Multiple Myeloma in the Non-transplant Setting

Antonio Palumbo, MD

University of Torino, Torino, I, EU

Standard of Care for Elderly PatientsStandard of Care

for Elderly Patients

Waage A et al. EHA 2010. Abstract 0567.

Meta-Analysis: MPT vs MPMeta-Analysis: MPT vs MP

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

• 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).

LMWH vs Warfarin vs Aspirinfor Lenalidomide and Thalidomide

LMWH vs Warfarin vs Aspirinfor Lenalidomide and Thalidomide

High Risk 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

Standard Risk of VTE

LMWH

WARWAR

ASAASA

Patients (%)Patients (%)

ThalidomideLenalidomide

0 1 2 3 4 5 6 7 8

Palumbo A et al. EHA 2009. Abstract 0214.

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*

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

VMP MP

24.0 mos (83 events)

16.6 mos(146 events)

HR = 0.483

p < .000001

VMP MP

72% 59%

HR = 0.644

p = .0032

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

Bortezomib: Once Weekly Bortezomib: Once Weekly

VMP(VISTA)

VMPtwice-weekly

VMP once-weekly

CR 30% 27% 23%

2-year PFS 48% 56% 58%

Sensory PN

Any grade 44% 44% 22%

Grade 3/4 13% 14% 2%

Discontinuation due to PN

na 16% 4%

Total planned dose 67.6 mg/m2 67.6 mg/m2 46.8 mg/m2

Total delivered dose na 40.1 mg/m2 39.4 mg/m2

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

New Treatment OptionsNew Treatment Options

• 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-ThalidomideBortezomib-Melphalan-Prednisone-ThalidomideVMPT-VT vs VMPVMPT-VT vs VMP

Bortezomib-Melphalan-Prednisone-ThalidomideBortezomib-Melphalan-Prednisone-ThalidomideVMPT-VT vs VMPVMPT-VT vs VMP

VMPCycles 1-9Bortezomib 1.3 mg/m2 IV Days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4

VMPTCycles 1-9Bortezomib 1.3 mg/m2 IV Days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4Thalidomide 50 mg/day continuously

RANDOMIZE

9 x 5-week cycles in both arms

MAINTENANCEBortezomib 1.3 mg/m2 IV Days 1,15Thalidomide 50 mg/day continuously

NO MAINTENANCE

Until relapse

Bortezomib-Melphalan-Prednisone-Thalidomide

Time to First Response and Time to CR

Bortezomib-Melphalan-Prednisone-Thalidomide

Time to First Response and Time to CR

% o

f p

atie

nts

Months

VMP VMPT VT

CR: VMPTVT

PR: VMPTVT

CR: VMP

PR: VMP

100

80

60

40

20

0

0 5 10 15 20 25 300 5 10 15 20 25 30

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

Bortezomib-Melphalan-Prednisone-ThalidomideBortezomib-Melphalan-Prednisone-Thalidomide

3-year PFS Median PFS

VMP

VMPT

32% 27.4 months

51% 37.2 months

HR 0.59

p < 0.0001

Time to next therapy 48% Reduced Risk of Progression

3-year TNT Median TTNT

VMP

VMPT

51% 37.6 months

70% Not reached

HR 0.52

p < 0.0001

Progression-free survival 41% Reduced Risk of Progression

Median follow-up 32 months

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

Prognostic FactorsPFS According to ISS and Cytogenetics

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

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

P=0.49

ISS 3

ISS 1 or 2

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Time (months)

Pat

ien

ts (

%)

Time (months)

Pat

ien

ts (

%)

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Time (months)

Pat

ien

ts (

%)

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Time (months)

Pat

ien

ts (

%)

P=0.0030.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

VMP

VMPT-VT

VMP

VMPT-VT

VMP

VMPT-VT

VMP

VMPT-VT

P<0.0001

P=0.51

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

Melphalan-Prednisone-LenalidomideN = 459, 82 centers in Europe, Australia, and Israel

MP

M: 0.18 mg/kg Days 1-4

P: 2 mg/kg Days 1-4

PBO: Days 1-21

MPR

M: 0.18 mg/kg Days 1-4

P: 2 mg/kg Days 1-4

R: 10 mg/day po Days 1-21Placebo

Placebo

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

RA

ND

OM

IZA

TIO

N

Double-Blind Treatment Phase

Continuous lenalidomidetreatment

Lenalidomide

(25 mg/day)

±

Dexamethasone

Open-Label Extension Phase

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

10 mg/daydays 1-21

Cycles (28-day) 1-9 Cycles 10+

M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging SystemPalumbo A et al. EHA 2010. Abstract 0566.

DiseaseProgression

Melphalan-Prednisone-LenalidomideProgression-Free Survival

Time (months)

65-75 Years of Age

0 5 10 15 20 25 30 35 40

0

25

50

75

100

Pat

ient

s (%

)

0 5 10 15 20 25 30 35 40

0

25

50

75

100

0 5 10 15 20 25 30 35 40

0

25

50

75

100

Pat

ient

s (%

)

HR 0.315

Log rank P < .001

HR 0.675

Log rank P = .031

2-Year PFS Median PFS

MPR-R 61% Not reached

MPR 27% 14.7 months

MP 10% 12.4 months

2-Year PFS Median PFS

MPR-R 61% Not reached

MPR 27% 14.7 months

MP 10% 12.4 months

58% Reduced Risk of Progression

0 5 10 15 20 25 30 35 40

0

25

50

75

100

Pat

ient

s (%

)

0 5 10 15 20 25 30 35 40

0

25

50

75

100

0 5 10 15 20 25 30 35 40

0

25

50

75

100

Time (months)

Pat

ient

s (%

) HR 0.423

Log rank P < .001

2-Year PFS Median PFS

MPR-R 55% Not reached

MP 16% 13.0 months

2-Year PFS Median PFS

MPR-R 55% Not reached

MP 16% 13.0 months

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

Palumbo A et al. EHA 2010. Abstract 0566.

0 5 10 15 20 25 300

25

50

75

100

Time (months)

Pat

ient

s (%

)

Melphalan-Prednisone-LenalidomideLandmark Analysis

69% Reduced Risk of Progression

HR 0.314 Log rank P < .001

MPR-R

MPR

Lenalidomide Continuous TherapyMPR

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

Palumbo A et al. EHA 2010. Abstract 0566.

Age-Adjusted Therapies

Safety meta-analysis of 6 MPT trials1

Impact of AEs on Outcome Impact of AEs on Outcome

1 Fayers P et al Blood 2011, in pressMPT, melphalan-prednisone-thalidomide; AE, adverse event

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.

Frail Patients: Treatment AlgorithmRISK FACTORS

- Age over 75 years

- Mild, moderate or severe frailty:

Help needed for household and personal care

- Comorbidities and organ dysfunction:

Cardiac Pulmonary Hepatic Renal

Dose level 0 Dose level -1 Dose level -2

No risk factors At least one risk factorAt least one risk factor

+ any G 3-4 non-hematologic AE

Go-go Moderate-go Slow-go

Palumbo personal communication

Agent Dose level 0 Dose level -1 Dose level -2

Bortezomib1.3 mg/m2 twice / wk

d 1,4,8,11 / 3 wks1.3 mg/m2 once / wkd 1,8,15,22 / 5 wks

1.0 mg/m2 once / wkd 1,8,15,22 / 5 wks

Thalidomide 100 mg/d 50 mg/d 50 mg qod

Lenalidomide25 mg/d

d 1-21 / 4 wks15 mg/d

d 1-21 / 4 wks10 mg/d

d 1-21 / 4 wks

Dexamethasone40 mg/d

d 1,8,15,22 / 4 wks20 mg/d

d 1,8,15,22 / 4 wks10 mg/d

d 1,8,15,22 / 4 wks

Melphalan0.25 mg/kg

d 1-4 / 4-6 wks0.18 mg/kg

d 1-4 / 4-6 wks0.13 mg/kg

d 1-4 / 4-6 wks

Prednisone 50 mg qod 25 mg qod 12.5 mg qod

Cyclophosphamide100 mg/d

d 1-21 / 4 wks50 mg/d

d 1-21 / 4 wks50 mg qod

d 1-21 / 4 wks

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

Frail Patients: Treatment AlgorithmDose Reductions

Palumbo & Anderson, New Engl J Med 2011

Copyright © 2011 Research To Practice. All rights reserved.

9%

10%

2%

71%

8%

0% 10% 20% 30% 40% 50% 60% 70% 80%

0

1

2-5

6-10

>10

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

Copyright © 2011 Research To Practice. All rights reserved.

What Clinicians Want to Know

A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical

Management of Select Hematologic Cancers

Sunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois

Faculty

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

ModeratorNeil Love, MD

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