1. Strategies for front-line treatment of Multiple Myeloma
Thierry FACON
Lille University Hospital, Lille, France
On behalf of IFM 1

2. Historical Perspective of Multiple Myeloma
Proteasome inhibitors
(Bortezomib)
Other immuno-modulatory agents
(Lenalidomide)
High-dose therapy with autologous stem cell support
ABMT
VAD
Bisphosphonates
High-dose melphalan
High-dose dexamethasone
Thalidomide
Oral melphalan and prednisone
Slide 6. Historical Perspective: MM
The first successful use of chemotherapy for MM was reported in 1958; a racemic mixture of D- and L-phenylalanine called “sarcolysine” was used. Tests of the 2 isomers demonstrated that the L-isomer was responsible for the anti-myeloma activity. In 1962, Bergsagel et al from SWOG reported that L-phenylalanine mustard (melphalan) produced remissions in about one-third of patients with MM
In 1967, Salmon et al reported that high doses of glucocorticoids could induce remissions in patients with refractory or relapsing MM. Subsequently, combination therapy with melphalan and prednisone was extensively studied, and in 1972 Alexanian et al reported on its efficacy
In 1983, McElwain and Powles reported that high-dose melphalan was effective for patients with MM and plasma cell leukemia. In 1984, Barlogie et al reported on the successful treatment of advanced MM with VAD. In 1986, the group described the efficacy of high-dose glucocorticosteroid therapy for the treatment of patients with resistant disease
In 1996, Berenson et al described the efficacy of bisphosphonate pamidronate in reducing skeletal events in patients with advanced MM
High-dose therapy with autologous stem cell support and thalidomide and arsenic trioxide treatment for patients with relapsed and refractory disease were introduced in 1999
At the beginning of the 21st century, other major advances included MAbs, proteosome inhibitors, and other IMiDs for treating patients with MM
1962
1983
1984
1986
1996
1999
2000+
Barlogie B et al. N Engl J Med. 1984;310:1353
Berenson JR et al. N Engl J Med. 1996;334:488
Alexanian R et al. Ann Intern Med. 1986;105:8
Bergsagel D. Cancer Chemother Rep. 1962;21:87
Salmon SE et al. Cancer Chemother Rep. 1967;51:179
Rousselot P et al. Cancer Res. 1999;59:1041
McElwain TJ, Powles RL. Lancet. 1983;2:822 2

3. Period estimates of 10-year survival of patients with MM by major age groups in defined calendar periods from to
Brenner et al; Blood 2008; 111: 3

4. Front-line treatment in multiple myeloma patients not eligible for stem cell transplantation4

5. Age- and Sex- Incidence Rates per 100 000/year for MM in the South Thames Area (1999-2000)
60.00
50.00
40.00
30.00
20.00
10.00
0.00
Males
Females
Females and Males combined
Rate per 100,000
16-24
25-34
35-44
45-54
55-64
65-74
75-84
85+
Age (years)
Phekoo et al; BJH 2004; 127:

6. Median 39.3 months (35.6-44.6) Median 32.7 months (30.5-36.6)
HR=0.83 in favour of MPT, P=.005
Cox model for treatment, with analysis sratified by study using a random effects (frailty) model

7. MRC Myeloma IX non intensive pathway Older less fit patients (approximately > 65 y)
Morgan et al. Blood 2007; 110:1051a(abs 3593)
Morgan et al. Blood 2008; 112:245 (abs 656) 7 7

8. 9 x 6-week cycles (54 weeks) in both arms
VISTA: VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with MP
Randomized, international, phase III trial of VMP vs MP in 682 previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT due to age (≥65 yrs) or co-morbid conditions
Stratification: β2-microglobulin, albumin, region
VMP
Cycles 1–4
Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 and prednisone 60 mg/m2:
d 1–4
Cycles 5–9
Bortezomib 1.3 mg/m2 IV: d 1,8,22,29 R A N D O M I Z E
Primary end point: TTP
Secondary end points: CR rate, ORR, time to response, DOR, time to next therapy (TNT), OS, QoL (PRO)
9 x 6-week cycles (54 weeks) in both arms MP
Cycles 1–9
Melphalan 9 mg/m2 and prednisone 60 mg/m2:
d 1–4
San Miguel et al. N Engl J Med 2008;359:906–17 8 8

9. VISTA:Efficacy data ORR: VMP 71%, MP 35% CR: VMP 30%, MP 4%
Time to progression
Overall survival
100
100
VMP MP
VMP MP 80 80 60 60
Patients without event (%)
Median follow-up: 25.9 months
3-year OS:
VMP: 72%
MP: 59% P = .0032 40 40
VMP: 24.0 months
MP: 16.6 months P < 20 20 3 6 9 12 15 18 21 24 27 4 8 12 16 20 24 28 32 36 40
Time (months)
Time (months)
Only 5% “true” non-responders
43% of MP patients received bortezomib upon progression
3-y OS VMP 68.5% vs MP 54%, median OS VMP not reached vs MP 43.1 mo. after a median FU 36.7 mo. Mateos et al.JCO,2010;28:

10. Spanish MPV; Mateos et al.Lancet Oncology 2010 Epub August 24.
MPV, an evolving standard of care From twice weekly to once weekly regimens
Spanish MPV; Mateos et al.Lancet Oncology 2010 Epub August 24.
Induction 6 cycles; one 6-week cycle, bortezomib 2x weekly, five 5-week cycles, bortezomib 1x weekly. Maintenance VT or VP
Italian MPV; Palumbo et al.JCO 2010 Epub October 12.Bringhen et al.Blood 2010 Epub August 31.
Induction Nine 5-week cycles, bortezomib 1x weekly.No maintenance in MPV but VT maintenance in VMPT
One-weekly schedule reduces the incidence of PN and decreases the rate of discontinuation without any reduction in efficacy

11. not eligible for a transplant
MM-015: phase III trial of MPR vs MP for long-term control in newly diagnosed MM
Randomized, placebo-controlled, double-blind trial in 51 centres in Europe, Australia, and Israel (N = 450)
Up to 9 courses in the absence of disease progression or unacceptable adverse events; treatment in 28-day cycles
Melphalan 0.18 mg/kg, days 1–4
Prednisone 2 mg/kg, days 1–4
Lenalidomide 10 mg/day p.o., days 1–21
Lenalidomide
Patients
with newly diagnosed,
untreated MM who are
not eligible for a transplant
Melphalan 0.18 mg/kg, days 1–4
Prednisone 2 mg/kg, days 1–4
Lenalidomide 10 mg/day p.o., days 1–21 R A N D O M I Z T
Placebo
Melphalan 0.18 mg/kg, days 1–4
Prednisone 2 mg/kg, days 1–4
Placebo days 1–21
Placebo
Primary end-point: PFS
Secondary end-points: OS, TTP, ORR, TTR, duration of response, and quality of life
All patients receive VTE prophylaxis with aspirin (75–100 mg/day)
Trial NCT Available from: 11 11 11

12. Progression-Free Survival All Patients5 10 15 20 25 30 35 40 50 75
100
Time (months)
Patients (%)
2-Year PFS
Median PFS
MPR-R
55%
Not reached
MPR
24%
14.1 months MP
16%
13.0 months
HR 0.423
Log rank P < .001
HR 0.850
Log rank P = .307
No. at Risk
MPR-R
152
115 89 66 35 17 2 –
MPR
153
120 90 36 7 MP
154
112 85 43 19

13. Progression-Free Survival 65 - 75 Years of Age5 10 15 20 25 30 35 40 50 75
100
Time (months)
Patients (%)
2-Year PFS
Median PFS
MPR-R
61%
Not reached
MPR
27%
14.7 months MP
10%
12.4 months
HR 0.315
Log rank P < .001
HR 0.675
Log rank P = .031
No. at Risk
MPR-R
116 91 75 57 31 15 2 –
MPR 97 77 16 7 MP 82 62 29 13 1

14. Treatment – Initial 9 cycles
MPRa MP
Discontinuation rateb, %
years of age 17 10
> 75 years of age 34 16
Cumulative dose intensityc, % 88 97 56
a MPR includes MPR-R and MPR for the initial 9 cycles.
b Discontinuation due to AEs or withdrawal of consent
c Cumulative dose intensity of melphalan and lenalidomide/placebo

15. x 4 cycles (cycle length : 28 d)
Len + high-dose Dex vs Len + low-dose Dex in newly diagnosed patients with myeloma
ECOG E4A03 Trial Design
Len. + high-dose Dex
x 4 cycles (cycle length : 28 d)
Rev. 25 mg/d, days 1-21
Dex. 40 mg/d, days 1-4, 9-12, 17-20
Newly diagnosed
MM patients (n = 445)
Primary objective: response rate and toxicity
Len. + low-dose Dex
x 4 cycles
Rev. 25 mg/d, days 1-21
Dex. 40 mg/d, days 1, 8, 15, 22
Rajkumar et al. Lancet Oncology 2010;11:29-37 15 15

16. ECOG/E4A03 Adverse events
Type (≥ Grade3)
RD (N=223)
Rd (N=220) P
DVT/PE
26 %
12 %
0.0003
Infection/Pneumonia
16 %
9 %
0.04
Cardiac ischemia
3 %
0.5 %
0.07
Any non Hem toxicity
(Grade ≥ 3)
65 %
48 %
0.0002
Toxicity of any type
(Grade ≥ 4)
21 %
14 %
Early deaths (< 4 mo. All pts)
5 %
0.003
Rajkumar et al. Lancet Oncology 2010;11:29-37

17. FIRST: Lenalidomide + LD-dex vs. MPT (IFM 07-01)
Pts: Previously untreated MM pts >65 yrs old or not a candidate for ASCT
Primary Endpoint: Progression-free survival (PFS)
LD (28-day cycle)
Oral dexamethasone on day 1, 8, 15, 22
Oral lenalidomide once daily on days 1-21 M
Treatment until progressive disease (PD)
LD (28-day cycle; up to 18 cycles)
Oral dexamethasone on day 1, 8, 15, 22
Oral lenalidomide once daily on days 1-21 R
MPT (6-wk cycle; up to 12 cycles)
Oral melphalan and prednisone on days 1-4
Oral thalidomide once daily on days 1-42 17 17

18. Treatment selection: elderly patients
Treatment should be selected based on:
Biological age, comorbidities, overall clinical impression
Dose adjustments:
Standard schedules for fit patients requiring quick relief from symptoms
Less intense treatment approach for frail patients and those with comorbidities (heart, lung, kidney, liver, diabetes) or aged >75 years
Need to do what is best for an average elderly MM patient

19. Newly diagnosed frail elderly patients with MM
Symptomatic treatments remain essential
Highest doses of drugs are not optimal
 Dexamethasone
 MP+ studies
Avoid excessive toxicity
 careful treatment monitoring
 dose reduction guidelines
 particularly in early stages of treatment
Need to consider Quality of life as factor 19

20. New options for patients eligible for transplantation
Induction regimens in the era of novel agents 20 20

21. Summary of post-transplant results in Phase III bortezomib trials
IFM 2005/01
GIMEMA
HOVON-GMMG
PETHEMA/GEM
Harousseau
VD vs VAD
(n=197 vs 184) (ASH 2008, joint ASH/ASCO symposium)
Cavo
VTD vs TD
(n=226 vs 234)
(IMW 2009; Abstract 451)
Sonneveld
PAD vs VAD
(n=150 vs 150)
(IMW 2009; Abstract 152)
Rosinol
VTD vs VBCMP/VBAD+V vs TD
(n=61 vs 58 vs 61)
(IMW 2009; Abstract 160)
Results post-ASCT CR
18% vs 10%*
41% vs 20%*
15% vs 4%*
48% vs 43% vs 23%
CR + nCR
40% vs 22%*
54% vs 29%*
n/a
≥VGPR
61% vs 44%*
75% vs 53%*
59% vs 47%
CR + PR
91% vs 91%
92% vs 77%*
77% vs 70% vs 62%
*significantly different
Bortezomib induction regimen results in high CR/nCR and VGPR rates post-transplant
n/a: not available

22. Phase III VD vs vTD as induction prior to ASCT IFM 2007/02Z E
Bortezomib 1.3 mg/m2 d1, 4, 8, 11
Dex 40 mg d1–4 and 8–11 (c3+4 only)
Bortezomib 1.0 mg/m2 d1,4,8,11
Thal 100 mg daily
Dex 40 mg d 1–4 and 8–11 (c3+4 only) VD
vTD
4 x 21-day cycles
Patients with <PR after cycle 2 could have bortezomib increased to 1.3 mg/m2 and thal increased to 200 mg in the absence of PN
Stratified by β2M and del(13) by FISH
Primary Objective: Induction CR rate
Secondary Objectives: ≥VGPR, ≥PR, toxicity (including PN)
FISH, fluorescent in situ hybridization
Harousseau et al. ASH 2009 (Abstract 354)

23. IFM 2007/02: VD vs vTD as induction treatment prior to ASCT Harousseau et al. ASH 2009, abs 354
205 patients from Mar to Jan (191 pts evaluable)
Response (%) VD
vTD CR 12 14
 VGPR* 36 50
 PR 81 91
*P=0.047
Toxicity (%) VD
vTD
Treatment reduction 17 7
PN gr  2* 28 14
PN gr  3 6 2
*P=0.02
vTD should be considered as a new standard for induction treatment prior to ASCT 23

24. Phase I/II: bortezomib, lenalidomide, dex (VRD) in newly diagnosed MM
Treatment
Up to 8 3-week cycles: Bortezomib 1.0/1.3 mg/m2, Len 15–25 mg, Dex 40/20 mg
Results
CR/nCR (%)
≥VGPR (%)
≥PR (%)
All patients (n=66)
Response at cycle 4 6 11 74
Response at cycle 8 23 53 95
Best response 39 67
100
Most common AEs:
Sensory PN (80%), fatigue (64%), constipation (61%), edema limb (45%), muscle pain (44%)
Grade 3 PN: 7%, no grade 4
Overall rate of DVT/PE: 6%
No treatment-related mortality
Median follow-up: 21 months
Median PFS not reached
Estimated 18-month PFS rate: 75%
No difference in PFS for pts undergoing ASCT or not
Median OS not reached
Estimated 18-month OS rate: 97%
Richardson et al. Blood 2010;116;

25. Post-Transplant Maintenance25 25

26. Thalidomide maintenance studies / Summary
Transplant setting
5/5 studies showed significant improvement in PFS
2/5 studies showed significant improvement in OS
Non-transplant setting
2/2 studies showed significant improvement in PFS
No significant improvement in OS
Considerations
- Short survival following relapse in some studies
Worse outcome in patients with poor cytogenetics

27. IFM 2005-02: Lenalidomide as maintenance therapy After ASCT for MM
Ongoing phase III randomized, placebo-controlled trial
Patients < 65 years, with non-progressive disease,  6 months after ASCT in first line
Randomize
Consolidation
Lenalidomide 25 mg/day p.o., days 1-21 of every 28 days for 2 months
However, 68% of patients enrolled in the IFM 99 trial experienced neuropathy
Thus revlimid , an analog of thal without neurological toxicity was an attractive candidate
And is evaluated in the current IFM protocol
After HDT, patients are to receive a consolidation with rev
Then they are randomized to receive rev or placebo as maintenance
More than 350 patients have been randomized and I hope to be able to present the results of this trial during the next few years.
Lenalidomide mg/day p.o., continuous dosing until relapse
Placebo until relapse
Primary end-point : PFS
Secondary end-points: CR rate, OS, feasibility of long-term lenalidomide. 27

28. IFM 2005-02 : PFS from randomization
Lenalidomide
p<10-7
Placebo
This result is illustrated on this slide
The PFS from randomization of patients treated with revlimid arm or in the placebo arm
P < 10-7

29. HOVON 65 MM / GMMG-HD4 Allogeneic Tx MM Stage II or III, Age 18–65
Accrual goal: 800 patients
MM Stage II or III, Age 18–65
Randomization
3 x VAD
3 x PAD
CAD + GCSF
CAD + GCSF
MEL PBSCT
MEL PBSCT
Depending on local policy for patients  PR MEL PBSCT
Allogeneic Tx
Depending on local
policy for patients
 PR MEL PBSCT
Thalidomide 50 mg/day for 2 years maintenance
Bortezomib 1.3 mg/m2/2 weeks for 2 years maintenance 29

30. IFM 2009/ DFCI Trial VRD x 3 SC collection VRD x 5 Rev maintenance
(HDM + ASCT at relapse)
Mel ASCT
VRD x 2
Major question: Can early SCT prolong EFS of at least 9 months? (1000 pts)

31. Jean-Paul Fermand Philippe Moreau Thierry Facon31 31