4 ginna laport

GINNA LAPORT, MDPalo Alto, USA

• Professor, Blood and Marrow Transplantation (BMT) at Stanford University School of Medicine

• Dr. Ginna Laport, MD is also Director of Clinical Research and the Biostatistical Core of the BMT Division. She was previously a faculty member in the Division of Hematology/Oncology at the University of Pennsylvania and at the University of Chicago. Dr. Laport is the current Chair of the Steering Committee of the BMT Clinical Trials Network and is a member of the Lymphoma Steering Committee of the National Cancer Institute. She is co-chair of the Lymphoma Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR) and is a member of the Executive Committee of the American Society for Blood and Marrow Transplantation.

Hematopoietic Cell Transplantation for Multiple Myeloma: Optimal Timing

Ginna G. Laport, MDProfessor of Medicine

Division of Blood and Marrow TransplantationStanford University School of Medicine

• Current Trends in Autologous SCT

• Transplant vs No Transplant

• Optimal Induction Regimen for Transplant-

Eligible Patients

– Depth of Response

• Maintenance Therapy after SCT

Outline

Multiple Myeloma

Current trends in the role of hematopoietic cell

transplantation in the era of novel agents

Trends in Autologous HCT for Myeloma in Europe

0

5000

10000

15000

20000

25000

30000

1991-1995 1996-2000 2001-2005 2006-2010

Auner HW et al. Bone Marrow Transplant 2014

Nu

mb

er

of

Tra

nsp

lan

ts

Time Period

0

500

1000

1500

2000

2500

3000

3500

4000

1991-1995 1996-2000 2001-2005 2006-2010

65-69

>70

Trends in Autologous HCT for Myeloma in Europe: Elderly Patients

Nu

mb

er

of

Tra

nsp

lan

ts

Time Period

> 70 years

Autologous HCT in Europe, 1991-2010:Overall Survival

Auner HW et al. Bone Marrow Transplant 2014;

Months after Transplant

65 – 69 years

ASCT vs Conventional Chemotherapy: Results of Randomized Studies

Patients(n)

CR(%)

EFS(months)

OS(months) P Value

IFM90[1] CTAuto Tx

100100

522

1827

37NR

0.03

MAG91[2] CTAuto Tx

9694

46

1925*

4848

MRC7[3] CTAuto Tx

200201

844

2032

42.354.1

0.03

IMMSG[4] CTAuto Tx

9995

625

1628

4358+

<0.001

PETHEMA[5] CTAuto Tx

8381

1130

3342

6661

1. Attal M et al. N Engl J Med. 1996;335:91.2. Fermand JP et al. J Clin Oncol. 2005;23:9227.

3. Child A et al. N Engl J Med. 2003;348:1875.4. Palumbo A et al. Blood. 2004;104:3052.

5. Blade J et al. Blood. 2005;106:3755.

*P=0.07

CT = chemotherapy

Problem

All these studies are old. None include novel agents such

IMiDs or proteasome inhibitor therapy

R

VD ± DCEP ASCT1 ± ASCT2

± Len cons. Len maint.

VAD ± DCEP ASCT1 ± ASCT2

± Len cons. Len maint.

IFM 2005-1

R

PAD ASCT1 ± ASCT2

Bort maint.

VAD ASCT1 ± ASCT2

Thal maint.

HOVON-65/GMMG-HD4

R

VTD ASCT1 + ASCT2

+ VTD cons. Dex maint.

TD ASCT1 + ASCT2

+ TD cons. Dex maint.

GIMEMA MM-BO2005

R

VTD ASCT1

CHT + Bort ASCT1

PETHEMA GEM05MENOS65

TD ASCT1 R Thal

VT

IFN

Meta-Analysis: Phase 3 Studies Comparing Bortezomib-

Based vs Nonbortezomib-Based Induction Before

Autologous SCT

Sonneveld P, et al. J Clin Oncol 2013;31:3279

100

80

0

Progression-Free Survival

20

60

Time (months)

12 24 36 42 48 54 60

p=0.0001

A

40

6 18 30

Non-bortezomib

based

Bortezomib based

100

80

0

Overall Survival

20

60

Time (months)

12 24 36 42 48 54 60

p=0.0402

B

40

6 18 30

Non-bortezomib based

Bortezomib based

Meta-Analysis: Phase 3 Studies Comparing Bortezomib-

Based vs Nonbortezomib-Based Induction

Before Autologous SCT

Sonneveld P, et al. J Clin Oncol 2013;31:3279

MM06-04-12_1.ppt

Effect of Pre-transplant Salvage Therapy Prior to Autologous Transplant

in Patients Not Responding to Initial Induction for Multiple Myeloma (MM)

.

Vij R, et al. Biol Bone Marrow Transplant (in press 2015)

Methods (1995 – 2010)

< PR to

induction

Salvage

Chemotherapy

Autologous

Transplant

Diagnosis and

Initial Induction

Autologous

Transplant

12 months from diagnosis to AHCT

Salvage Cohort

No Salvage Cohort

AHCTDiagnosis

Vij R, et al. Biol Bone Marrow Transplant (in press 2015)

Outcomes with/without Pre-HCT Salvage

Years

0 2 4 1086

100

0

20

40

60

80

90

10

30

50

70

SALVAGE(n=324)

NO SALVAGE(n=251)

Progression-Free Survival

Years

0 2 4 1086

0

100

20

40

60

80

90

10

30

50

70

SALVAGE(n=324)

NO SALVAGE(n=251)

Overall Survival

P= 0.35 P= 0.2622

Vij R, et al. Biol Bone Marrow Transplant (in press 2015)

Probability of Survival based on Response to Initial Chemotherapy

Years

0 2 4 1086

100

0

20

40

60

80

90

10

30

50

70

<PR to induction

therapy (n=575)

CR/PR to induction

therapy (n=2326)

Progression-Free Survival

Years

0 2 4 1086

0

100

20

40

60

80

90

10

30

50

70

<PR to induction

therapy (n=575)

CR/PR to

induction therapy

(n=2326)

Overall Survival

p=0.0001 P = 0.0007

Vij R, et al. Biol Bone Marrow Transplant (in press 2015)

Autologous SCT vs No Transplant with

Maintenance Therapy

Gay et al ASH 2014, abstr 198

2007-20092009-2013

Gay et al ASH 2014, abstr 198

Gay et al ASH 2014, abstr 198

Prognostic Factors for PFS and Overall Survival

• Karnofsky performance status > 80%

• ISS stage 1 disease

• >VGPR after lenalidomide-dexamethasone induction

• Absence of del 17 or t(4;14)

Gay et al ASH 2014, abstr 198

Autologous SCT +Maintenance Therapy

N Engl J Med 2012

May 10 issue

American- CALGB

French - IFM

Lenalidomide: 10–15 mg/d until relapse

Placebo until relapse

First-line

ASCT<65 years

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

Primary end point: PFS

≤6 monthsNo PD

N=614

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

Consolidation

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

NEJM 2012; 366: 1759-1769

-Stage 1–3, -<70 years-Therapy at least 2 cycles -Stable disease or better

Placebo

Lenalidomide10 mg/d with ↑↓ (5–15 mg)

CRPRSD

Mel 200

ASCT

CALGB 100104: Lenalidomide as Consolidation/Maintenance Post-ASCT

McCarthy PL et al. NEJM 2012

Lenalidomide Placebo p value

Prog-Free Survival 43% 22% <.001

Median PFS 41 m 23 m <.0001

4 yr Overall Survival 73% 75%

NEJM 2012; 366: 1759-1769

Lenalidomide Placebo p value

Risk of Progression 37% 58%

Time to Progression 46 m 27 m <.001

3 yr OS 88% 80% .03

Median OS Not reached Not reached

CALGB - American

IFM -French

CALGB French

Len Placebo Len Placebo

Hematologic 8 1 13 5

Solid Tumor 10 5 10 4

Skin (non melanoma) 4 3 5 3

TOTAL 22 9 28 12

Secondary Cancers

Lenalidomide maintenance after HCT:- Improved progression free survial- Mixed results with overall survival- Increased risk of secondary cancers- Death from myeloma significantly higher than

death from secondary cancer- Benefits of lenalidomide vs cost/risk?

Early vs Late Transplant

IFM/DFCI 2009 Study

Newly Diagnosed MM Pts (SCT candidates)

Lenalidomide 12 mos

VRD x 3

VRD x 2

VRD x 5

Lenalidomide 12 mos

Melphalan

200mg/m2* +

ASCT

Induction

Consolidation

Maintenance

CY (3g/m2)

MOBILIZATIONGoal: 5 x106 cells/kg

VRD x 3

CY (3g/m2)

MOBILIZATIONGoal: 5 x106 cells/kg

Randomize, stratification ISS & FISH

Collection

SCT at relapse

Summary

• Number of SCT for myeloma increasing esp in older population

• Response to initial induction regimen predicts longer term

outcomes

• Bortezomib-based regimens induce

– Higher remission rates prior to SCT

– Improve survival after SCT

• Maintenance therapy with lenalidomide improves PFS and OS

• Whether early or late, once or twice , HCT remains an active

agent that can be extremely effective in all stages of the patients

disease journey.