Hablemos de mantenimiento: posTMO: La conjetura de la€¦ · 01/02/2016  · Hablemos de...

Hablemos de mantenimiento:

posTMO: La conjetura de la

cronología

Javier de la RubiaHospital Doctor Peset, Valencia

Adaptado de Kurtin et al. Clin J Oncol Nurs. 2013; 17 Suppl:7-11

Multiple myeloma. Clinical evolution

ATSP vs. QTc

Estudio

IFM90 (NEJM 96)

MRC7 (NEJM 03)

MMSG It. (Blood 04)

MAG91 (ASH 99)

PETHEMA (Blood 05)

US Interg. (JCO 06)

Nº casos

200

401

194

190

164

516

Edad

≤65

≤65

50-70

55-65

<65

<70

RC (%)

5 vs. 22

8 vs. 44

6 vs. 25

-

11 vs. 30

11 vs. 11

Mediana SLE

18 vs. 28

19 vs. 31

16 vs. 28

19 vs. 25

34 vs. 42

21 vs. 25

Mediana SG

44 vs 57

42 vs. 54

42 vs. 58+

45 vs. 42

67 vs. 65

53 vs. 58

De la Rubia J. 2007

Complete response

• OS is not a realistic end-point

• TTP/PFS while acceptable will take years to complete

• CR is an important goal of therapy and it can be

reliably defined

• CR rates even with new regimens is less than 30-40%

• CR is recommended as an appropriate surrogate end-

point for regulatory purposes

Rajkumar SV 2006

Depth of response

MR

PR

VGPRnCR

CRsCR

Treatment initiation

Progression

Time

Depth of response is related to TTP

Importance of achieving complete

response

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 nCR or vs. SD CR vs PR nCR vs PR

P= 0.01P< 10-6

P= 0.04

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

1,0C

um

ula

tiv

e P

rop

ort

ion

Ev

en

t F

ree S

urv

ivin

gCR vs nCR or PR or SD nCR vs PR nCR vs SD

P< 10-5

P= 0.07P= 0.7

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

EFS OS

Lahuerta et al. ASH 2008 (abstract 161), oral presentation

Outcome according to post-transplant response

CR nCR PR SD PD

Medians EEF (months) 61 40 34 44 13

Medians OS (months) NR NR 61 NR 15

Tratamiento futuro de 1ª línea en jóvenes

Diagnóstico

Estratificación según riesgo

(ISS, citogenética convencional, FISH)

Riesgo estándar Alto riesgo

Nuevos esquemas de inducción (EC)

ATSP-1

ATSP-2 si <MBRP

o si recaída >2 años

Nuevos esquemas de inducción (EC)

¿ATSP nuevo acondicionamiento?

¿Alo-TPH (AIRE)?

Mantenimiento

De la Rubia J. 2007

Mantenimiento

The true value of CR relies on the MRD status,

and CR w/o MRD is no better than PR

The true value of CR relies on the MRD status,

and CR w/o MRD is no better than PR

MRD allows for more stringent evaluation and can provide

prognostic information

All levels of MRD are usually associated with

unsustained remissions

1. Martinez-Lopez et al., Blood. 2014;123:30732. Mateos MV. Blood Rev 2015;29:387–403

3. Poon ML. Cancer Therapy 2008;6:275-284.

Adaptado de Poon ML.3

But MRD- today means that we don’t detect myeloma cells

with actual techniques…

there is still undetectable residual disease

1. Martinez-Lopez et al., Blood. 2014;123:30732. Mateos MV. Blood Rev 2015;29:387–403

3. Poon ML. Cancer Therapy 2008;6:275-284.

MRD reappearance during follow-up monitoring

predicts clinical relapses

Patients in CR + flow CRafter up-front

treatment

MRD monitoring during follow-up

MRD reappearance:85% had clinical relapse

MRD reappearance

Ongoing major MRDresponse

MRD persistence

Paiva B, et al. Haematologica. 2014;99 Suppl 1:246-7.Ferrero S, et al. Leukemia. 2015;29:689-95.

• Therapy administered for a prolonged period of

time to maintain the response previously

achieved

• Maintenance therapy must be convenient, be

safe and well-tolerated long-term

• Not prevent the use, or reduce the efficacy, of

other future treatments

Why maintenance?

Treatment for patients with newly diagnosed multiple myeloma in 2015.

Mateos MV, Ocio EM, Paiva B, Rosiñol L, Martínez-López J, Bladé J, Lahuerta JJ, García-Sanz R, San Miguel JF.; Blood Rev. 2015;29:387-403

(Intro section on maintenance)

MRD and “Operational Cure”

CR, complete response; MRD, minimal residual disease; PR, partial response;

sCR, stringent CR; VGPR, very good PR. Mateos MV, et al. Blood Rev 2015;29:387.

Multiple myeloma. Clinical evolution

Adaptado de Kurtin et al. Clin J Oncol Nurs. 2013; 17 Suppl:7-11

Multiple myeloma. Clinical evolution

Adaptado de Kurtin et al. Clin J Oncol Nurs. 2013; 17 Suppl:7-11

It is generally accepted that the PFS and OS benefits for MM patients

mainly arise from first-line therapy. Thus, maintaining the response

achieved after first-line therapy is an important objective because most

patients will eventually experience a relapse and their disease will

progress.

ALCYONE: PFS

• Consistent PFS benefit across subgroups

PF

S (

%)

0

20

40

60

80

0 3 6 9 12 15 18 27

Mos

356

350

303

322

276

312

261

298

231

285

127

179

61

93

0

0

2

10

Pts at Risk, n

VMP

Dara-VMP

21 24

18

35

12-mo PFS 18-mo PFS

HR: 0.50

(95% CI: 0.38-0.65; P < .0001)

VMP

Median PFS: 18.1 mos

Dara-VMP

Median PFS: not reached

87%

72%

76%

50%

100

50% reduction in risk of

progression or death in

Dara-VMP arm

Median f/u: 16.5 mos (range: 0.1-28.1)

Mateos MV, et al. ASH 2017. Abstract LBA-4.

Front-line. Transplant candidates

Dex, dexametasona; Len, lenalidomida; TTP, tiempo hasta progresión.

Los pacientes que recibieron Len + Dex demostraron un incremento estadísticamente significativo en

el TTP comparado con pacientes que recibieron Placebo + Dex (P < .001)1

1. Dimopoulos M, et al. Leukemia. 2009;23:2147-2152.

300 10 20

100

0

25

50

75

TTP (Meses)

Pacie

nte

s (

%)

Placebo + Dex, mediana 4.6 meses

Len + Dex, mediana 13.4 meses

P < .001

El Uso Continuado de Lenalidomida + Dexametasona Aumenta

Significativamente el TTP.

Subanálisis de MM-009/0010

• The recommended starting dose for LEN maintenance therapy is

10 mg once daily given continuously (days 1-28 of 28-day cycles)

until PD or unacceptable toxicity2

– After 3 cycles, the dose can be increased to 15 mg once daily if tolerated

Key studies to support LEN maintenance

CALGB, Cancer and Leukemia Group B; IFM, Intergroupe Francophone Multiple Myelome; LEN, lenalidomide; OS, overall survival; PD, progressive disease.

1. McCarthy PL. N Engl J Med. 2012;366:1770-1781. 2. Revlimid (lenalidomide) [package insert]. Summit, NJ. Celgene Corporation. 2017. 3. Attal M. N Engl J Med.

2012;366:1782-1791.

Analyses supported approval

of LEN Maintenance

IFM

2005-02

Study

unblinding3

Jul 7, 2010

Survival

update3

Oct 1, 2011

Updated

efficacy and

safety2

Mar 1, 2015

Updated OS2

Feb 1, 2016

CALGB

100104

Study

unblinding1

Dec 17,

2009

Survival

update1

Oct 31,

2011

Updated

efficacy and

safety2

Mar 1, 2015

Updated OS2

Feb 1, 2016

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

CALGB 100104: Study design and endpoints

• Primary endpoint: TTP (time from ASCT to PD/death)

• Secondary endpoints: OS, post-ASCT response, long-term LEN

feasibility

aAll patients received thromboprophylaxis; bLEN dose adjustments between 5-15 mg permitted.

ASCT, autologous stem cell transplant; β2-M, β2-microglobulin; CALGB, Cancer and Leukemia Group B; CR, complete response; LEN, lenalidomide; MEL200, melphalan 200

mg/m2; MR, minimal response; OS, overall survival; PD, progressive disease; PR, partial response; R, randomization; SD, stable disease; THAL, thalidomide; TTP, time to

progression; Tx, treatment.

McCarthy PL. N Engl J Med. 2012;366:1770-1781.

R 1:1CR, PR,

MR, SD

Placebo

(n = 229)

MEL200

ASCT

N = 460

• ≤ 70 years of age

• ≤ 1 yr from start of Tx

• Stratified by β2-M and

THAL and LEN use

during induction

LEN

10 mg/dayb

(n = 231)

MaintenanceaRestaging(Within 100 days)

23

CALGB 100104: Event-Free Survival & SPM

ASCT, autologous stem cell transplant; CALGB, Cancer and Leukemia Group B; EFS, event-free survival; HR, hazard ratio; LEN, lenalidomide; PBO, placebo; PD, progressive

disease; SPM, second primary malignancy.

McCarthy PL. N Engl J Med. 2012;366:1770-1781.

• EFS analysis (time to SPM, PD, or death) demonstrated a positive

benefit-risk profile for LEN maintenance despite higher SPM incidence

– Hematologic SPM: 8 (LEN; 3.5%) vs 1 (PBO; 0.4%)

– Solid-tumor SPM: 10 (LEN; 4.3%) vs 5 (PBO; 2.2%)

Cutoff: Oct 2011

24

CALGB 100104: Overall Survival

• LEN maintenance significantly prolonged OS vs placebo

ASCT, autologous stem cell transplant; CALGB, Cancer and Leukemia Group B; HR, hazard ratio; LEN, lenalidomide; N/A, not applicable; OS, overall survival; PBO, placebo.

McCarthy PL. N Engl J Med. 2012;366:1770-1781.

CALGB 100104: Progression-Free Survival

CALGB, Cancer and Leukemia Group B; HR, hazard ratio; LEN, lenalidomide; PBO, placebo; PFS, progression-free survival.

Revlimid (lenalidomide) [package insert]. Summit, NJ. Celgene Corporation. 2017.

Cut-off: March 1, 2015

PFS, mos

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 48 60 72 84 96 108

Su

rviv

al P

rob

ab

ilit

y

HR (95% CI): 0.38 (0.28, 0.50)

Number of patients at risk:

LEN 231 194 158 121 102 82 40 16 5 0

PBO 229 116 57 29 20 18 11 3 0

Median PFS Events, n (%)

LEN 68.6 mos 97 (42)

PBO 22.5 mos 116 (51)

CALGB 100104: Overall Survival

CALGB, Cancer and Leukemia Group B; HR, hazard ratio; LEN, lenalidomide; NE, not estimable; OS, overall survival.

Revlimid (lenalidomide) [package insert]. Summit, NJ. Celgene Corporation. 2017.

OS at Updated Analysis (1 Feb

2016)

LEN

(n = 231)

Placebo

(n = 229)

OS events, n (%) 82 (35) 114 (50)

Median, mos (95% CI) 111.0 (101.8-NE) 84.2 (71.0-102.7)

HR (95% CI) 0.59 (0.44-0.78)

IFM 2005-02: Study Design and Endpoints

aAs measured by FISH; bConsolidation phase added at first protocol amendment (Sept 2006).

ASCT, autologous stem cell transplant; β 2-M, β2-microglobulin; del: deletion; EFS, event-free survival; FISH, fluorescence in situ hybridization; IFM, Intergroupe Francophone

du Myélome; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival; pts, patients; R, randomization; SD, stable

disease; VGPR, very good partial response.

Attal M. N Engl J Med. 2012;366:1782-1791.

LEN 25 mg/day

days 1-21

Placebo

(n = 307)

N = 614

•NDMM; < 65 yrs of age

•≥ SD within 6 mos of

ASCT

•Stratified according to

β2-M (≤ 3 or > 3, del(13),a

≥ VGPR post-ASCT

LEN

10-15 mg daily

(n = 307)

Maintenanceuntil progression

Consolidationb

2 × 28-day cycles

R 1:1

28

IFM 2005-02: Progression-Free Survival

• At the updated data cutoff (median follow-up of 86.0 mos), LEN

maintenance prolonged median PFS vs placebo

HR, hazard ratio; IFM, Intergroupe Francophone du Myélome; LEN, lenalidomide; PBO, placebo; PFS, progression-free survival.

Revlimid (lenalidomide) [package insert]. Summit, NJ. Celgene Corporation. 2017.

Cutoff: March 1, 2015

PFS, mos

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 48 60 72 84 96 108

Su

rviv

al P

rob

ab

ilit

y

HR (95% CI): 0.53 (0.44, 0.64)

Number of patients at risk:

LEN 307 243 208 158 124 105 87 49 5 0

PBO 307 225 140 92 61 47 36 19 1

Median PFS Events, n (%)

LEN 46.3 mos 191 (62)

PBO 23.8 mos 248 (81)

29

IFM 2005-02: Overall Survival

• With a median follow-up of 96.7 mos at a Feb 1, 2016 cutoff,

median OS was 105.9 vs 88.1 mos for LEN vs placebo

HR, hazard ratio; IFM, Intergroupe Francophone du Myélome; LEN, lenalidomide; NE, not estimable; OS, overall survival.

Revlimid (lenalidomide) [package insert]. Summit, NJ. Celgene Corporation. 2017.

OS at Updated Analysis (1 Feb 2016)LEN

(n = 307)

Placebo

(n = 307)

OS events, n (%) 143 (47) 160 (52)

Median, mos (95% CI) 105.9 (88.8-NE) 88.1 (80.7-108.4)

HR (95% CI) 0.90 (0.72-1.13)

Myeloma XI: LEN Mantenimiento en MMND

Diseño Estudio

• Endpoint primario: SLP y SG

• N = 1551 (Elegibles = 828; No elegibles = 723)

• Mediana seguimiento: 27 mesesLEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; pt, patient; TE,

transplant-eligible;

TNE, transplant non-eligible.

Jackson GH, et al. Lenalidomide is a Highly Effective Maintenance Therapy in Myeloma Patients of all Ages: Results of the Phase III Myeloma XI Study. ASH 2016,

abstract 1143.

MMND

Elegibles y no

elegibles a TAPH

Tratados en

protocolos de

inducción Myeloma XI

N = 1551

Tratamiento

hasta PE

LEN

Mantenimiento

LEN 10 mg D1–21

28-day cycles

No

Mantenimiento

RA

ND

OM

IZA

CIO

N 1

:1

Myeloma XI: LEN Mantenimiento en MMND

SLP según riesgo citogenético

• Se observó un beneficio en SLP en pts con alto riesgo citogenético en

mantenimiento con LEN frente al no mantenimiento

LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; PFS, progression-free survival; pt, patient.

Jackson GH, et al. Lenalidomide is a Highly Effective Maintenance Therapy in Myeloma Patients of all Ages: Results of the Phase III Myeloma XI Study.

ASH 2016, abstract 1143.

33

LEN Maintenance After ASCT in MM: OS AnalysisMethods

• A meta-analysis of RCTs was prospectively planned with the

following inclusion criteria:

– A LEN maintenance arm vs a control arm (placebo or no maintenance)

after ASCT

– Database lock had previously occurred for primary efficacy analysis

– Primary patient-level source data were available

ASCT, autologous stem cell transplant; CALGB, Cancer and Leukemia Group B; GIMEMA, Gruppo Italiano Malattie EMatologiche dell'Adulto; IFM, Intergroupe Francophone

Multiple Myelome; LEN, lenalidomide; MM, multiple myeloma; OS, overall survival; RCT, randomized controlled trial.

McCarthy PL. IMW 2017, abstract #OP-010.

34

LEN Maintenance After ASCT in MM: OS AnalysisMethods

• A meta-analysis of RCTs was prospectively planned with the

following inclusion criteria:

– A LEN maintenance arm vs a control arm (placebo or no maintenance)

after ASCT

– Database lock had previously occurred for primary efficacy analysis

– Primary patient-level source data were available

ASCT, autologous stem cell transplant; CALGB, Cancer and Leukemia Group B; GIMEMA, Gruppo Italiano Malattie EMatologiche dell'Adulto; IFM, Intergroupe Francophone

Multiple Myelome; LEN, lenalidomide; MM, multiple myeloma; OS, overall survival; RCT, randomized controlled trial.

McCarthy PL. IMW 2017, abstract #OP-010.

17 studies identified

4 studies randomized

LEN maintenance vs

control arm

3 studies fulfilled all criteria:

IFM 2005-02

CALGB 100104 (Alliance)

GIMEMA RV-MM-PI-209

13 studies

No control arm

1 study

Myeloma XI UK

(not completed)

Search of LEN

maintenance studies

35

LEN Maintenance After ASCT in MM: OS AnalysisOS (Median Follow-Up, 80 mos)

• There is a 25% reduction in risk of death, representing an estimated

2.4-yr increase in median survival (March 2015 data cutoff)a

a Log-rank test and Cox model stratified by study to assess impact of LEN maintenance on OS. Median for LEN treatment arm was extrapolated to be 115 mos based on median

of the control arm and HR (median, 86 mos; HR = 0.75).

ASCT, autologous stem cell transplant; HR, hazard ratio; LEN, lenalidomide; maint, maintenance; MM, multiple myeloma; NR, not reached; OS, overall survival.

McCarthy PL. IMW 2017, abstract #OP-010.

36

LEN Maintenance After ASCT in MM: OS AnalysisOS: Hazard Ratios

• Individual HRs are in the same direction, favoring LEN maintenance effect

– All studies contribute to the positive results of the meta-analysis

• No qualitative heterogeneity (P = .75)

• Quantitative heterogeneity (P = .047)a The size of the box is related to the size of the individual study. The confidence interval is a function of the overall sample size.

ASCT, autologous stem cell transplant; HR, hazard ratio; LEN, lenalidomide; maint, maintenance; MM, multiple myeloma; OS, overall survival.

McCarthy PL. IMW 2017, abstract #OP-010.

LEN Maintenance After ASCT in MM

• LEN maintenance significantly prolongs OS post-ASCT (estimated 2.4-

yr improvement in median OS)

• LEN maintenance after ASCT can be considered a standard of care

• Developing early endpoints as surrogates for long-term outcome and

OS, particularly MRD-negativity, is critically important for the future.

• Otherwise, incorporation of new and efficacious therapies into clinical

practice will be significantly delayed

ASCT, autologous stem cell transplant; HR, hazard ratio; LEN, lenalidomide; MM, multiple myeloma; OS, overall survival.

1. McCarthy PL. IMW 2017, abstract #OP-010. 2. Attal M. J Clin Oncol. 2016;34(suppl):8001.