Clinical Challenges in the Transplant-Eligible Patient With Newly Diagnosed Multiple Myeloma
Multiple Myeloma in the Non-transplant Setting
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Multiple Myeloma in the Non-transplant Setting
Antonio Palumbo, MD
University of Torino, Torino, I, EU
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Standard of Care for Elderly PatientsStandard of Care
for Elderly Patients
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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).
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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.
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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
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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.
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New Treatment OptionsNew Treatment Options
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• 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
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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.
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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.
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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.
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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
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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.
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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.
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Age-Adjusted Therapies
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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.
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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
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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
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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?
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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