1. Multiple Myeloma in the Non-transplant Setting
Antonio Palumbo, MD
University of Torino, Torino, I, EU

2. Standard of Care for Elderly Patients2

3. 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 Abstract 0567.

4. LMWH vs Warfarin vs Aspirin for Lenalidomide and Thalidomide
Standard Risk of VTE
Lenalidomide
Thalidomide
LMWH
WAR
ASA 1 2 3 4 5 6 7 8
Patients (%)
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
Palumbo A et al. EHA Abstract 0214.

5. 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*
VMP MP
24.0 mos (83 events)
16.6 mos (146 events)
HR = 0.483
p <
VMP MP
72%
59%
HR = 0.644
p = .0032
* Median follow-up 25.9 months, median OS not reached
San Miguel JF et al. ASH Abstract 650. 5 5

6. Bortezomib: Once Weekly
VMP
(VISTA)
twice-weekly
once-weekly CR
30%
27%
23%
2-year PFS
48%
56%
58%
Sensory PN
Any grade
44%
22%
Grade 3/4
13%
14% 2%
Discontinuation due to PN na
16% 4%
Total planned dose
67.6 mg/m2
46.8 mg/m2
Total delivered dose
40.1 mg/m2
39.4 mg/m2
Bringhen S et al. Blood 2010;116(23):

7. New Treatment Options 7

8. Bortezomib-Melphalan-Prednisone-Thalidomide VMPT-VT vs VMP
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
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
VMPT
Thalidomide 50 mg/day continuously R A N D O M I Z E
9 x 5-week cycles in both arms
MAINTENANCE
Bortezomib 1.3 mg/m2 IV Days 1,15
Thalidomide 50 mg/day continuously
NO MAINTENANCE
Until relapse
*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):

9. Bortezomib-Melphalan-Prednisone-Thalidomide Time to First Response and Time to CR
VMP
VMPT  VT
100 80 60 40 20
PR: VMPTVT
PR: VMP
% of patients
CR: VMPTVT
CR: VMP
Months
Palumbo A et al. Proc ASH 2010;Abstract 620.

10. 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
VMP
VMPT
32%
27.4 months
51%
37.2 months
3-year TNT
Median TTNT
VMP
VMPT
51%
37.6 months
70%
Not reached
HR 0.52
p <
HR 0.59
p <
Palumbo A et al. J Clin Oncol 2010;28(34):

11. Prognostic Factors PFS According to ISS and Cytogenetics
ISS 1 or 2
Absence of t(4;14) or t(14;16) or del17
0.00
0.25
0.50
0.75
1.00 10 20 30 40 50 60
Time (months)
Patients (%)
1.00
0.75
VMPT-VT
VMPT-VT
Patients (%)
0.50
VMP
VMP
0.25
P<0.0001
P=0.003
0.00 10 20 30 40 50 60
Time (months)
ISS 3
Presence of t(4;14) or t(14;16) or del17
0.00
0.25
0.50
0.75
1.00 10 20 30 40 50 60
1.00
VMPT-VT
0.75
VMPT-VT
Patients (%)
Patients (%)
VMP
0.50
VMP
P=0.51
0.25
P=0.49
0.00 10 20 30 40 50 60
Time (months)
Time (months)
Palumbo A et al. Proc ASH 2010;Abstract 620.

12. Melphalan-Prednisone-Lenalidomide
N = 459, 82 centers in Europe, Australia, and Israel
Double-Blind Treatment Phase
Open-Label Extension Phase
Cycles (28-day) 1-9
Cycles 10+
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
Continuous lenalidomide treatment
10 mg/day days 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
Disease Progression
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 Abstract 0566.

13. Melphalan-Prednisone-Lenalidomide Progression-Free Survival
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 5 10 15 20 25 30 35 40 50 75
100
100
100
100
100
MPR
MPR - - R R
55%
55%
Not reached
Not reached
MPR
MPR - - R R
61%
61%
Not reached
Not reached
MPR
MPR
27%
27%
14.7 months
14.7 months 75 75 75 75 75 MP MP
16%
16%
13.0 months
13.0 months MP MP
10%
10%
12.4 months
12.4 months
HR 0.315
HR 0.423 50 50 50 50 50
Log rank P
< .001
Log rank P
< .001
Patients (%)
Patients (%)
Patients (%)
Patients (%) 25 25 25 25 25
HR 0.675
Log rank P
= .031 5 5 10 10 15 15 20 20 25 25 30 30 35 35 40 40 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 Abstract 0566.

14. Lenalidomide Continuous Therapy
Melphalan-Prednisone-Lenalidomide Landmark Analysis 69% Reduced Risk of Progression
MPR
Lenalidomide Continuous Therapy 5 10 15 20 25 30 50 75
100
Time (months)
Patients (%)
MPR-R
MPR
HR 0.314
Log rank P < .001
MPR-R: melphalan-prednisone-lenalidomide/lenalidomide continuous treatment;
MPR: melphalan-prednisone-lenalidomide
Palumbo A et al. EHA Abstract 0566.

15. Age-Adjusted Therapies15

16. 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 = p = 0.004
Median PFS, MP vs MPT: 14.9 mo vs 20.3 mo Estimated HR = p <
– 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

17. Frail Patients: Treatment Algorithm
RISK 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 factor +
any G 3-4 non-hematologic AE
Go-go Moderate-go Slow-go
Palumbo personal communication

18. Frail Patients: Treatment Algorithm
Dose Reductions
Agent
Dose level 0
Dose level -1
Dose level -2
Bortezomib
1.3 mg/m2 twice / wk
d 1,4,8,11 / 3 wks
1.3 mg/m2 once / wk
d 1,8,15,22 / 5 wks
1.0 mg/m2 once / wk
Thalidomide
100 mg/d
50 mg/d
50 mg qod
Lenalidomide
25 mg/d
d 1-21 / 4 wks
15 mg/d
10 mg/d
Dexamethasone
40 mg/d
d 1,8,15,22 / 4 wks
20 mg/d
Melphalan
0.25 mg/kg
d 1-4 / 4-6 wks
0.18 mg/kg
0.13 mg/kg
Prednisone
25 mg qod
12.5 mg qod
Cyclophosphamide
Wk, week; d, day; qod, every other day
Palumbo & Anderson, New Engl J Med 2011

19. For how many patients with MM have you used subcutaneous (SQ) bortezomib?19 19

20. 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, :00 PM – 9:30 PM Chicago, Illinois
Moderator
Neil Love, MD
Faculty
Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD
Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek 20 20