice toward the specific patient

– Take advantage of different mechanisms of action

• How many drugs should I use?– Aim for a triplet– Monitor closely and mange the side effects– Staying on treatment is the key

Two Important Questions• Which drugs do I use in the combination?

– Individualize the drug choice toward the specific patient

– Take advantage of different mechanisms of action

• How many drugs should I use?– Aim for a triplet– Monitor closely and mange the side effects– Staying on treatment is the key

49

Plethora of New Randomized Studies to Help Guide Treatment Decisions

Control Arm Comparator Arm Trial Name

Lenalidomide and dexamethasone

Carfilzomib, lenalidomide, and dexamethasone ASPIRE

Elotuzumab, lenalidomide, and dexamethasone

ELOQUENT 2

Ixazomib, lenalidomide, and dexamethasone TOURMALINE 1

Bortezomib and dexamethasone

Carfilzomib and dexamethasone ENDEAVOR

Panobinostat, bortezomib, and dexamethasone PANORAMA 1

Dexamethasone Pomalidomide and dexamethasone MM03 NIMBUS

No transplant High-dose melphalan Myeloma X

Study N Treatment

ASPIRE1 792Carfilzomib-lenalidomide-dexamethasone (KRd) vs lenalidomide-dexamethasone (Rd)

ELOQUENT-22 646Elotuzumab-lenalidomide-dexamethasone (Erd) vs lenalidomide-dexamethasone (Rd)

TOURMALINE-MM13 722Ixazomib-lenalidomide-dexamethasone (Ird)vs placebo-lenalidomide-dexamethasone (Rd)

ENDEAVOR4 929Carfilzomib-dexamethasone (Kd)vs bortezomib-dexamethasone (Vd)

Differences Between Studies in Baseline Characteristics

1. Stewart AK et al. N Engl J Med. 2015;372:142.2. Lonial S et al. N Engl J Med. 2015;373:621.

3. Moreau P et al. N Engl J Med. 2016;374:1621.4. Dimopoulos MA et al. Lancet Oncol. 2016;17:27.

Proportion of patients with refractory disease, disease stage ISS III, low creatinine clearance, high risk cytogenetics

50

ASPIRE: Carfilzomib-Lenalidomide-Dexamethasone (KRd) vs Lenalidomide-Dexamethasone (Rd)

• Phase 3, open-label, randomized, multicenter study

N=792RRMM patients

• Prior treatment with 1–3 regimens

• ≥ PR to ≥1 prior regimen

RdLEN: 25 mg, d 1–21DEX: 40 mg, d 1, 8, 15, 2228-day cycles until progression

KRdCFZ: 27 mg/m2, d 1, 2, 15, 16LEN: 25 mg, d 1–21DEX: 40 mg, d 1, 8, 15, 22Six 28-day cycles

*Carfilzomib is administered at 20 mg/m2 on Days 1 and 2

• Stratified for previous Bortezomib therapy• Patients received antiviral and antithrombotic prophylaxis• Primary end point: PFS • Secondary end points: OS, ORR, DoR, HRQoL, safety

KRdCFZ: 20/27 mg/m2, d 1–2*, 8–9, 15–16LEN: 25 mg, d 1–21DEX: 40 mg, d 1, 8, 15, 22Twelve 28-day cycles

RdLEN: 25 mg, d 1–21DEX: 40 mg, d 1, 8, 15, 22Until PD

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

17.226.3

38.131.1

17.75.1

14.1

4.3

0

20

40

60

80

100

KRd(n=396)

Rd(n=396)

Pa

tie

nts

, %

Response rates sCRCRVGPRPR

ORR: 87.1%

ORR: 66.7%

≥PR, ≥VGPR and ≥CR: P<0.001

ASPIRE: KRd vs RdEfficacy

• Median follow-up was 32.3 months for KRd and 31.5 months for Rd

• PFS benefit for KRd was observed across all predefined subgroups ‡

KRd(n=396)

Rd(n=396)

HR; P value

Median PFS, months 26.3 17.6 HR = 0.69; P=0.0001*

Median OS, months2-year OS, %

NR73.3

NR65.0

HR = 0.79; P=0.04†

Time to response, months 1.0 1.0 ─

Median DOR, months 28.6 21.2 NR

*Prespecified stopping boundary was met† Interim analysis, prespecified stopping boundary was not met‡ Predefined subgroups included sex, age, geographic region, β2M level, cytogenetics,

peripheral neuropathy at baseline, prior BORT, prior LEN, any prior IMiD, nonresponsive to BORT in prior regimen, refractory to prior IMiD Stewart AK et al. N Engl J Med. 2015;372:142.

51

ASPIRE: KRd vs RdProgression-Free Survival

Figure 1, page 148

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

Rd (n = 325)LEN: 25 mg, d1–21DEX: 40 mg, d1, 8, 15, 2228-day cycles until progression

N=646RRMM

1–3 prior linesNot LEN-refractory

ERd (n = 321)ELO: 10 mg/kg, d1, 8, 15, 22 IV(cycles 1–2); d1, 15 (cycles ≥ 3);LEN: 25 mg, d1–21DEX: weekly equivalent, 40 mg

28-day cycles until progression

• Primary end points: PFS, ORR• Secondary end points: OS, DoR, QoL, safety

ELOQUENT 2: Elotuzumab-Rd (ERd) vs Rd

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

52

CRVGPRPR

ELOQUENT-2: ERd vs RdEfficacy

*Values may not sum due to rounding.

46 38

2821

4

7

0

20

40

60

80

100

ERd Rd

Pat

ien

ts (

%)

ORR 79%a

ORR 66%*

n=321 n=325

P<0.001 ERd(n=321)

Rd(n=325)

HR; P value

Median PFS, months2 19.4 14.9 0.73;

0.0014

Median TTNT, months2 33 21

0.62(95% CI

0.50–0.77)

Median OS, months2 43.7 39.6 0.77;

0.0257

Median DoR, months1 20.7 16.7 NR

Responses1

1. Lonial S et al. N Engl J Med. 2015;373:621-31.2. Dimopoulos MA et al. Blood. 2015;126: Abstract 28.

ELOQUENT-2: ERd vs RdProgression-Free Survival

Dimopoulos MA et al. Blood. 2015;126: Abstract 28.

ERd(n=321)

Rd(n=325)

Median PFS, mos (95% CI)

19.4 (16.6−22.2) 14.9 (12.1−17.2)HR=0.73 (95% CI 0.60−0.89; P=0.0014)

3-yr PFS, % 26 18

Figure 1, page 627


53

FOLLOW-UP Every 4 weeks until PD, then every 12

weeks for OS

TOURMALINE-MM1: Ixazomib-Lenalidomide-Dexamethasone vs Lenalidomide-Dexamethasone

• Primary end point: PFS by independent review committee using IMWG criteria• Key secondary end points: OS, OS in high-risk patients† with del(17)

*10 mg for pts with CrCl ≤ 60 or ≤ 50 mL/min, depending on local practice/label.†High-risk was defined as del(17p), t(4;14), or t(l4;16), including 10% del(17p).

IRdLEN: 25 mg* PO d1–21DEX: 40 mg PO d1, 8, 15, 22IXA: 4 mg PO d1, 8, 1528-day cycles

Rd + PlaceboLEN: 25 mg* PO d1–21DEX: 40 mg PO d1, 8, 15, 22Placebo: PO d1, 8, 1528-day cycles

1:1

Stratification:• Prior treatment • ISS stage • PI exposure

Moreau P et al. N Engl J Med. 2016;374:1621.

N=722Pts with RRMM

1–3 prior therapiesNot LEN- or PI-refractory

30 33

36 32

12 7

0

20

40

60

80

100

IRd Rd

Pat

ien

ts (

%)

TOURMALINE-MM1: IRd vs RdEfficacy Summary

n=360 n=362

P<0.001

Responses

*Values may not sum due to rounding.

ORR 78%*ORR 72%a

CRVGPRPR

CR: P=0.019;CR + VGPR: P=0.014


Table 2, page 1626


54

• Consistent PFS benefit across pre-specified patient subgroups

TOURMALINE-MM1: IRd vs RdPFS Analysis

Figure 1, page 1627


ENDEAVOR Study Design

Dimopoulos MA et al. Lancet Oncol. 2016;17:27.

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, 11Dexamethasone 20 mg

Days 1, 2, 4, 5, 8, 9, 11, 1221-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

• Primary end point: PFS

55

ENDEAVOR: Kd vs Vd in RRMMProgression-Free Survival

• Median follow-up: 11.9 mos for Kd; 11.1 mos for Vd Kd(n=464)

Vd(n=465)

Median PFS, months(95% CI)

18.7(15.6−NE)

9.4(8.4−0.4)

Hazard ratioP value

0.53 (0.44−0.65)<0.0001


*Predefined subgroups included sex, age, geographic region, ECOG performance status baseline creatinine clearance, previous peripheral neuropathy, disease stage, cytogenetics, number of prior regimens, prior transplant, prior BORT, prior IMiD, prior LEN, prior THAL, refractory to prior BORT, refractory to prior LEN.

• A consistent PFS benefit for Kd was observed across predefined subgroups

PF

S (

%)

0

20

40

60

80

100

0 6 12 18 24 30Time (years)

Kd

Vd

PANORAMA 1: Panobinostat + Bortezomib and Dexamethasone vs Bortezomib and Dexamethasone

• Multicenter, randomized, double-blind, placebo-controlled, phase 3 study

Study population

• N = 768

• 1–3 lines prior therapy

• Measurable M protein component in serum or urine at study screening

• ECOG ≤2

Treatment phase 1 (TP1) Treatment phase 2 (TP2)

PanVD (42-day cycle)Panobinostat• 20 mg PO as TP1 + on d22, 24, 26, 29, 31, 33Bortezomib• 1.3 mg/m2 IV d1, 8, 22, 29Dexamethasone• 20 mg PO on d1, 2, 8, 9, 22, 23, 29, 30

Placebo + VD (42-day cycle)PlaceboBortezomib• As aboveDexamethasone• As above

R

• Primary end point: PFSSan Miguel JF et al. Lancet Oncol. 2014;15:1195.

Placebo + VD (21-day cycle)PlaceboBortezomib• As aboveDexamethasone• As above

PanVD (21-day cycle)Panobinostat• 20 mg PO on d1, 3, 5, 8, 10, 12Bortezomib• 1.3 mg/m2 IV on d1, 4, 8, 11Dexamethasone• 20 mg PO on d1, 2, 4, 5, 8, 9, 11, 12

56

PanoVD for RRMM Patients Who Received Prior Bortezomib and IMiDs

• Subgroup analysis of patients who received ≥2 previous treatments, including bortezomib and an IMiD indication based on subgroup analysis

San-Miguel JF et al. J Clin Oncol. 2015;33: Abstract 8526.Richardson PG et al. Blood. 2016;127:713.

Figure 1, page 716

Richardson PG et al. Blood. 2016;127:713.

MM-003 NIMBUS: Pomalidomide Dexamethasone vs Dexamethasone

*Thromboprophylaxis was indicated for those receiving POM or with deep vein thrombosis history. San Miguel JF et al. Lancet Oncol 2013;14:1055.

(n=302)POM*: 4 mg/day Day 1–21 +LoDEX: 40 mg (≤75 years)

20 mg (>75 years)Day 1, 8, 15, 22

RA

ND

OM

IZA

TIO

N 2

:1(N

=45

5)

Follow-up for OS and SPM until

5 years post-enrollment

(n=153)HiDEX: 40 mg (≤75 years)

20 mg (>75 years) Day 1–4, 9–12, 17–20

28-day cycles

PD

PD Companion trialMM-003C

POM 21/28 days

Stratification• Age (≤75 vs >75 yrs)• Number of prior treatments (2 vs >2)• Disease population (primary refractory vs relapsed/refractory vs intolerance/failure)

• Primary end point: PFS

57

MM-003 NIMBUS: POM + LoDEX vs HiDEX PFSMedian Follow-Up 15.4 months

Adapted from Figure 2, page 1059

San Miguel JF et al. Lancet Oncol 2013;14:1055.

Myeloma X: Autologous Transplantation vs Ongoing Chemotherapy

Bortezomib, doxorubicin, dexamethasone (PAD)

Response ≥SD

PBSC mobilization

Follow-up

RR

PDor

CD34+ cells <2×106/kg

Off study

Cook G et al. Lancet Oncol. 2014;15:874.

N=297

N=89 N=89

Melphalan 200mg/m2 IVASCT

Cyclophosphamide 400 mg/m2 PO/week × 12

58

Myeloma X: Autologous Transplantation vs Ongoing Chemotherapy PFS

Figure 2, page 879

Cook G et al. Lancet Oncol. 2014;15:874.

ASPIRE: Carfilzomib (KRd vs Rd)Safety Profile

• 15% of patients in the KRd group and 18% in the Rd group discontinued treatment due to AEs• 8% of patients in the KRd group and 9% in the Rd group died while on treatment or within 30 days of last dose

Table 3, page 151

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

59

ENDEAVOR: Carfilzomib (Kd vs Vd)Cardiac Substudy

All grades

Cardiac Substudy Overall Safety Population

Kd (N=74)n (%)

Vd (N=74)n (%)

Kd (N=463)n (%)

Vd (N=456)n (%)

Cardiac arrhythmias (SMQN) 3 (4.1) 3 (4.1) 29 (6.2) 43 (9.4)

Cardiac failure (SMQN) 8 (10.8) 3 (4.1) 38 (8.2) 13 (2.9)

Decreased ejection fraction 4 (5.4) 2 (2.7) 10 (2.2) 4 (0.9)

Cardiac failure 3 (4.1) 1 (1.4) 15 (3.2) 4 (0.9)

Cardiac failure acute 1 (1.4) 0 4 (0.9) 1 (0.2)

Cardiac failure chronic 1 (1.4) 0 1 (0.2) 0

Right ventricular failure 0 1 (1.4) 1 (0.2) 1 (0.2)

Ischemic heart disease (SMQN) 0 2 (2.7) 13 (2.8) 9 (2.0)

Respiratory, thoracic, and mediastinal disorders 31 (41.9) 25 (33.8) 264 (57.0) 161 (35.3)

Hypertension 15 (20.3) 6 (8.1) 115 (24.8) 40 (8.8)


ELOQUENT-2: Elotuzumab (ERd vs Rd) Safety Profile


Table 3, page 630


60

TOURMALINE-MM1: IRd vs Rd Safety Profile

Table 4, page 1630


MM03 NIMBUS Pom Dex vs Dex Safety Profile

Table 4, page 1630

San Miguel JF et al. Lancet Oncol2013;14:1055.

61

Conclusions• Many choices

– Good response, improved PFS, good safety profiles

• Individualize the choice toward the specific patient– Type of relapse– Previous therapy received– Previous side effects– Oral vs IV

• Aim for a triplet• Monitor closely and manage side effects

– Staying on treatment is the key

The Way Forward: Immunotherapy

Paul G. Richardson, MDR.J. Corman Professor of Medicine

Harvard Medical SchoolClinical Program Leader and Director of Clinical Research

Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute

Boston, Massachusetts

62

Key Targets in MM• Excess protein production

>> Target protein degradation

• Genomic abnormalities and acquired resistance

>> Target and overcome mutations

• Immune suppression

>> Restore anti-MM immunity

WGS at Diagnosis

Courtesy of Nikhil Munshi MD, DFCI

63

Courtesy of Nikhil Munshi MD, DFCI

WGS at Relapse

Restoring Immune Function• Immunomodulatory drugs, other small

molecules (eg, HDACi’s)

• Monoclonal antibodies

• Checkpoint inhibitors

• Vaccines

• Cellular therapies

64

MM cells

Bone marrow stromal cells

Dendritic cells

IL-6

TNFα

IL-1βA

IL-2

IFN

CD8+ T cells

C

E

Bone marrow vessels

ICAM-1

VEGFbFGF

D

B

NK cellsNK-T cells

PKCNFAT

PI3K

IL-2

CD28

Lenalidomide and Pomalidomide in MM

Hideshima T et al. Blood. 2000;96:2943.Davies FE et al. Blood. 2001;98:210.Gupta D et al. Leukemia. 2001;15:1950.Mitsiades N et al. Blood. 2002;99:4525.

Lentzsch S et al. Cancer Res. 2002;62:2300.LeBlanc R et al. Blood. 2004;103:1787.

Hayashi T et al. Br J Haematol. 2005;128:192.

Immunomodulatory AgentsIMiDs: Mechanism of Action

Krönke J et al Science. 2014;343:301. Lu G et al. Science 2014;343:305.

Adapted from Figure, page 347

Stewart AK. Science. 2014;343:256.

65

Model of Lenalidomide and Pomalidomide Costimulationof T Cells via Degradation of Aiolos and Ikaros

Figure 9, page 819

Gandhi AK et al. Br J Haematol. 2014;164:811.

3 1 7

30 24

12 8

0

10

20

30

40

50

MM 002 MM 003

MRPRVGPRCR/sCR

Efficacy Results of POMALIDOMIDE + LoDEX in Advanced RRMM (Phase 2/3: MM002 & MM003)

ORR = 33% ORR = 32%

Per

cen

tag

e R

esp

on

se

MM-002 (n=113)1MM-0021 MM-0032,3

Median follow-up, months 14.2 15.4

Median DoR, months 8.3 7.5

Median PFS, months 4.2 4.0

Median OS, months 16.5 13.1

1. Richardson PG et al. Blood. 2014;123:1826.2. San Miguel J et al. Lancet Oncology. 2013;14:1055.

3. San Miguel J et al. Blood. 2013;122; Abstract 686.

MM-002 (n=113)1 MM-003 (n=302)2,3

66

Monoclonal Antibodies Kill MM Through Multiple Mechanisms

DIRECT EFFECTS INDIRECT EFFECTSInterferes with

survival ordelivers myeloma-killing substances

Labels myeloma cells for killing by complement

Labels myeloma cells for killing by NK cells

Monoclonal antibody

Myeloma cell surface target

Complement

Fc receptor

NK cell toxins

Activates T cells by taking the brakes off

Checkpoint inhibitor

Adapted from Richardson PG, ASH 2012

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

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

1. Hsi ED et al. Clin Cancer Res. 2008;14:2775.2. Collins SM et al. Cancer Immunol Immunother. 2013;62:1841.

Directly activating natural killer cells

A

Tagging for recognition (ADCC)

B

EAT-2

Perforin,granzyme Brelease

ElotuzumabNatural killer cell

SLAMF7

Myeloma cellMyelomacell

DegranulationDownstreamactivating signalingcascade

EAT-2SLAMF7

Polarization

Natural killer cell

Granule synthesis

Myelomacell death

Elotuzumab: Immunostimulatory Mechanism of Action

67

ELOQUENT-2: Primary Analysis

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

ELOQUENT-2 demonstrated clinical benefits of E-Ld

compared with lenalidomide and dexamethasone (Ld)

alone1

ELOQUENT-2 demonstrated clinical benefits of E-Ld

compared with lenalidomide and dexamethasone (Ld)

alone1

Figure 1, page 627

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

From Table 2, page 629

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

1.0

0.8

0.6

0.4

0.2

0.0

Pro

ba

bil

ity

Pro

gre

ss

ion

Fre

e 0.9

0.7

0.5

0.3

0.1

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

PFS (months)

Elotuzumab in High-Risk Patients

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

ELOQUENT-2 Study ResultsProgression-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

ba

bil

ity

Pro

gre

ss

ion

Fre

e 0.9

0.7

0.5

0.3

0.1

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

68

Daratumumab: Mechanism of Action• Human CD38 IgGκ

monoclonal antibody • Direct and indirect anti-

myeloma activity1-5

• Depletes CD38+ immunosuppressive regulatory cells5

• Promotes T-cell expansion and activation5

1. Lammerts van Bueren J et al. Blood. 2014;124: Abstract 3474. 2. Jansen JHM et al. Blood. 2012;120: Abstract 2974.3. de Weers M et al. J Immunol. 2011;186:1840. 4. Overdijk MB et al. MAbs. 2015;7:311.

5. Krejcik J et al. Blood. 2016;128:384.

Lokhorst HM et al. N Engl J Med. 2015;373:1207. Lonial S et al. Lancet. 2016;387:1551.

69

Daratumumab Monotherapy: Efficacy in Combined Analysis

Usmani SZ et al. Blood. 2016;128:37.

Figure 4, page 42

Usmani SZ et al. Blood. 2016;128:37.

20

35

5

OR

R, %

10

25

15

0

Lonial S et al. Lancet. 2016;387:1551.

40

30

Daratumumab Phase 2 StudySingle Agent in RRMM

33 3330

21 20

30 29 28 28 2621

ORR by Subgroup

Refractory to

70

Daratumumab Phase 2 StudySingle Agent in RRMM

Progression-Free and Overall Survival

20

80

Pat

ien

ts

Pro

gre

ssio

n-F

ree

and

Aliv

e (%

)

40

0

100

60

0 2 4 6 8 10 12 14 16Months From Start of Treatment

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

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


Figure 4, page 1558


Synergistic With Other Standard MM Therapies, Including Bortezomib and Lenalidomide

Modified from Figure 1, page e42

van der Veer MS et al. Blood Cancer J.2011;1:e41.

71

Palumbo A et al. N Engl J Med. 2016;375:754.

Phase 3 Randomized Controlled Study of DVd vs Vd in Pts With Relapsed or Refractory MM: CASTOR

CASTOR Study DesignMulticenter, randomized, open-label, active-controlled phase 3 study

Key eligibility criteria

• RRMM

• ≥1 prior line of therapy

• Prior bortezomib exposure, but not refractory

Primary end point• PFSSecondary end point• TTP• OS• ORR, VGPR, CR• MRD• Time to response• Duration of response

RANDOMIZE

DVd (n=251)Daratumumab (16 mg/kg IV)Every week: cycles 1–3Every 3 weeks: cycles 4–8Every 4 weeks: cycles 9+Vel: 1.3 mg/m2 SC, days 1, 4, 8, 11: cycles 1–8Dex: 20 mg PO-IV, days 1, 2, 4, 5, 8, 9, 11, 12: cycles 1–8

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

1:1

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

Statistical analyses• 295 PFS events: 85%

power for 4.3 month PFS• Interim analysis: ~177

PFS eventsDaratumumab IV administered in 1,000 mL to 500 mL;

gradual escalation from 50 mL to 200 mL/hour permitted


72

Phase 3 Randomized Controlled Study of DVd vs Vd in Pts With Relapsed or Refractory MM: CASTOR

CASTOR Efficacy

DVd Vd HR 95% CI P Value

N 251 247 ─ ─ ─

PFS (mos) NR 7.2 0.39 0.280.53 <0.0001

1-year PFS (%) 60.7 26.9

Median TTP (mos) NR 7.3 0.30 0.210.43 <0.0001

ORR (%) 83 63 ─ ─ <0.0001

≥VGPR 59 29 ─ ─ <0.0001

≥CR 19 9 ─ ─ 0.0012

MRD-negative (10-4) (%) 14 3 ─ ─

Median duration of response (mos) NR 7.9 ─ ─ ─


Phase 3 Randomized Controlled Study of DVd vs Vdin Pts With Relapsed or Refractory MM: CASTOR

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15

DVd

Vd26.9%

60.7%

1-year PFS*Median: not reached

Median: 7.2 months

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

po

rtio

n S

urv

ivin

g

Wit

ho

ut

Pro

gre

ssio

n

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

No. at riskVd 247 182 106 25 5 0

DVd 251 215 145 56 11 0

CASTOR PFS


73

Daratumumab + Lenalidomide + Dexamethasone: Overall Response Rate

• ORR = 81%• Clinical benefit rate (ORR + minimal response) = 88%

From Table 4, page 1825

Plesner T et al. Blood. 2016;128:1821.

Dimopoulos M et al. N Engl J Med. 2016;375:1319.

74

Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX

POLLUX Study DesignKey eligibility

criteria• RRMM• ≥1 prior line of

therapy• Prior lenalidomide

exposure, but not refractory

• Patients with creatinine clearance ≥30 mL/min

Primary end point• PFS

Secondary end point• TTP• OS• ORR, VGPR, CR• MRD• Time to response• Duration of response

RANDOMIZE

DRd (n=286)Daratumumab 16 mg/kg V• Qw in Cycles 1–2, q2w in Cycles 3–6, then q4w until

PD

R 25 mg PO• Days 1–21 of each cycle until PD

d 40 mg PO• 40 mg weekly until PD

Rd (n=283)R 25 mg PO• Days 1–21 of each cycle until PD

d 40 mg PO• 40 mg weekly until PD

1:1

Cycles: 28 days

Statistical analyses• 295 PFS events: 85%

power for 7.7 month PFS improvement

• Interim analysis: ~177 PFS eventsPre-medication for the DRd treatment group consisted of

dexamethasone 20 mga, paracetamol, and an antihistamine.

Stratification factors• No prior lines of therapy• ISS stage at study entry• Prior lenalidomide


POLLUX PFS

Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15

Pro

po

rtio

n S

urv

ivin

gW

ith

ou

t P

rog

ress

ion

No. at riskRd 283 249 206 179 139 36 5 0

DRd 286 266 248 232 189 55 8 0

63% reduction in the risk of disease progression or death for DRd vs Rd

18 24

DRd78%

18-month PFS*12-month PFS*

Median PFS: 18.4 months

HR: 0.37 (95% CI, 0.27–0.52); P<0.0001

83%

Rd

60%52%


75

Phase 3 Randomized Controlled Study of DRd vs Rdin Pts With Relapsed or Refractory MM: POLLUX

POLLUX Efficacy

DRd Rd P Value

N 286 283 ─

ORR (%) 93 76 <0.0001

≥VGPR 76 44 <0.0001

≥CR 43 19 <0.0001

Median duration of response (mos)

NR 17.4 ─


Phase 3 Randomized Controlled Study of DRd vs Rdin Pts With Relapsed or Refractory MM: POLLUX

POLLUX MRD-Negativity Rate50

40

30

20

10

0

MR

D-n

egat

ive

Rat

e (%

)

MRD-neg (10-4) MRD-neg (10-5) MRD-neg (10-6)

45

35

25

15

5

30%

8%

23%

5%

10%

2%

P<0.0001

P<0.0001

P<0.0001

DRdRd


76

20

35

5

OR

R, %

10

25

15

0

Lonial S et al. J Clin Oncol. 2015;33. Abstract LBA 8512.

40

30

Daratumumab in High-Risk Patients

33 3330

21 20

30 29 28 28 2621

Daratumumab Phase 2 StudySingle Agent in RRMM ORR by Subgroup

Refractory to

Updated Data From a Dose Finding Phase II Trial of Single Agent Isatuximab (Anti-CD38 mAb)

in Relapsed/Refractory Multiple Myeloma [ASCO 2016]

Joshua Richter,1 Thomas Martin,2 Ravi Vij,3 Craig Cole,4 Djordje Atanackovic,5 Jeffrey Zonder,6Jonathan Kaufman,7 Joseph Mikhael,8 William Bensinger,9 Meletios Dimopoulos,10 Todd

Zimmerman,11 Nikoletta Lendvai,12 Parameswaran Hari,13 Enrique Ocio,14 Cristina Gasparetto,15

Shaji Kumar,16 Corina Oprea,17 Eric Charpentier,17 Stephen Strickland,18 Jesús San Miguel19

1Hackensack University Medical Center, Hackensack, NJ, USA; 2University of California at San Francisco, San Francisco, CA, USA; 3Washington University, St. Louis, MO, USA; 4University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA; 5Huntsman Cancer Institute, Salt Lake City, UT, USA; 6Karmanos Cancer Center,

Detroit, MI, USA; 7Winship Cancer Institute of Emory University, Atlanta, GA, USA; 8Mayo Clinic, Scottsdale, AZ, USA; 9Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 10National and Kapodistrian University of Athens, Athens, Greece; 11University of Chicago, Chicago, IL, USA; 12Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 13Medical College of Wisconsin, Milwaukee, WI, USA; 14University Hospital of Salamanca, Salamanca, Spain; 15Duke University Medical

Center, Durham, NC, USA; 16Mayo Clinic, Rochester, MN, USA; 17Sanofi-Genzyme Oncology, Cambridge, MA, USA; 18Vanderbilt-Ingram Cancer Center, Nashville, TN,19University of Navarra, Pamplona, Spain

Isatuximab

CD38

77

ASCO 2016: Summary• Isatuximab was generally well tolerated at ≥10 mg/kg

– Most infusion reactions were grade 1/2, and occurred during the first infusion

– Median infusion duration is shorter following the first infusion• Isatuximab demonstrated single-agent activity in heavily pretreated patients

with RRMM– Median 5 (2–14) prior lines of therapy

• The ORR was 20%–29% at isatuximab ≥10 mg/kg– ORR was similar across subgroups, including high-risk cytogenetics– Median duration of response was 8.75–12.9 (3.7–14.8) months

• At isatuximab ≥10 mg/kg, PFS was 3.65 months and OS was 18.63 months– 11 patients remained on treatment at data cutoff– Median OS has not been reached in the 20 mg/kg QW/Q2W and 10 mg/kg

Q2W/Q4W cohortsRichter JR et al. J Clin Oncol. 2016;34: Abstract 8005.

NK B

NKT

CD4

CD8

pDC, MDSC induced immune suppression

MMMM MM

Stroma

IL-6, IL-10, TGFβ, PGE, ARG1, NO, ROS, COX2

Depletion of cysteine

MM induced immune

suppression

Tumor promotion and induction of PD-L1

expression

MMPD-L1

Treg

PD-L1

TAMPD-L1

MDSCPD-L1

PD1PD1

pDC

Görgün GT et al. Blood. 2013;121:2975.

Immune Suppressive Microenvironment in MM

PD1

PD1PD1

78

Target PD-1, PDL-1

Allow T cells to function

Current agents under investigation in MM: nivolumab and pembrolizumab

Activity only in combination with other MM agents

Immune Checkpoint Inhibitors in MM

Immune Checkpoint Inhibitors for Relapsed/Refractory Multiple Myeloma

Keynote-023: Pembrolizumab + Lenalidomide and Dexamethasone1

Phase 2 of Pembrolizumab + Pomalidomide and Dexamethasone2

Patient populationRRMM for whom ≥2 prior therapies, including a proteasome inhibitor and an IMiD, have failed

RRMM for whom ≥2 prior therapies, including a proteasome inhibitor and an IMiD, have failed

Dosing

Pembrolizumab 200 mg fixed dose* 200 mg IV every 2 weeks

IMiD Lenalidomide: 25 mg Pomalidomide: 4 mg daily 21 days

Dexamethasone 40 mg (low-dose) 40 mg weekly

Response 17 patients; 76% response rate 11 of 22 evaluable patients (50% response rate)

*Used in the phase 2 portion of study based on MTD/MAD

1. San Miguel J et al. Blood. 2015;126: Abstract 505.2. Badros AZ et al. Blood. 2015;126: Abstract 506.

79

Durvalumab

Figure 1, page 475

Ibrahim R et al. Semin Oncol. 2015;42(3):474.

Harnessing the Immune System to Fight Myeloma

Passive Active

Monoclonal antibodies

Chimeric antigen receptor (CAR) T cells

Vaccines (therapeutic not preventive)

Types of Immunotherapy, Immuno-Oncology

Direct effects

CDC

Cell death

ADCC

NK cell

Myeloma cellFc receptor

LysisMAC

C1q

Antigen

Monoclonal antibody

3. Infuse MM-targeted cells back to

patient

2. Modify andexpand cells

in lab

1. Extract WBCsfrom patient

80

Phase 1 Trial of Vaccination With DC/MM Fusions in RRMM

• Well tolerated, no autoimmunity

• Induced tumor reactive lymphocytes in a majority of patients

• Induced humoral responses to novel antigens (SEREX analysis)

• Disease stabilization in 70% of patients

• DC/MM fusions induce anti-MM immunity in vitro and inhibit MM cell growth in vivo in xenograftmodels

Rosenblatt J et al. Blood. 2011;117:393.Vasir B et al. Br J Haematol. 2005;129:687.

Figure 1, page 396

Rosenblatt J et al. Blood.2011;117:393.

• Goal is to prevent evolution of smoldering to active myeloma

• Cocktails of immunogenic HLA-A2-specific XBP1, CD138, CS1 peptides to induce MM-specific and HLA-restricted CTL responses

• Clinical trials: – Immune responses to vaccine in all patients – Lenalidomide with vaccine to augment immune response– Lenalidomide and PDL-1 with vaccine to induce memory– Immune response against myeloma Bae J et al. Leukemia. 2011;25:1610.

Bae J et al. Br J Haematol. 2011;155:349.Bae J et al. Br J Haematol. 2012;157:687.Bae J et al. Clin Can Res. 2012;17:4850.

Bae J et al. Leukemia. 2015;29:218.

Vaccines Targeting MM-Specific Peptides in Smoldering MM

81

Therapeutic Vaccines in Development

MM Vaccine Patient TypesStudyPhase Sites

Dendritic cell fusion vaccine + CT-011 (monoclonal antibody) Post-transplant* 2 Beth Israel Deaconess Medical Center/

Dana-Farber

Hiltonol (MAGE-A3 vaccine Poly-ICLC) Post-transplant* 2 University of Pennsylvania

Oncolytic measles virus (MV-NIS) RR 1 Mayo Clinic (Rochester, MN)

Oncolytic measles virus (MV-NIS) RR 2 University of Arkansas

PVX-410 SMM 1/2

Emory/Illinois Cancer Specialists/Beth Israel Deaconess Medical Center/Massachusetts General Hospital/ DFCI/ MD Anderson Cancer Center

PVX-410 Post-transplant 2 Emory University

*Goal of eliminating any remaining cancer cells

Immune Cell Therapy in DevelopmentType Trial Patient Types

StudyPhase Site(s)

CAR T

CART-19 for multiple myeloma Relapsed/ refractory 1 University of Pennsylvania

Safety study of CAR-modified T cells targeting NKG2D-ligands Relapsed/ refractory 1 Dana-Farber Cancer Institute

Study of T cells targeting B-cell maturation antigen (BCMA) for previously treated multiple myeloma Relapsed/ refractory 1 National Cancer Institute

University of Pennsylvania

MILs

Tadalafil and lenalidomide maintenance with or without activated marrow infiltrating lymphocytes (MILs) in high-risk myeloma

Newly diagnosed; relapsed (without prior ASCT)

2 Sidney Kimmel Comprehensive Cancer Center

Adoptive immunotherapy with activated marrow-infiltrating lymphocytes and cyclophosphamide graft-versus-host disease prophylaxis in patients with relapse of hematologic malignancies after allogeneic hematopoietic cell transplantation

Relapsed/ refractory 1 Sidney Kimmel Comprehensive Cancer Center

Affinity-enhanced T cells

Engineered autologous T cells expressing an affinity-enhanced TCR specific for NY-ESO-1 and LAGE-1

Relapsed/refractory 1/2 City of Hope

University of Maryland

DLI CD3/CD28 activated Id-KLH primed autologous lymphocytes Post-transplant 2 University of Pennsylvania

82

Myeloma CAR Therapy• Multiple promising targets:

– CD19, CD138, CD38, CD56, kappa, Lewis Y, CD44v6, CS1 (SLAMF7), BCMA

• Functional CAR T cells can be generated from MM patients• CAR T and NK cells have in vitro and in vivo activity against MM• Clinical trials under way

– Anecdotal prolonged responses but no robust efficacy data available yet

• Many questions remain about CAR design:– Optimal costimulatory domains– Optimal vector– Optimal dose and schedule– Need for chemotherapy– Perhaps “cocktails” of multiple CARs or CARs + chemotherapy will be

required for best outcomes

MM Pt #1: Response to CD19 CAR Therapy

Figures 1 and 2, page 1042

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

83

First-in-human phase 1 trial

• CAR-BCMA expression determined by flow cytometry

CAR-BCMA T Cells in MM: Study Design

Pts with advanced RRMM; ≥3 prior lines of therapy; normal organ function;

clear, uniform BCMA expression on MM cells

(N=12)

CAR-BCMA T cells*Single infusion

Cyclophosphamide 300 mg/m2

Fludarabine 30 mg/m2

QD for 3 days

*Dose escalation of CAR+ T cells/kg

0.3 × 106

1.0 × 106

3.0 × 106

9.0 × 106

Ali SA et al. Blood. 2016;128:1688.

CAR-BCMA T Cells in MM: Response

Table 1, page 1690

Ali SA et al. Blood. 2016;128:1688.

84

Bi-Specific Antibody (bsAb) Constructs

~

BivalentAntibody

conjugates TetravalentSmall molecules

(eg, BiTEs)

Derived from Kontermann RE, Brinkmann U. Drug Discov Today. 2015;20:838.Zonder J. Presented at: 15th International Myeloma Workshop . Rome, Italy. September 2015.

Integration and Impact of Novel Agents, including Immune Therapies

• Innovations (PIs, IMiDs) to date have produced significant improvements in PFS and OS: recent approvals (eg, carfilzomib, ixazomib) will augment this

• Next wave of therapies…crucially, agnostic to mutational thrust?

• Baseline immune function appears to also be a key barrier to success but may be targetable (eg, use of PD1/PDL1 blockade)

• MoAbs (Elo, DARA, ISA) have activity in high-risk disease and represent true new novel mechanisms, as well as other immuno-therapeutics (eg, checkpoint inhibitors, vaccines)

• New insights to mechanisms of drug action (eg, AC 241) are further expanding therapeutic opportunities with combinations

• Numerous other small molecule inhibitors show promise (eg, HDACis, CXCR4, BCL, AKT, CDK, HSP 90, Nuclear Transport, KSP, BET bromodomain proteins/Myc, DUBs, MEK)

• Further refinement of prognostics and MRD will guide therapy

85

Continuing Evolution of MM Treatment: Selected New Classes and Targets 2016

*Not yet FDA-approved for MM; available in clinical trials

1st-Generation Novel Agents 2nd-Generation Novel Therapies/Immunotherapy

Chemotherapy

Monoclonal antibody

Proteasome inhibitor

IMiD HDAC inhibitor

20122003 2006 2007 2013 2015

Carfilzomib

Bortezomib

Thalidomide

Lenalidomide

Pomalidomide

Panobinostat

Bortezomib + Doxil

2016+

Elotuzumab Isatuximab*

CAR-T*

Adoptive T cell therapy

Vaccines

Atezolizumab*Durvalumab*

Nivolumab*Pembrolizumab*

Checkpoint inhibitors

Vaccines*

Ixazomib

DaratumumabAC-241/1215*

Marizomib*

3rd Generation IMiDs*

Melflufen*

Academia

FDAEMEA

NIHNCI

AdvocacyMMRF/C;IMFIMWG; IMS

Pharmaceuticals

Progressand hope

19 new FDA-approved drugs/combos/indications in last 13 yrs

Ongoing MM Collaborative Model for Rapid Translation From Bench to Bedside

86

Documents

Multiple Myeloma Patient Management: New Agents, New … · 1 Multiple Myeloma Patient Management: New Agents, New Challenges 8:15 AM – 8:25 AM Community Case 1 Robert M. Rifkin,