presentación de powerpoint · 2014. 6. 24. · snp-based mapping array 16q deletions 12p deletions...

• Second most common hematological malignancy

– Incidence: ~4/100,000 persons/year

– Prevalence: 60,000 patients (Europe)

– Incidence increases with age: 80% of patients > 60 years (rare in < 35 y.)

• Clinical Course: Remitting and Relapsing disease- In spite of the progress in survival with novel agents…….

eventually… refractory state (incurable)

With current treatment

– 5-year surival 50% - 70%

– Potentially cured ~ 10%

Multiple myeloma

IMWG criteria for the classification of monoclonal

gammopathies

Monoclonal component

Bone MarrowPlasma Cells (%)

End Organ Damage a

< 30 g/L serum

AND

< 10%

AND

Absent

30 g/L serum

AND/OR

10%

AND

Absent

Present(serum/urine)AND

10%

AND

Present

MonoclonalGammopathy of uncertain significance(MGUS)

Smoldering MultipleMyeloma (SMM)

SymptomaticMultipleMyeloma(MM)

Dimopoulos et al. Blood 2011;117: 4701-4705

-Calcium levels increased: serum calcium >11 mg/dl ( > 2·75 mmol/l)

-Renal insufficiency: creatinine > 2mg/dl (>173 mmol/l)

-Anemia: hemoglobin 2 g/dl below the lower limit of normal or hemoglobin <10 g/dl

-Bone lesions: lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify)

Other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (> 2 episodes in 12m)

DEFINITIONS OF MYELOMA AND EARLY MYELOMA

FEATURES

CRAB Criteria

PC>60%Pre-CRAB High FREELITE

MRI/Other Changes

Spanish CriteriaMayo Criteria

MM

Ultra-HR-SMM

HR-SMM

LR-SMM

MGUS

Multiple Myeloma: A model for investigation of mechanisms involved

in the transition form a “pre-malignant” into a “malignant” disease

MM is preceded by MGUS in most patients*

What dictates a clonal “benign” PC to become “malignant” or to remain

dormant for >30years?

Is this drived by the specific characteristics of the malignant clone or is it also

drived by the dialogue between the PC clone and its microenvironment ?.......

selection of a dominant clone

*Weiss et al Bood 2009; Landgren et al Blood 2009

MGUS MMSmoldering MM

MM Pathogenesis

- Genetic abnormalities of MM cell

- MM cell & microenvironment

Treatment

Novel drugs with Singular

Mechanism of Action

Multiple Myeloma: From Biology to Therapeutics

Prognostic Factors

Myeloma Subtypes

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

Numerical abnormalities in MM

Trisomies

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

Monosomies

p

q

Structural abnormalities in MM

“Genomic chaos” of MM: Almost all cases are cytogenetically abnormal

Chesi, Blood 1998; Avet-Loiseau, GCC 1999; Gutiérrez et al, Haematologica 2000 y Leukemia 2001

IGH q32

Primary IGH

Translocations

11q136p21

16q2320q114p16

Mutations of N, K-RAS

Del/Mutat de p53

Secondary IGH Transl: C-MYC

MM Pathogenesis: Host-tumor interactions

1-integrins: VLA-4 (CD49d), VLA-5 (CD49e), VLA-6 (CD49f)

BMSC

SDF1

ECM (Fibronectin, laminin)

1-integrinsCXCR4

ICAM-2

CD138

IL-6

IGF-1

VEGF

TNF

VCAM-1

VLA-4

ICAM-1

LFA-1

CD44

MM cell

Cell adhesion induces a drug resistance phenotype in the Myeloma cell:

1) cell cycle arrest ( p27); 2) apoptosis inhibition ( FLIP-1 –FAS inhibitor-); 3) protection from drug-induced DNA damage

PC adhesion to Fn induces overexpresion of 53 genes ( 11 regulated by NFkB)

San Miguel, Hematol J. 2003

Direct contact & soluble molecules

ISS

P < .0001

B2micro+albúmine

Prognostic FactorsAgeECOG

PATOGENIA

¿Cómo se desarrolla el

tumor?

PATOGENIA

¿Cómo se desarrolla el

tumor?

Greip P, San Miguel J et al JCO 2005

San Miguel, et al Blood 1999

S-phaseG0

G1

G

2

S

Cell

co

un

t

->

1.0

p=0’0025

P53 deletion

Perez-Simon Blood 1996, Gutierrez , Leukemia 2007

CD28, CD19/81, CD117

Mateo JCO 2008, Paiva Leukemia 2012

SNP-basedmapping array

16q deletions

12p deletions

5q gains

1q gains

Genetic markers with prognostic significance

FISH analysis

IGH translocations

Genomic imbalances

t(14;16)

t(4;14)

t(11;14)

Non-hyperdiplid

1q gains

Monosomy 13

17p deletions

1p deletions

Gene expressionprofiling

TC classification

Molecular classifications (UAMS & Hovon)

17 gene-model (Arkansas group)

15 gene-model (Intergroupe Francophone)

Perez-Simon, Blood 1999; Fonseca Blood 2003; Chang Blood 2005; Gutierrez Leukemia 2007; Avet- Loiseau JCO 2010 & Blood 2011; Boyd

Leukemia 2011, Kumar Blood 2012; Zhan Blood 2006, Saughnessy Blood 2007; Deacaux Blood 2008; Broyl Blood 2010; Tapper JCO 2011:

0 12 24 36 48 60 72 84 96

Months from diagnosis

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

CR vs VGPR VS PR P=0.001

0 12 24 36 48 60 72 84 96

Months from diagnosis

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Cu

mu

lati

ve P

rop

ort

ion

Ev

en

t F

ree S

urv

ivin

g

CR vs VGPR or PR P<10-5

CR, n=278 VGPR, n=124 PR, n=280 PD, n=25

EFS OS

Lahuerta et al. JCO 2008;26:5775–5782

Response to Therapy:depth of response correlates with EFS & OS

PETHEMA-GEM 2000: Outcome according to post-transplant response

CR

VGPR

PRPD

The definition of CR is suboptimal and requires

further improvements

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) *

MRI & FDG-PET in MM

Sagittal STIR MRI Sagittal FDG PET Ant MIP FDG PET

- 3m post-ASCT: Complete FDG suppression at PET/CT ……Longer PFS & OS

Zamagni et al. Blood 2011;118(23):5989-95

Immunophenotypic Remission The better the quality of the response the longer the survival: - GEM2000 & 2005 -

PFS OS

Immunop. CR vs CR: P < 0.001

months months

Median f/u: 46 months (updated)

Immunophenotypic CR, n=193 CR, 292 nCR, n=164 PR, n=364

1251007550250

100

80

60

40

20

0

Immunop. CR vs CR: P = 0.007

1251007550250

100

80

60

40

20

0

Immun. CR

CR

nCRPR

Immun. CR

CR

nCR

PR

Paiva et al; Blood. 2008, JCO 2011

MM Pathogenesis

- Genetic abnormalities of MM cell

- MM cell & microenvironment

Treatment

Novel drugs with singular

Mechanism of Action

Multiple Myeloma: From Biology to Therapeutics

Prognostic Factors

Myeloma Subtypes

TREATMENT OF MULTIPLE MYELOMA:

Should all patients be treated?

PATIENTS WHO SHOULD NOT BE TREATED

"Smoldering” MM (MC >3 g/dl &/or PC > 10%)

- Asymptomatic & NO: bone lesions, anemia, renal insufficiency or hypercalcemia

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

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

Bisphosponates6,7………………….No benefit in OR/TTP/OS

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.

Perez-Persona E, et al. Blood. 2007;110:2586-92.

Smoldering multiple myeloma: Risk of

transformation into Symptomatic MM

> 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%

based on the % of aberrant PCs by immunophenotype plus immunoparesis

High Risk

Low Risk

50454035302520151050

1.0

0.8

0.6

0.4

0.2

0.0

Randomized trial Lenalidomide+dex vs no treatment

in High Risk SMM (n = 120) ITT analysis

Median follow-up: 40 m

Len+dex

No treatment

TTP: 21m

46 Progressions (74%)

Bone disease (21); RI (8)

HR: 5.6; 95% IC (2.9–11);

p < 0.0001

Time from inclusion1009080706050403020100

1.0

0.8

0.6

0.4

0.2

0.0

Len+ Dex

No treatment

Time from inclusion

HR: 3,5; 95% IC (1–10);

p=0.01

Lenalidomide + Dex: 94% at 5 y

No treatment: 78% at 5 y

OS TTP

Mateos et al NEJM 2013

- Newly diagnosed

- Transplant candidates (Young)

- Non-Transplant candidates (Elderly)

- Relapsed patient

- Experimental Agents

Myeloma Treatment

“Old” Transplant candidate patient approach

Induction (VAD or TD)

ASCT (Mel 200)

Maintenance (IFN +/- Predn)

Do we have something better than VAD or TD?:

Response obtained with Novel Induction Regimens

0

10

20

30

40

50

60

70

80

90

100

VAD TD TAD LD BzD BzTD BzLD

VRD

BzLCD

VRDCInduction Regimen

Pe

rce

nt

Res

po

ns

e

ORR

CR

BzCD

VCD

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

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

ASCT Upfront or at Relapse:

Intensive vs. gentle approaches:

The patient is more fit to tolerate intensive and repetitive therapies

Significant increase in CR rate together with a long treament-free

interval & good quality of life……..& cost

Relapses after MEL200 are sensitive to novel agents…… but we

don´t know the long term effcicacy of the opposite (Mel200 after

novel agents)

Arguments in favor of intensive upfront treatment

Maintenance treatment with Thalidomide*

Attal (Blood 2006; 108:3289); Spencer (JCO 2008;26:3735 ); Barlogie (NEJM 2006; 354:1021); Lokhorst

(Blood 2010; 115:1113); Morgan (ASH 2010, Abstr 623); Stewart (ASH 2010, Abstr 39)

6 Randomized trials have compared Thalidomide +/- Pred.......

vs Nothing or Pamidronate or Prednisone or IFN

> PFS in all 6…………….. but OS in only 3

Meta-analysis: modest benefit in PFS & OS (+/- 6 m)

Lenalidomide vs Placebo after ASCT: PFS from randomization

0.0

00.2

50.5

00.7

51.0

0

0 6 12 18 24 30 36

Placebo Revlimid

P < 10-7

OS: 75% at 5y in both arms

Secondary Malignancies: 6,5% vs 2%;

(Hemtol: 3,6% vs 1%; solid: 3,9% vs 1%)

Attal M. NEJM 2012, 366: 1782-91

Lena

Placebo

41 m

23 m P < 10-8

Lena

Placebo

46 m

27 m P < 10-8

IFM 2005-02 CALGB 100104

OS: 35 vs 59 deaths, p=0.03

Secondary Malignancies: 8 vs 3 % ;

(Hematol: 3,46% vs 0%; solid: 4,3% vs 2,1%)

McCarthy P, NEJM 2012, 366: 1770-81

PFS PFS

Auto/Allo-RIC vsTandem Auto

1.Garban, Blood 2006 and Moreau, Blood 2008; 2. Lokhorst ASH 2008 (Abstr 461);

3.Rosinol, Blood 2008; 4. Krishnan, ASH 2010 (abst 41) 5. Bruno, NEJM 2007 (updated EBMT 2009);

5. Gahrton, ASH 2009 (Abst 52)

6. Knop, ASH 2009 (abst 51)

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 programs”

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

Transplant candidate patient: standard treatment from tomorrow

Induction (VAD)

ASCT (Mel 200)



ASCT (Mel 200)


Induction (Bz-Thal-Dx)




ASCT (Mel 200 +Bz)



ASCT (Mel 200 +Bz)

CR

Maintenance (Len +/- Bz )



ASCT (Mel 200 +Bz)

CR


Consolidation(Bz-Len-Dx)

No CR



ASCT (Mel 200 +Bz)

CR



No CR

VRD

VRD

VRD

. . . . .



ASCT (Mel 200 +Bz)

CR



No CR

VRD

VRD

VRD

. . . . .

Late ASCT

- Newly diagnosed



- Relapsed patient


Myeloma Treatment

Thalidomide + MP (MPT) vs MP: Efficacy in Newly

Diagnosed Elderly Patients With Myeloma

6 Randomized 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

1Facon. Lancet. 2007;370:1209-1218; 2Hulin. J Clin Oncol. 2009; 27(22):3664-70; 3Wijermans. J Clin Oncol.

2010; 28: 3160-6; 4Palumbo. Blood. 2008; 112: 3107-3114; 5Beksac. Eur J Haematol. 2010; 86:16-22; 6Waage. Blood. 2010;116(9):1405-1412 & ASCO 2010 (abstr 8130); Kapoor. Leukemia. 2011.

Palumbo. NEJM 2012, 366: 1759-69

PFS

MPR-R 31 m

MPR 14 m

MP 13 m

HR

0.398

P<0.000

0001

Time (months)

0 5 10 15 20 25 30 35 40

0

25

50

75

100

HR

0.804

P=0.153

Lenalidomide + MP (MPR): MPR-R vs MPR vs MP

1

0 5 10 15 20 25 30 35 400

25

50

75

100

Time (months)P

atients

(%

)

0 5 10 15 20 25 30 35 400

25

50

75

100

0 5 10 15 20 25 30 35 400

25

50

75

100

Time (months)P

atients

(%

)

• Small number of events, median follow-up of 21 months

1-year overall survival: 92 - 93%

2-year overall survival: 75 - 82%

MPR-R

MPR

MP

MPR-R

MPR

MP

Overall Survival

OS @3y: 70%, 62%, 66%

FIRST: Phase 3 trial of Lenalidomide +

low-dose Dex vs MPT (IFM 07-01; MM-020)

Inclusion criteria

N = 1,623

• Previously untreated MM

• Age 65 years or not eligible

for a transplant

• No neuropathy

of grade > 2

Rd (28-day cycle; until disease progression)

Lenalidomide 25 mg/day, days 1–21

Dexamethasone* 40 mg/day, days 1, 8, 15, and 22

Rd (28-day cycle; up to 18 cycles)

Lenalidomide 25 mg/day, days 1–21

Dexamethasone* 40 mg/day, days 1, 8, 15, and 22

*In patients aged > 75 years: Dex 20 mg/day, melphalan 0.20 mg/kg/day, thalidomide 100 mg/day

MPT (6-week cycle; up to 12 cycles )

Melphalan* 0.25 mg/kg/day, days 1–4

Prednisone 2.0 mg/kg/day, days 1–4

Thalidomide* 200 mg/day

Primary end-point: PFS

R

A

N

D

O

M

IZ

A

TI

O

N

• PFS: 28% reduction in the risk of DP/death for Rd (til DP) vs MPT

• OS: 22% reduction in the risk of death for Rd (til DP) vs MPT

Facon T, et al. Blood. 2013;122:abstract 2.

Len-dex will be a new standard of care for elderly newly diagnosed MM pts, or....

new backbone

FIRST Trial: PFSContinuous Rd reduced the risk of disease progression by 28% vs. MPT

mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone.


Median PFS

Rd (n= 535) 25.5 mos

Rd18 (n= 541) 20.7 mos

MPT (n= 547) 21.2 mos

Rd 535 400 319 265 218 168 105 55 19 2 0

Rd18 541 391 319 265 167 108 56 30 7 2 0

MPT 547 380 304 244 170 116 58 28 6 1 0

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)

Pa

tie

nts

(%

)100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

72

wks

30

FIRST Trial: Overall Survival Interim Analysis574 deaths (35%)


Pati

en

ts (

%)

Rd

Rd18

MPT

535

541

547

488

505

484

457

465

448

433

425

418

403

393

375

338

324

312

224

209

205

121

124

106

43

44

30

5

6

3

0

0

0

4-year OS

Rd (n= 535) 59.4%

Rd18 (n= 541) 55.7%

MPT (n= 547) 51.4%

Overall survival (months)

100

80

60

40

20

0

0 6 12 18 24 30 36 42 48 54 60

Hazard ratio

Rd vs. MPT: 0.78; P = 0.017 ( 22% risk of death with Rd)

Rd vs. Rd18: 0.90; P = 0.307

Rd18 vs. MPT: 0.88; P = 0.184

31

Bortezomib + MP (VMP) vs MP: Efficacy Data (682 Patients)

San Miguel. N Engl J Med. 2008;359:906; Mateos MV. J Clin Oncol. 2010;28:2259.

0 3 6 9 12

Time (months)

15 18 21 24 27

0

20

40

60

80

100

VMP

MP

Pa

tie

nts

with

ou

t e

ve

nt (%

)

Time (months)

0 4 8 12 16 20 24 28 32 36 40

0

20

40

60

80

100

VMP

MP

Pa

tie

nts

with

ou

t e

ve

nt (%

)

Time to Progression Overall Survival

TTP OS: 13,3 months benefit

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 VMP (VTP) followed by maintenance (VT/VP):

GEM2005 spanish trial

Similar results reported with VMPT+VT (Palumbo et al JCO 2010, 28:5101-9)

* Subcutaneous administration of Bortezomib

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

Biweekly VMP Weekly VMP

Significant reduction of PN 13% 5%

Improved CR rate 30% 42%

Prolonged PFS 21m 35m

- Newly diagnosed



- Relapsed patient


Myeloma Treatment

Strategies at Relapse: How to make the right choice?

Type of relapse

Further options

Efficacy of

previous

treatments

Toxicity of

previous

treatments

2nd Generation of Novel Drugs in MM

• Derivatives from the already approved

• Novel Proteasome Inhibitors: Carfilzomib, Ixazomib

• Novel IMIDs: Pomalidomida

• Novel Alkylators:Bendamustina

• Novel Mechanisms of action

• MoAb: anti CS1 & anti-CD38

• Deacetylase Inhibitors: Panobinostat

• KSP inhibitors

Current Treatment Approaches in

Multiple Myeloma

Progress in MM Cell Biology

Prognostic factors

&

Myeloma subtypes*

Discovery of New Drugs

Singular Mechanism of action

Individualize & Tailor Treatment

* MM sould not be considered a single entity

presentación de powerpoint · 2014. 6. 24. · snp-based mapping array 16q deletions 12p deletions...

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