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Multiple Myeloma in the Non-transplant Setting. Antonio Palumbo, MD University of Torino, Torino, I, EU. Standard of Care for Elderly Patients. Meta-Analysis: MPT vs MP.

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Multiple Myeloma in the Non-transplant Setting

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Multiple myeloma in the non transplant setting

Multiple Myeloma in the Non-transplant Setting

Antonio Palumbo, MD

University of Torino, Torino, I, EU


Standard of care for elderly patients

Standard of Care for Elderly Patients


Multiple myeloma in the non transplant setting

Meta-Analysis: MPT vs MP

  • Meta-analysis of randomized clinical trials (GIMEMA, IFM, HOVON, NMSG and TMSG)N = 1,682 (MP, n = 868 vs MPT, n = 814)

    • Median overall survival (OS), 32.7 mo vs 39.3 mo Overall hazard ratio for OS = 0.82

    • Median progression-free survival (PFS), 14.9 mo vs 20.4 mo Overall hazard ratio for PFS = 0.67

  • Test of heterogeneity between studies was statistically significant for OS (p = 0.26) and for PFS (p = 0.23).

MPT: melphalan-prednisone-thalidomide; MP: melphalan-prednisone

Waage A et al. EHA 2010. Abstract 0567.


Lmwh vs warfarin vs aspirin for lenalidomide and thalidomide

LMWH vs Warfarin vs Aspirinfor Lenalidomide and Thalidomide

StandardRisk of VTE

Lenalidomide

Thalidomide

LMWH

WAR

ASA

0

1

2

3

4

5

6

7

8

Patients (%)

HighRisk of VTE

  • Previous VTE, infection, immobilization, CVC, doxorubicin

  • LMWH is suggested

ASA: Acetylsalicylic acid; LMWH: low molecular weight heparin; VTE: venous thromboembolism;

CVC: central venous catheter; PE: pulmonary embolism

Palumbo A et al. EHA 2009. Abstract 0214.


Multiple myeloma in the non transplant setting

VMP (Bortezomib/Melphalan/Prednisone) –Current Standard of Care

  • ~52% reduced risk of progression

  • ~36% reduced risk of death

Progression-free survival

3-year overall survival*

* Median follow-up 25.9 months, median OS not reached

San Miguel JF et al. ASH 2008. Abstract 650.


Bortezomib once weekly

Bortezomib: Once Weekly

Bringhen S et al. Blood 2010;116(23):4745-53.


New treatment options

New Treatment Options


Bortezomib melphalan prednisone thalidomide vmpt vt vs vmp

Bortezomib-Melphalan-Prednisone-ThalidomideVMPT-VT vs VMP

R

A

N

D

O

M

I

Z

E

VMP

Cycles 1-9

Bortezomib 1.3 mg/m2 IV Days 1,8,15,22*

Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4

NO MAINTENANCE

9 x 5-week cycles in both arms

Until relapse

VMPT

Cycles 1-9

Bortezomib 1.3 mg/m2 IV Days 1,8,15,22*

Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4

Thalidomide 50 mg/day continuously

MAINTENANCE

Bortezomib 1.3 mg/m2 IV Days 1,15

Thalidomide 50 mg/day continuously

  • 511 patients (older than 65 years) randomized from 61 Italian centers

  • Patients: Symptomatic multiple myeloma/end-organ damage with measurable disease

    • ≥ 65 yrs or < 65 yrs and not transplant-eligible; creatinine < 2.5 mg/dL

*66 VMP patients and 73 VMPT-VT patients were treated with twice weekly infusions of bortezomib

Palumbo A et al. J Clin Oncol 2010;28(34):5101-9.


Bortezomib melphalan prednisone thalidomide time to first response and time to cr

Bortezomib-Melphalan-Prednisone-ThalidomideTime to First Response and Time to CR

VMP

VMPT  VT

100

80

60

40

20

0

PR: VMPTVT

PR: VMP

% of patients

CR: VMPTVT

CR: VMP

0 5

10 15

20 25 30

Months

Palumbo A et al. Proc ASH 2010;Abstract 620.


Bortezomib melphalan prednisone thalidomide

3-year TNT

Median TTNT

VMPT

70%

Not reached

VMP

51%

37.6 months

Bortezomib-Melphalan-Prednisone-Thalidomide

Median follow-up 32 months

Progression-free survival 41% Reduced Risk of Progression

Time to next therapy 48% Reduced Risk of Progression

3-year PFS

Median PFS

VMPT

51%

37.2 months

32%

27.4 months

VMP

HR 0.52

p < 0.0001

HR 0.59

p < 0.0001

Palumbo A et al. J Clin Oncol 2010;28(34):5101-9.


Prognostic factors pfs according to iss and cytogenetics

1.00

0.75

Patients (%)

0.50

0.25

0.00

0

10

20

30

40

50

60

Time (months)

1.00

0.75

0.50

0.25

0.00

0

10

20

30

40

50

60

Prognostic FactorsPFS According to ISS and Cytogenetics

ISS 1 or 2

Absence of t(4;14) or t(14;16) or del17

1.00

0.75

VMPT-VT

VMPT-VT

Patients (%)

0.50

VMP

VMP

0.25

P=0.003

P<0.0001

0.00

0

10

20

30

40

50

60

Time (months)

ISS 3

Presence of t(4;14) or t(14;16) or del17

1.00

0.75

VMPT-VT

VMPT-VT

Patients (%)

Patients (%)

0.50

VMP

VMP

0.25

P=0.51

P=0.49

0.00

0

10

20

30

40

50

60

Time (months)

Time (months)

Palumbo A et al. Proc ASH 2010;Abstract 620.


Melphalan prednisone lenalidomide

Melphalan-Prednisone-Lenalidomide

Double-Blind Treatment Phase

Open-Label Extension Phase

N = 459, 82 centers in Europe, Australia, and Israel

Cycles 10+

Cycles (28-day) 1-9

Continuous lenalidomidetreatment

RANDOMIZATION

MPR-R

M: 0.18 mg/kg Days 1-4

P: 2 mg/kg Days 1-4

R: 10 mg/day po Days 1-21

10 mg/daydays 1-21

Lenalidomide

(25 mg/day) ±

Dexamethasone

MPR

M: 0.18 mg/kg Days 1-4

P: 2 mg/kg Days 1-4

R: 10 mg/day po Days 1-21

DiseaseProgression

Placebo

MP

M: 0.18 mg/kg Days 1-4

P: 2 mg/kg Days 1-4

PBO: Days 1-21

Placebo

Stratified by age (≤ 75 vs > 75 years) and stage (ISS I/II vs III)

M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System

Palumbo A et al. EHA 2010. Abstract 0566.


Melphalan prednisone lenalidomide progression free survival

Melphalan-Prednisone-LenalidomideProgression-Free Survival

100

75

50

25

0

0

5

10

15

20

25

30

35

40

58% Reduced Risk of Progression

65-75 Years of Age

2

2

-

-

Year PFS

Year PFS

Median PFS

Median PFS

2

2

-

-

Year PFS

Year PFS

Median PFS

Median PFS

100

100

100

100

100

61%

61%

Not reached

Not reached

MPR

MPR

-

-

R

R

MPR

MPR

-

-

R

R

55%

55%

Not reached

Not reached

MPR

MPR

27%

27%

14.7 months

14.7 months

75

75

75

75

75

10%

10%

12.4 months

12.4 months

MP

MP

16%

16%

13.0 months

13.0 months

MP

MP

HR 0.315

HR 0.423

Log rank

< .001

P

50

50

50

50

50

Log rank

P

< .001

Patients (%)

Patients (%)

Patients (%)

Patients (%)

25

25

25

25

25

HR 0.675

Log rank

= .031

P

0

0

0

0

0

0

0

5

5

10

10

15

15

20

20

25

25

30

30

35

35

40

40

0

0

0

5

5

5

10

10

10

15

15

15

20

20

20

25

25

25

30

30

30

35

35

35

40

40

40

Time (months)

Time (months)

MPR-R: melphalan-prednisone-lenalidomide/lenalidomide continuous treatment;

MPR: melphalan-prednisone-lenalidomide; MP: melphalan-prednisone

Palumbo A et al. EHA 2010. Abstract 0566.


Melphalan prednisone lenalidomide landmark analysis 69 reduced risk of progression

100

75

Patients (%)

50

25

0

0

5

10

15

20

25

30

Time (months)

Melphalan-Prednisone-LenalidomideLandmark Analysis 69% Reduced Risk of Progression

MPR

Lenalidomide Continuous Therapy

HR 0.314

Log rank P < .001

MPR-R: melphalan-prednisone-lenalidomide/lenalidomide continuous treatment;

MPR: melphalan-prednisone-lenalidomide

Palumbo A et al. EHA 2010. Abstract 0566.


Age adjusted therapies

Age-Adjusted Therapies


Multiple myeloma in the non transplant setting

Impact of AEs on Outcome

Safety meta-analysis of 6 MPT trials1

Median OS, MP vs MPT: 32.7 mo vs 39.3 mo HR = 0.83 p = 0.004

Median PFS, MP vs MPT: 14.9 mo vs 20.3 mo Estimated HR = 0.68 p < 0.0001

– In practice, clinicians would vary the actual dose according to patient's status, evidence of response or relapse and occurrence of side effects or toxicity.

– A substantial proportion of patients in all studies either stopped thalidomide prematurely or dose reduced.

MPT, melphalan-prednisone-thalidomide; AE, adverse event

1 Fayers P et al Blood 2011, in press


Multiple myeloma in the non transplant setting

Frail Patients: Treatment Algorithm

Go-go Moderate-go Slow-go

Palumbo personal communication


Multiple myeloma in the non transplant setting

Frail Patients: Treatment Algorithm

Dose Reductions

Wk, week; d, day; qod, every other day

Palumbo & Anderson, New Engl J Med 2011


For how many patients with mm have you used subcutaneous sq bortezomib

For how many patients with MM have you used subcutaneous (SQ) bortezomib?


Multiple myeloma in the non transplant setting

What Clinicians Want to KnowA Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic CancersSunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois

Moderator

Neil Love, MD

Faculty

Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD

Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek


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