HOW TO TREAT MULTIPLE MYELOMA WITH SO MANY DRUGS

Jesús San-Miguel

University of Navarra, Spain

To search for an appropriate balance between treatment efficacy, toxicity & costs

In very elderly patients (> 80-85y): to ensure QoL & avoid additional costs of

expensive treatments

In fit elderly patients (65-80y) & young ones with severe co-morbidities: treatment

goal should be to prolong survival and ensure QoL

In young patients (<65y): In reference centres and large cooperative groups… to

investigate therapeutic schemes with a cure in the horizon

WHAT SHOULD BE THE

TREATMENT GOAL IN MM PATIENTS?

To eradicate the tumour clone (stem cells)… necessary for cure in most

malignancies… to achieve and maintain the best possible response

A small number of residual tumour cells may persist under control of immune

system for a long time (MM & low-grade NHL)

Some long term survivors do not achieve CR and revert to MGUS-like profile.

Not to confuse this with suboptimal response (PR or VGPR)…

Avoid over-treatment

ACTIONS TO ACHIEVE CURE

CR… Negative Inmunofixation & < 5% PC in BM (+normal FLC for stringent)

Outside BM… Imaging techniques (MRI & CT-PET)

BM Level… Immunophenotypic remission (by multiparametric flow)

Molecular remission (by RT-PCR): (Sensitivity 10-4 - 10-6)

THE DEFINITION OF CR IS

SUBOPTIMAL AND REQUIRES FURTHER

IMPROVEMENTS

PFS according to post-ASCT PET-CT in

patients achieving conventionally defined CR

ASCT candidates (192 pts)1

• 3-m post-ASCT: Complete FDG suppression

at PET-CT… Longer PFS and OS

• The 4-year estimate of PFS for PET-positive

pts was significantly shorter in comparison

with that of PET-negative pts (30% vs. 61%;

p=0.02)

IFM 2009: PET-CT normalisation

before maintenance

Impact on PFS and OS (62% normalised)2

• Normalisation of PET-CT before

maintenance was associated with a

significant improvement in:

• PFS – 30-month PFS rate:

54.4% in PET-CT positive pts vs.

75.9% in PET-CT negative pts

(p=0.0004)

• OS – 30-month OS rate:

69.9% in PET-CT positive pts vs.

94.6% in PET-CT negative pts

(p=0.01)

PREDICTIVE VALUE OF PET/CT

AFTER TREATMENT IN MM PATIENTS:

THE CONCEPT OF PET-CR

ASCT, autotransplantation; FDG, fluorodeoxyglucose

1. Zamagni E, et al., Blood 2011; 118(23):5989-95; 2. Moreau P, et al., Blood 2015;126:395

IMMUNOPHENOTYPIC &

MOLECULAR REMISSION

The deeper the response, the longer the survival:

Immunphenotyping

P-value (trend) : p<0.0001

<10-6

[10-6;10-5[

[10-5;10-4[

>=10-4

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Patients

without pro

gressio

n (

%)

79 79(0) 70(9) 59(11) 50(9) 38(11) 28(6) 6(9) 0(3)[10-4;10

-3[

49 49(0) 47(2) 45(2) 43(2) 34(7) 22(4) 8(6) 2(0)[10-5;10

-4[

31 31(0) 30(1) 28(2) 27(0) 22(4) 17(1) 8(2) 4(1)[10-6;10

-5[

87 87(0) 87(0) 85(2) 83(2) 74(6) 54(4) 31(3) 8(0)<10-6

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at pre-maintenance PFS

NGS

Months

Immunop. CR vs. CR: P = 0.007

1251007550250

100

80

60

40

20

0

Immun. CR

CR

nCRPR

OS

1. Paiva B, et al., Blood. 2008, J Clin Oncol 2011; 29(12):1627-1633; 2. Avet-Loiseau H, et al., Blood 2015;126:191

Figures courtesy of Prof San-Miguel

Response subcategory Response criteria

IMW

G M

RD

neg

ativ

ity

crit

eria

(Req

uir

es C

R a

s d

efin

ed b

elo

w)

Sustained

MRD-negative

MRD negative in the bone marrow (by next-generation flow cytometry or next-generation

sequencing) and by imaging as defined below, confirmed 1 year apart; subsequent evaluations

can be used to further specify the duration of negativity (e.g. MRD negative at 5 years)

Imaging MRD-

negative

MRD negative as defined below (by next-generation flow cytometry or next-generation

sequencing) PLUS

Disappearance of every area of increased tracer uptake found at baseline or a preceding

PET/CT

Flow MRD-

negative

Absence of phenotypically aberrant clonal plasma cells by next-generation flow cytometry on

bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in

MM (or a validated equivalent method), with a minimum sensitivity of 1 in 105 nucleated cells or

higher

Sequencing

MRD-negative

Absence of clonal plasma cells by next-generation sequencing on bone marrow aspirates in

which the 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 a

validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher

IMWG CRITERIA FOR MRD IN

MULTIPLE MYELOMA

IMWG, International Myeloma Working Group

Kumar SK, et al., Lancet Oncology 2016; manuscript accepted for publication.

EARLY INTERVENTION

REVISED INTERNATIONAL

STAGING SYSTEM (R-ISS) FOR

MULTIPLE MYELOMA

Non-transplantation-based regimens Transplantation-based regimens

Immunomodulatory-based regimens Proteasome inhibitor-based regimens

Stage Factor % of

patients

5-year PFS 5-year OS

I Absence of adverse factors — no high LDH, ISS stage II or III, t(4;14) t(14;16) or del(17p) 28% 55% 82%

II Not R-ISS stage I or III 62% 36% 62%

III ISS stage III and either high-risk CA by iFISH or high LDH 10% 24% 40%

Source: GIMEMA, PETHEMA/GEM, HOVON/GMMG, and IFM trials. CA, chromosomal abnormalities; iFISH, interphase fluorescence in

situ hybridisation assay; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survivalPalumbo A, et al., J Clin Oncol 2015; 33: 2863-2869. Reprinted with permission. 2015 American Society of Clinical Oncology.

All rights reserved.

PATIENTS WHO SHOULD NOT BE TREATED

"Smoldering” MM (MC >3 g/dl &/or PC > 10%....No CRAB)

TREATMENT OF MULTIPLE

MYELOMA: SHOULD ALL PATIENTS

BE TREATED?

Early MP vs. deferred MP1,2,3… No benefit

Thalidomide4,5… only 30% PR & No benefit in TTP/OS

Bisphosphonates6,7… No benefit in OR/TTP/OS

1. Hjorth M, et al., Eur J Haematol. 1993;50:95-102

2. Grignani G, et al., Br J Cancer. 1996;73:1101-07

3.Riccardi A, et al., Br J Cancer. 2000;82

4. Rajkumar SV, et al., Am J Hematol 2010; 85(10):737-40

5. Barlogie B, et al., Blood. 2008;112:3122-25

6. Musto P, et al., Leuk Lymphoma. 2011;52(5):771-775

7. Musto P, et al., Cancer. 2008;113:1588-95

SMOLDERING MULTIPLE MYELOMA:

RISK OF TRANSFORMATION INTO SYMPTOMATIC MMBased on the % of aberrant PCs by immunophenotype plus immunoparesis

> 95% aPC/BMPC or paresis

n = 22 (10 progr.)

>95% aPC/BMPC + paresis

n = 39 (28 progr.)

No adverse factors

n = 28 (1 progr.)

120967248240

1.0

0.8

0.6

0.4

0.2

0.0

Months

TT

P (

%)

Median not reached

Median 73 months

p = 0.003

Median 23 months

8%

42%

82%

High Risk

Low Risk

Perez-Persona E, et al., Blood. 2007;110:2586-92. Figure courtesy of Prof San-Miguel

OS TTP

Lenalidomide + dex

14 Progressions (25%)

No treatment

TTP: 21m53 Progressions (85%)

Bone disease (21); RI (8)

HR: 6.1; p < 0.0001

Time from inclusion

Pro

port

ion

of p

atie

nts

prog

ress

ion

-fre

e

Lenalidomide + Dex

No treatment

Time from inclusion

Pro

port

ion

of p

atie

nts

aliv

e

HR: 4.6; p=0.001

Lena + Dex………94% at 7 yrs

No treatment….…64% at 7 yrs

80706050403020100

1.0

0.8

0.6

0.4

0.2

0.0

RANDOMISED TRIAL LENALIDOMIDE

+ DEX VS. NO TREATMENT IN HIGH RISK SMM (N = 120)

ITT analysis: Median follow-up: 64 months

Mateos MV, et al., N Engl J Med 2013; 369:438-447; Mateos MV. ASH 2014 (Abs3465) .

Figures courtesy of Prof San-Miguel

Induction 6 cycles of KRd (20/36)

ASCT (melphalan 200)

Maintenance (Len-dex for 2yrs) (Len:10; Dex:20mg)

Consolidation (2 cycles of KRd)

Primary objective: To evaluate the proportion of patients in sustained immunophenotypic response

at 5 years

Hypothesis: At least 50% of patients will achieve the objective

MRD

MRD

MRD

MRD

CURATIVE STRATEGY FOR HIGH

RISK SMOLDERING (CESAR TRIAL) (N:90)

20 centres

Clonal BM PC≥10% or biopsy proven bony or extramedullary plasmacytoma and

ANY ONE OR MORE OF THE FOLLOWING MYELOMA DEFINING EVENTS (MDE)

End organ damage (CRAB) that attributed to the PC disorder

Hypercalcemia: > 11 mg/dL

Renal insufficiency: Cr Cl <40 ml/minute or Serum Cr > 2 mg/dL

Anaemia: Hb value <10 g/dL or >2 g/dL below the lower limit of normal

Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT

Any one or more of the following New biomarkers of malignancy (Early MM)

≥ 60% PC in BM

Involved/uninvolved serum free light chain ratio ≥100

>1 focal lesions on magnetic resonance imaging studies

REVISED INTERNATIONAL

MYELOMA WORKING GROUP DIAGNOSTIC

CRITERIA FOR MULTIPLE MYELOMA

Rajkumar SV, et al., Lancet Oncol 2014, 15(12): e538-48

Newly diagnosed

Transplant candidates (young)

Non-transplant candidates (elderly)

Relapsed patient

Experimental agents

MYELOMA TREATMENT

Induction (VAD or TD)

ASCT (Mel 200)

Maintenance (IFN +/- Predn)

“OLD” TRANSPLANT CANDIDATE

PATIENT APPROACH

This translates into prolonged PFS: VTD or PAD >VAD or TD

HAVE THE NEW INDUCTION REGIMENS

IMPROVED OUTCOME COMPARED TO VAD OR TD?

Response to induction

Stewart K, Richardson P , San-Miguel JF. How I treat MM in younger patients. Blood 2009; 114: 5436-43.

Figure courtesy of Prof San-Miguel

0

10

20

30

40

50

60

70

80

90

100

VAD TD TAD LD BzD BzTD BzLD

VRD

KRD

Induction regimen

Res

pons

e (%

)

ORR

CR

BzCD

VCD

IRD

VTD

N = 157

VCD

N = 154

P value

> = CR

> = VGPR

> = PR

14.0%

70.7%

98.7%

9.1%

60.4%

90.3%

0.17

0.05

0.001

Stage 3: 20% vs. 4% CR

High Risk: 23% vs. 8% CR

IFM 2013-04 (4 Cycles)2

Median number CD34+ stem cells higher in the

VTD (10.68 vs. 9.17; p, 0.05)

Retrospective pair-mate analysis (3 Cycles)1

VTD VERSUS VCD AS INDUCTION

PRIOR TO ASCT

VTD

N = 236

VCD

N = 236

P value

> = CR

> = VGPR

> = PR

19%

64%

93%

6%

37%

81%

0.001

0.001

0.001

1. Cavo M, et al., Leukemia 2015; 29(12):2429-31; 2. Moreau P, Blood 2016;127(21):2569-74

Doctor, what about continuous

optimised treatment with novel

agents, with the goal of controlling

the disease for as long as possible,

and to reserve ASCT for relapse?

Bz-Len-Dex x3

Bz-Len-Dex x5

Lenalid x12m

Stem Collection

Bz-Len-Dex x3

ASCT

Lenalid x12m

Stem Collection

Bz-Len-Dex x2

ASCT at relapse

“EARLY (UP-FRONT) VS. LATE (AT

RELAPSE) TRANSPLANT”

IFM-DFCI

PFS OS

IFM/DFCI 2009: EARLY VS. LATE

ASCT RESPONSE, PFS AND OS

(MEDIAN FW/UP 39 M)

Conventional dose treatment (RVD arm= 8 cycles of Lenalidomide, Bortezomib and Dexamethasone, plus stem cell mobilization after 3 cycles of RVD

utilizing high dose cyclophosphamide and G-CSF);

RVD with ASCT (Transplant arm= 3 induction cycles of RVD, followed by stem cell collection, and then ASCT conditioned with Melphalan 200 mg/m2,

followed by 2 cycles of RVD as consolidation).

Maintenance treatment with Lenalidomide (10 to 15 mg/d) was used in both arms for one year.

Attal M, Presented at ASH 2015. Blood 2015;126:391

• ASCT improved PFS (p<0.0002; HR=1.5, 95%

CI= 1.2–1.9)

• 3-year post-randomisation PFS rate was 61% in

the transplant arm vs. 48% in the RVD arm

• 3-year post-randomisation rate of OS

was extremely high (88%) and similar

between the ASCT and non-ASCT study

groups (stratified

p-value for log rank test = 0.25)

GIMEMA MM-RV-209… Rd-MPR vs. Rd-Mel200 (2nd rand: +/- maintenance)

EMN MM-RV-441… Rd-CRD vs. Rd-Mel200 (2nd rand: R vs. RP Maint.)

COMPARISON OF EARLY VS. LATE

ASCT: POOLED ANALYSIS OF TWO

TRIALS (N=529)

Only 53% of CCT patients received ASCT at relapse

Gay (EHA 2016): benefit in all subgroups, but higher in good prognosis (Stage I and low risk cytog)

Gay F, et al., EHA21 2016

Palumbo A, et al., N Engl J Med 2014; 371:895-905

Early ASCT Late ASCT P

PFS (months) 42 24 < 0.001

4-year OS 84% 70% <0.001

4-y OS

(upfront vs. rescue ASCT)84% 73% <0.001

VCD x three-four 21-d cycles Bort 1.3 mg/sm twice weekly; CTX 500 mg/sm d1-8; Dex 40 mg on day of

and after bort

Lenalidomide 10 mg/day, d1-21/28

CTX (2-4 g/sm) + G-CSF + PBSC collection

R1

R2

VRD x two 28-d cyclesBort 1.3 mg/sm, twice weekly;

len 25 mg d1-21;

dex 20 d1-2-4-5-8-9-11-12

No consolidation

therapy

VMP x 4 cycles HDM x 1-2 courses

EMN02/HO95 MM TRIAL: STUDY

DESIGN (N= 1192)

Upfront ASCT was associated with a significant improvement in PFS vs. VMP in the overall

patient population (Median PFS: NR vs. 46m)

Superior PFS with ASCT vs. VMP was retained across pre-specified subgroups of patients at

low (NR vs. 46m) and high risk (42 vs. 32m)Cavo M, ASCO Annual Meeting 2016, Abstract No 8000. Courtesy of Prof CavoUpfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study

of the European Myeloma Network (EMN02/HO95 MM trial).

Consolidation1

Improve response/deeper

following therapy

By administration of

treatment for a limited period

Maintenance2

Maintain response achieved

following therapy

By administration of treatment

for prolonged period

VTD: Upgrade to CR post-consolidation by 30%

(molecular and PFS)

What is the role of

consolidation or

maintenance therapy?

Thalidomide (6 trials)… PFS: + 6/6 OS: +3/6

Bortezomib (2 Trials)…. PFS: + 2/2 OS: +1/2

Lenalidomide (3 trials)… PFS: +3/3 OS: + 1/3

1. Cavo M, et al., Blood 2012;

120(1):9-19.

2. Morgan GJ, et al., Blood 2012;119(1):7-15; Kagoya Y, et al., Leuk Res 2012;36(8):1016-21;

Attal M, et al., ASH 2013 (Abstract 406), McCarthy PL. IMW 2013, Gay F, et al., ASH 2013 (Abstract

2089), Sonneveld P, et al., ASH 2013 (Abstract 404), Rosinol L, et al., ASH 2012

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

Placebo Revlimid

P < 10-7

OS: 75% at 5y in both arms

2nd malignancies: 6.5% vs. 2%

Lena

Placebo

42 m

24 m P < 10-8

Lena

Placebo

53 m

27 m P < 10-8

IFM 2005-021

PFS

CALGB 1001042

PFS

OS: 76 vs NR, p=0.001

2nd malignancies: 8% vs. 3%

Lena

Placebo

42 m

22 m

3-year OS: 88% vs. 79%. p=0.14

GIMEMA MM-RV-2093

PFS

LENALIDOMIDE VS. PLACEBO

AFTER ASCT

PFS from randomisation

1. From NEJM, Attal M, et al., 2012, 366: 1782-91; Copyright © 2012) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

2. From NEJM, McCarthy P, et al., 2012, 366: 1770-81; Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society3. From NEJM, Palumbo A, et al., 2014; 371:895-905. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

OVERALL SURVIVAL: MEDIAN

FOLLOW-UP OF 80 MONTHS

0.00 10 20 30 40 50 60 70 80 90 100 1 10 120

0.2

0.4

0.6

0.8

1.0

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

increase in median survival*

605 578 555 509 474 431 385 282 200 95 20 1 0

604 569 542 505 458 425 350 271 174 71 10 0

Overall survival, mos

Sur

viva

l pro

babi

lity

Patients at

risk

7-yr OS

62%

50%

N = 1209 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)

.001

*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).

HR, hazard ratio; NE, not estimable; OS, overall survival.

Attal M. Presented at ASCO 2016. Abstract 8001. Courtesy of Prof Attal

DOUBLE VS. SINGLE ASCT

Double

ASCTSingle ASCT P

PFS (months) 41 20 0.003

OS (months) 67 31.5 <0.001

In patients with high-risk cytogenetics and who

failed CR after bortezomib-based induction

(EU Phase 3 trials: 606 patients)

Is there still room for

Double ASCT?

Cavo M, et al., ASH 2013 (Abstract 767)

Is there an age

limit for ASCT ?PAD MEL100-ASCT

LP

consolidation

L

maintenance

CR or VGPR 55% 76% 80% 82%

CR 12% 33% 48% 53%

VGPR 43% 43% 32% 29%

PR 33% 17% 14% 13%

Median follow-up: 66 months

PFS: 48 months, 5-year PFS 43%

OS not reached, 5-year OS 63%

Death related to adverse events (8/102) higher in patients >70 years

(19% vs. 5%, P=0.024) ( 5/26 vs. 3/76)

ASCT in the Elderly (65-75y) (n:102)Bortez, reduced-intensity ASCT (Tandem MEL100), Lena consol & maint

This sequential approach may represent a valid alternative for selective MM patients <70 years old

Gay F. Blood 2013;122(8): 1376-83

4 studies (IFM1, HOVON2, PETHEMA3, BMTCTN4)… No benefit

2 studies (GIMEMA5, EBMT6)… Significant benefit (EFS, OS)

The role of Allo should be revisited in the era of novel drugs: “integrated

programmes”

... Early relapses (after optimised induction & ASCT) + high risk cytogenetics

AUTO/ALLO-RIC VS. TANDEM AUTO

1. Garban F, Blood 2006 107(9):3474-80 and Moreau P, Blood 2008;107:3474-3480

2. Lokhorst H, ASH 2008 (Abstr 461);

3. Rosinol L, Blood 2008; 112(9):3591-3

4. Krishnan A, ASH 2010 (abstr 41)

5. Bruno B, NEJM 2007; 356:1110–20 (updated EBMT 2009);

5. Gahrton G, ASH 2009 (Abstr 52)

6. Knop S, ASH 2009 (abstr 51)

Induction (VAD)

ASCT (Mel 200)

Induction (VTD or KRD)+(Dara)

ASCT (Bu-MEL) (Tandem)

CR

Maintenance (Len +/- Bz )

Consolidation(Bz-Len-Dx)

No CR

KRD+Dar

KRD+Dar

KRD+Dar

. . . . .

Late ASCT

TRANSPLANT CANDIDATE

PATIENT: STANDARD TREATMENT

Maintenance(IFN +/- Predn)

Newly diagnosed

Transplant candidates (young)

Non-transplant candidates (elderly)

Relapsed patient

Experimental agents

MYELOMA TREATMENT

Until recently only MP,

but now Thal, Lena, Bortz

THALIDOMIDE + MP (MPT) VS. MP

Efficacy in newly diagnosed elderly patients with myeloma

6 Randomised trials… > PFS in 5… >OS in 3

PFS: 20.4 vs. 15 m (6 m)… HR 0.67

OS: 39.3 vs. 33 m (6 m)… HR 0.82

Thal maintenance in Italian, Nordic, Hovon

1. Facon T, Lancet. 2007;370:1209-1218; 2. Hulin C, J Clin Oncol. 2009; 27(22):3664-70; 3. Wijermans P, J Clin Oncol. 2010; 28: 3160-6;

4. Palumbo A, Blood. 2008; 112: 3107-3114; 5. Beksac M, Eur J Haematol. 2010; 86:16-22; 6. Waage A, Blood. 2010;116(9):1405-1412

& ASCO 2010 (abstr 8130); Kapoor P, Leukemia. 2011.

BORTEZOMIB + MP (VMP) VS. MP

(682 PATIENTS)

0 3 6 9 12

Time (months)

15 18 21 24 27

0

20

40

60

80

100

VMP

MP

Pat

ient

s w

ithou

t eve

nt (

%)

Time (months)

0 4 8 12 16 20 24 28 32 36 40

0

20

40

60

80

100

VMP

MP

TTP1 OS: 13.3 months benefit2

Median follow-up 60.1 m

VMP: 56.4m

MP: 43m , P=0.0004VMP: 24.0 months

MP: 16.6 months, P<0.000001

*Weekly and/or subcutanous administration reduced PN (G3) from 14% to 5% - 3%

1. From N Engl J Med 2008. San- Miguel J, et al., Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma;

359:906. Copyright © 2008 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Mateos MV, et al., Lancet Oncology. 2010;10(11):934-42;

San-Miguel J, JCO 2013,31:448-55.

FIRST TRIAL: LENA- DEX

(18 CYCLES OR CONTINUOUS) VS. MPT

Median PFS

Rd (n= 535) 25.5 mos

Rd18 (n= 541) 20.7 mos

MPT (n= 547) 21.2 mos

Hazard ratio

Rd vs. MPT: 0.72; P = 0.0006

Rd vs. Rd18: 0.70; P = 0.0001

Rd18 vs. MPT: 1.03; P = 0.70349

Time (months)

Pat

ient

s (%

)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

72 w

ksPFS

4-year OS

Rd (n= 535) 59.4%

Rd18 (n= 541) 55.7%

MPT (n= 547) 51.4%

OS

20

100

80

60

40

0540 6 12 18 24 30 36 42 48 60

Rd vs. MPT: 0.78; P = 0.017

From The New England Journal of Medicine, Benboubker L, et al., Lenalidomide and Dexamethasone in Transplant-Ineligible Patients with

Myeloma, 371, 906–1. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

Symptomatic newly diagnosed MM pt > 65 y

MPV x 9cycles Lendex x 9 cycles

RdMPV MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd

Sequential scheme

Alternating scheme*

N: 240 pts74 weeks

Hypothesis: - Higher efficacy for the alternating scheme

- Less probability of cell scape

- Lower cumulative toxicity

GEM/PETHEMA GEM2010 TRIAL

*Half of the patients will start by VMP and half by Rd

Median follow-up: 30 m (9-43)

OSPFS

VISTA trial: 21 m

FIRST trial: 25 m (cont Rd); 21 m (Rd18)

VISTA trial: 68% at 3 yrs

FIRST trial: 59% at 4 yrs (cont Rd); 56% at 4 yrs (Rd18)

OUTCOME IN TERMS OF PFS

AND OS

Mateos MV, et al., Blood. 2016;127(4):420-5

• Progressive disease or death occurred in

59 patients (50%) in the sequential arm

and 55 (48%) in the alternating scheme

• Median PFS did not differ between the

sequential group (32 months) and the

alternating group (34 months) (p=0.65)

• Deaths occurred in 28 patients treated

with the sequential approach (24%) and

25 patients (22%) in the alternating arm

• Median OS was not reached, and the 3-

year OS was almost identical in the

sequential (72%) and alternating (74%)

arms (p=0.63)

0

5

10

15

20

25

30

35

40

45

50

PFS (Median)

0

10

20

30

40

50

60

70

80OS (Median)

Rd RdVRd VRd

Med

ian

PF

S, m

onth

s

Med

ian

OS

, mon

ths

30

43

64

75

HR= 0.712

P= 0.0018 **HR= 0.709

P= 0.025*

VRd

Rd

VRd

Rd

*Two-sided p-value**One-sided p-value

Multivariate analysis: VRd, stage III, and >65y

ORR: 81.5% vs. 71.5% % CR: 15.7 vs. 8.4

VRD VERSUS RD:

OUTCOMES COMPARISON

Durie B, et al., Presented at ASH 2015. Blood 2015 126:25

Newly diagnosed

Transplant candidates (Young)

Non-Transplant candidates (Elderly)

Relapsed patient

Experimental Agents

MYELOMA TREATMENT

Type of relapse

Further options

Efficacy of

previous

treatments

Toxicity of

previous

treatments

STRATEGIES AT RELAPSE: HOW

TO MAKE THE RIGHT CHOICE?

Derivatives from already approved

Novel proteasome inhibitors

Novel IMIDs

Novel mechanisms of action

MoAb: anti-CS1 & anti-CD38

Deacetylase inhibitors

CDK inhibitors

AKT inhibitors

Kinesin spindle protein inhibitors

Anti PD-L1, PD1

NOVEL DRUGS IN MM

Reprinted by permission from Macmillan Publishers Ltd: Ocio EM, et al., Leukemia 2014;28:525–42. Copyright 2014

DOUBLETS & TRIPLETS WITH NEW

PROTEASOME INHIBITORS IN RELAPSED MM

Survival on Phase III trials

ENDEAVOR trial (Kd vs. Vd)2:

PFS 18.7 vs. 9.4 months (HR 0.53, p=0.0001) ……▲ 9.3 months

OS NE vs. 24 months (HR 0.79, p=0.06)

ASPIRE trial (KRd vs. Rd)1:

PFS 26.3 vs. 17.6 months (HR 0.69, p=0.0001) ……▲ 8.7 months

OS at 2 years: 73% vs. 65% (HR 0.79, p=0.01)

TOURMALINE–MM1 trial (IRd vs. Rd)3:

PFS 20.6 vs. 14.7 months (HR 0.74, p=0.01) ……▲ 5.9 months

IRd, ixazomib+lenalidomide+dexamethasone; Kd, carfilzomib+dexamethasone; KRd, carfilzomib+lenalidomide+dexamethasone; Vd,

bortezomib+dexamethasone

1. Stewart AK, et al., N Engl J Med 2015; 372: 142-152; 2. Dimopoulos MA, et al., Lancet Oncol 2016; 17: 27-38;

3. Moreau P, N Engl J Med 2016; 374: 1621-1634.

POMALIDOMIDE-DEX IN

REFRACTORY MM (& COMBINATIONS)

MM-0031 STRATUS

(MM-010)2

Pom-Dex vs.

Pom-Cyclo-Dex3 Pom-Btz-Dex4

Treatment PD PD PD PCD PVD

n 302 604 36 34 34

Population Failed Bort & Len & refr to last line At least 2 prior lines & Len-refractory1-4 prior lines & Len-refractory

ORR, % 31 35 39 65 85

≥ VGPR, % 14 12 45

PFS, months 4.0 4.2 4.4 9.5 -

OS, months 13.1 11.9 16.8 NR -

*EFS at 12 months

1. San-Miguel J, Lancet Oncology 2013; 2. Dimopoulos MA, et al., ASH 2014. Abstract 80; 3. Baz RC, et al., ASH 2014. Abstract 303;

4. Richardson PG, et al., ASH 2015. Abstract 3036

Derivatives from already approved

Novel PIs

Novel IMiDs

Novel mechanisms of action

Deacetylase inhibitors

mAbs: anti-CS1 and anti-CD38

CDK inhibitors

Akt inhibitors

Kinesin spindle protein inhibitors

Anti-PD-L1 and anti-PD-1

NOVEL DRUGS IN MM

CDK, cyclin-dependent kinase

Reprinted by permission from Macmillan Publishers Ltd: Ocio EM, et al., Leukemia 2014;28:525–42. Copyright 2014.

PANORAMA 1: PANOBINOSTAT +

BTZ + DEX VS. PBO + BTZ + DEX

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

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

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

MonthsNumber of patients at risk

PAN-BTZ-Dex

PBO-BTZ-Dex

PF

S P

roba

bilit

y, %

PAN-BTZ-Dex

PBO-BTZ-Dex

PAN-BTZ-Dex PBO-BTZ-Dex

Median PFS

(months)12 (10.3–12.9) 8.1 (7.6–9.2)

HR (95% CI) 0.63 (0.52–0.76)

ORR 60.7% vs. 54.6% CR: 27.6% vs. 15.7%

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

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

Number of Patients at Risk

PAN-BTZ-Dex

PBO-BTZ-Dex

Months

PF

S P

roba

bilit

y, %

100

80

60

40

20

0

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

Censoring times

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

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

Subgroup analysis by prior treatment:

PFS prior BTZ + IMiDs with ≥2 prior linesPAN-BTZ-Dex PBO-BTZ-Dex

Median PFS

(months)12.5 (7.3–14.0) 4.7 (3.7–6.1)

HR (95% CI) 0.47 (0.31–0.72)

100

80

60

40

20

0

PFS

No benefit in OS

BTZ, bortezomib; Dex, dexamethosone; PAN, Panobinostat; PBO, placebo.

San-Miguel JF, et al., Lancet Oncol 2014; 15: 1195-1206. Reprinted from The Lancet, Copyright 2014, with permission from Elsevier.

Direct targeting of

surface tumour antigens

Monoclonal antibodies

Boosting immune

effectors:

Adoptive cell therapy

Activating tumour

specific immunity:

Vaccines

Overcoming inhibitory

immune suppression:

Immunomodulators:

IMIDs, Checkpoint inh

HOW CAN WE IMPROVE

ANTI-CANCER IMMUNITY?

Four major targets for cancer immunotherapy

ORR (ELd vs. Ld): 79% vs 66%. ≥VGPR: 32.7% vs. 27.9%

Median OS: 43.7 vs. 39.6 mos, P= 0.02, pre-specified interim

analysis for overall survival indicates a strong trend (p=0.0257) with

early separation sustained over time

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

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

Pro

babi

lity

prog

ress

ion

free

E-Ld

Ld0

.

1

1-year PFS 2-year PFS 3-year PFS

PFS (months)

68%

41%

26%

57%

27%

18%

PFS: 19.4 vs. 14.9

HR 0.73 (95% CI 0.60, 0.89)

p=0.0014

PFS (19.4 vs. 14.9 m)

460 2 4 6 14 16 20 22 26 28 32 34 36 40 448 10 12

E-Ld

Ld

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time to next treatment (months)

Pro

babi

lity

of p

atie

nts

with

out n

ext t

reat

men

t

18 24 30 38 4842

0.1

TNT: 33 vs. 21 m

HR 0.62 (95% CI 0.50, 0.77)

TNT (33 vs. 21 m)

Len “prepares” immune cells & then

Elotuzumab induces ADCC

ELOTUZUMAB

(SLAMF7: Signaling lymphocytic activation molecule F7: Anti-CS1)

PHASE III (Eloquent): ELd vs. Ld

Lonial S, et al., N Engl J Med 2015; 373:621-631; Copyright © 2015, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Dimopoulos M, ASH 2015 Abst 28

ANTI CD38 ANTIBODIES:

MECHANISMS OF ACTION

Direct ON-TUMOUR Actions IMMUNOMODULATORY Actions

Daratumumab binds to CD38

MYELOMA

CELL DEATH

CDCComplement-dependent

cytotoxicity

ADCCAntibody-dependent cell-

mediated cytotoxicity

ADCPAntibody-dependent cellular

phagocytosis

Apoptosis

Modulation of tumour

microenvironment

Depletion of immuno-

suppressive cells

Increase in cytotoxic &

helper T cells

T cells

Myeloma cell

Palumbo A, et al., ASCO Annual Meeting 2016. Courtesy of Prof Palumbo

ANTI CD38 IN MM: SINGLE AGENT

ACTIVITY IN RRMM

Dara/SAAR are CD38 MoAB showing activity as single agents in RRMM patients

1. Lokhorst HM, et al, NEJM 2015, 363:8; 1. Lokhorst HM, et al., ASCO 2014; Abstract 8513; Lonial S, JCO 2015, 3. Martin T, et al.,

ASCO 2014; Abstract 8532; 4. Usmani S, et al., ASH 2015 oral presentation 29; 5. Martin T, ASH 2015 oral presentation 509

Daratumumab Isatuximab

Study details3 studies: GEN5011, SIRIUS2 &

combined analysis4

First in-human, phase 1 dose

escalation3

PatientsPts with rel/ref MM

n=148 (SIRIUS n=42 and GEN501 n=106)Pts with rel/ref MM

n=40

Dose 16 mg/kg Dose is not yet defined

Results

• ORR 31% (36% GEN501 & 29% SIRIUS)

• Median DOR: 7.6 m

• 1 year OS: 77% / 69%

• Median PFS: 5.6 m, 3.7 m, Infusion-related reactions gr 1-2

• At ≥ 10 mg/kg: 29%

• At 20 mg/kg: 24%5

• Infusion-reactions mainly grade 1/2, only with first dose

0 3 6 9 12 150

0.2

0.4

0.6

0.8

1.0

Months since randomisation

Pro

port

ion

surv

ivin

g w

ithou

t pro

gres

sion

No. at risk

Vd

DVd

247

251

182

215

106

146

25

56

5

11

0

0

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

Median PFS: 7.2 months

Median PFS: NR

0 3 6 9 12 150

0.2

0.4

0.6

0.8

1.0

Months since randomisation

Pro

port

ion

surv

ivin

g w

ithou

t pro

gres

sion

No. at risk

Vd

DVd

247

251

181

214

106

145

25

56

5

11

0

0

DVdVd

PFS TTP

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

DVdVd

Median TTP: NR

Median TTP: 7.3 months

ORR (DVd vs. Vd): 83% vs. 63% CR (DVd vs. Vd): 20% vs. 9%

AE: I45% infusion reations (most during the first & Gr ½); PN: 4,5 vs. 6,8%

Treatment discontinuation due to AE 7.4% vs. 9.3%

DVD VERSUS VD IN RELAPSED MM

- PHASE III CASTOR TRIAL

Efficacy data: ORR, PFS and TTP

Palumbo A, et al., ASCO 2016. Courtesy of Prof Palumbo

Daratumumab significantly improved PFS (63% reduction in risk of progression/death) DRd was associated with a manageable safety profile consistent with the profile of D and Rd.

ORR (DRd vs. Rd): 93% vs. 76% CR (DRd vs. Rd): 43% vs. 19%

TTP (DRd vs. Rd): NR vs. 18.4 DOR (DRd vs. Rd): NR vs. 17.4 m

Median Follow-up: 13.5 m

DARATUMUMAB-LEN-DEX (DRD) VS.

LEN-DEX (RD) IN RELAPSED MM

Phase III POLLUX trial (569 Pts)

Dimopoulos M, et al., EHA 2016. Abstract LB2238. Obtained from the EHA website http://www.ehaweb.org

HOW CAN WE IMPROVE

ANTI-CANCER IMMUNITY?

Four major targets for cancer immunotherapy

Direct targeting of

surface tumour antigens

Monoclonal antibodies

Boosting immune

effectors:

Adoptive cell therapy

Activating tumour

specific immunity:

Vaccines

Overcoming inhibitory

immune suppression:

Immunomodulators:

IMIDs, Checkpoint inh

CARs (Chimeric antigen receptor) are engineered fusion proteins that contain an extracellular antigen-binding

domain (composed of a single chain variable fragment (scFv) derived from an antibody), linked in tandem to the

CD3z chain of the TCR complex and the endodomain of costimulatory molecules such as CD28 or CD137.

By means of retroviral or lentiviral transduction, or by electroporation transfer, the T cells are reprogrammed in

order to specifically target tumour cells, by combining the specificity of an antibody with the potent cytotoxic and

memory functions of a T cell.

CD137

CD28

CD3ζ

ENGINEERED T CELLS: CARS

Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Immunology. Restifo NP, et al., 2012; 12:269-81. Ccopyright 2012

Reprinted by permission from Macmillan Publishers Ltd on behalf of Cancer Research UK: Nature Reviews Cancer. Kershaw MH, ,et al.,

2013;13:525–541. Copyright 2013

Serum and urine IFE-negative

- Patient 10 experienced cytokine release syndrome

including fever, tachycardia, hypotension, elevated liver

enzymes, and elevated creatinine kinase-all resolved in

2 weeks or less

Patient 10 obtained SCR of chemotherapy-resistant IgA myeloma after CAR-BCMA T-cell infusion

FIRST-IN-HUMAN CLINICAL TRIAL

OF T CELLS EXPRESSING AN ANTI-B-CELL

MATURATION ANTIGEN CHIMERIC ANTIGEN

RECEPTOR: 4/12 PTS ( 2 PR, 1 VGPR; 1 SCR)

BCMA: B-cell maturation Ag a member of the TNF superfamily

Abbas S, & Kochenderfer JN, ASH 2015 (LBA1); Abbas S, et al., Blood 2016 ;28:1688-1700

Patient 10:

• Before initiation of protocol treatment, patient 10 had a

hypercellular bone marrow (hematoxylin and eosin). CD138

staining showed that bone marrow cells were ≥90% plasma

cells. BCMA expression was dim but present

• Eight weeks after CAR T-cell infusion, the bone marrow was

recovering with an overall cellularity of 25%, plasma cells

remained absent, and bone marrow flow cytometry-negative

PD1 Upregulated on the surface of activated T-cells

Ligands: PD-L1 & PD-L2, are expressed on the surface

of APC & tumour cells

Binding of the PD-1 receptor to its ligands, PD-L1 and

PD-L2, inhibits T-cell activation

The PD-1 pathway is often exploited by tumours to

evade immune surveillance1,2,3

TILs have been shown to express significantly

higher levels of PD-14

Up-regulation of PD-L1 expression levels have

been described in: melanoma (40-100%), NSCLC

(35-95%), and linked to poor clinical outcomes5,6

PD-1/ PD-L1: PROGRAMMED DEATH

RECEPTOR (RELEASING THE BRAKES)

Selective MoAb against PD-1 or PD-L1:

Directly blocks interaction between PD-1 and

PD-L1/PD-L2

1. Topalian SL, et al., Curr Opin Immunol.2012;24:207-12; 2.Chen DS, et al., Clin Cancer Res. 2012;18:6580-7

3. Butte MJ, et al., Immunity. 2007;27:111-22; 4. Mellman I, et al., Nature, 2011;480:480-9

5. Konishi J, et al., Clin Cancer Res 2004;10:5094-100; 6. Liu J, et al., Blood. 2007;110:296-304

PEMBROLIZUMAB TREATMENT IN

RRMM

KEYNOTE-023 (PhI):

PEMBRO-LEN-DEX1

Ph I/II:

PEMBRO – POMA –DEX2

Study designPEMBRO 200 mg/2QW LEN 25 mg 1-21

DEX 40 mg weekly

PEMBRO 200 mg/2QW POMA 4 mg 1-21

DEX 40 mg weekly

Patient population- > 2 prior lines

- PI & IMID exposure

- >2 prior lines

- RRMM

- PI & IMID exposure

Refractory status

75% Len-refractory

63% Bort-refractory

50% double/triple/cuadruple refractory

89% Len-refractory

82% Bort-refractory

70% double-refractory

ORREfficacy populat. (n= 40): 50%

Len-refr (n=29): 38%

Total (n=38): ORR: 66%

Double refractory (n=31): 65%

Median PFS 14m

Safety

AEs consistent with individual drug safety

profiles for approved indications

IRAEs: no pneumonitis. No colitis.

65% AEs grade 3-5, 33% neutropenia

Good safety profile

irAEs: 38%

Pneumonitis: 14%

1. San Miguel JF, ASH 2015 oral presentation 505; 2. Badros A, ASH oral presentation 585

Progress in MM Cell Biology

Prognostic factors

and

Myeloma subtypes*

Discovery of New Drugs

Singular mechanism of action

Individualised and tailored treatment

MULTIPLE MYELOMA: A MODEL

FOR SCIENTIFIC AND CLINICAL PROGRESS

FROM BIOLOGY TO THERAPEUTICS

*MM should not be considered a single entity.

THANK YOU!