1. Terapia nei pazienti non candidati
                                                             The Mediterranean School of Oncology
LLC e MM oggi: un paradigma per nuovi standard nelle patologie ematologiche
Terapia nei pazienti non candidati
a trapianto
Federica Cavallo
Divisione di Ematologia, Universita’ di Torino
Orvieto, Novembre, 2009

2. 31% 36% 33% 65-75 years 25-64 years 75-101 years Multiple Myeloma
ASL TORINO: people
INCIDENCE: 1974: 5.9/ : 8.9/ Median age at diagnosis: years
31%
33%
36%
65-75 years
25-64 years
years
Regione Piemonte, Assessorato Sanità 2006,15

3. Survival outcomes for multiple myeloma
Age at diagnosis
Years Mortality Ratio Increased ratio
(ref.) % % % % %
60 years  4-year survival
70 years  3-year survival
Kristinsson SY, et al. J Clin Oncol. 2007;25:

4. OS From Time of Diagnosis in 6-yr Intervals Based on Date of Diagnosis20 40 60 80
100
120
140
Survival
0.0
0.2
0.4
0.6
0.8
1.0
1971–76
1994–00
1989–94
1977–82
2001–06
1983–88
OS From Time of Diagnosis in 6-yr Intervals Based on Date of Diagnosis
This slide shows the Kaplan-Meier curves for OS from the time of diagnosis grouped into 6-year intervals based on the date of diagnosis. The outcome for patients with MM has improved in recent years, both in the relapsed setting as well as at diagnosis The outcome of myeloma patients has improved in recent years. In their paper, recently published on Blood, Kumar and colleagues demonstrated a significantly higher overall survival from the time of diagnosis in patients diagnosed between two thousand and one and two thousand and six.
Kumar SK et al. Blood Nov 1 [Epub ahead of print]
Kumar SK et al. Blood. 2008; 111: 2516

5. MP vs Dexamethasone-Based Regimens (IFM 95-01 Trial)
488 patients aged yr (median 70) randomized to MP, MD, D, or D-IFN (12 courses at 6-wk intervals)
FU 82.8 mo, OS 35.0 mo (415/488), EFS 18.3 mo (473/488) for whole series
Standard MP gold standard for treatment of older pts
Regimen MP MD D
D-IFNa n
109
110
101
≥PR↓ (P<0.001)
51%
74%
40%
42%
CR (P=NS) 1% 3%
EFS (mo)
21.1 ± 1.7
22.9 ± 2.0
12.2 ± 1.0*
15.2 ± 2.7*
OS (mo)
34.0 ± 3.6
39,6 ± 3.1
33.4 ± 2.0
32.0 ± 5.3
MP vs Dexamethasone-Based Regimens (IFM Trial)
This study, evaluated the MP regimen against 3 dexamethasone-based regimens: melphalan/dexamethasone, dexamethasone alone, and dexamethasone/interferon. EFS was significantly shorter for patients not receiving melphalan (P<0.0001). The OS did not differ significantly between groups. CR rates were rare in all treatment groups, PR rates were significantly higher in patients receiving melphalan plus dexamethasone. Morbidity associated with the dexamethasone regimens was significantly higher than with MP. Blood. 2006; 107:1292
MP vs Dexamethasone-Based Regimens (IFM Trial) This study represent the largest multicenter randomized trial in elderly pts (65-75) inelegible for high dose th comparing MP with various Dex regimen before the availability of new drugs. Median fu 7 y
This study, evaluated the MP regimen against 3 dexamethasone-based regimens: melphalan/dexamethasone, dexamethasone alone, and dexamethasone/interferon.
The study evaluated 488 patients who received 12 courses of therapy.
M .25 mg/kg P 2 mg/kg x4 gg
D 40 mg/day 4 days on day 1, 9 and 17 (first 2 cycles) and then 1-4 for 10 cycles
MD: M=MP; D=D
D-IFNalfa: INFalfa 3 MU 3 times weekly
Median PFS was significantly longer in M-groups than in D without M
Mean follow-up was 63.1 months, the combined event-free survival was 18.3 months and did not significantly differ between groups. The overall survival was 35.1 months and did not differ significantly between groups even if this difference did not translate into a survival advantage. There was a longer survival after relapse for pts not receiving M (alkilating based regimen at first relapse). Results confirmed adjusting on prognostic factors. Disease control achieved with Dex and D-inf was clearly inferior to that achieved by M containing treatment.
TOX: early deaths (3 months) significantly more frequent in D without M (early death mainly related to MM PD, second cause pyogenic infection). In M group significantly higher second tumor (MDS). No differences in mortality after first 3 months
When combining all severe non-hematologic complications the incidence was lower in the MP group than in the Dex containing groups- p=.01 (also wen comparison only con M-Dex or Dex alone). Dex related tox is frequently age related.
The standard MP remained the best treatment choice in elderly pts; it does or exclude that the use of D in individual pts and selected situations (renal failure, cord compression, reduced blood count) could be an option. D containing regimen has been used in the pre-transplant setting o avoid M exposure, but they have been extrapolated in the non-transplant setting without convincing results.
*P<0.001 for pts not receiving Melphalan
Facon T et al. Blood. 2006; 107:1292

6. Thal/Dex vs MP in newly diagnosed MM
274 patients, median age 72 yr
Median follow-up: 28.1 months
Thal 200 mg/d, Dex 40 mg (odd: d 1–4, 15–18; even: d 1–4),
Melphalan 0.25 mg/kg/d (d 1–4) + prednisone 2 mg/kg, d 1–4, q 4–6 wks
0.07 43 25
PFS (months)
0.45
51%
68%
> PR 58
15% MP
(n=138)
0.029 45
OS (months)
0.001
31%
CR/nCR
P value
Thal/Dex
(n=136)
Results
Randomized to Tal IFN o IFN alone maintenance
Time to resonse ant time to best response were shorter in TD (6 vs 16 and 16 vs 25 wks)
Tendency for more early discontinuation (15 vs 11 wk p= ns) in TD arm and
higher mortality in the first treatment year (31 vs 17, p=.026)
Age: pts younger than 72: no difference in OS; pts >72 : 46.5 vs 25.4 p< .06
Maintenance: no difference in OS
Toxicity: MP higher incidence of g3-4 leucopenia
TD: more g2-3 neuropathy , constipation, psycological .
Conclusions: TD resulted in a significant higher rate ot CR/nCR rate and ORR,
a significantly shorter time to response and to best response.
Similar EFS but significant shorter OS in TD, particularly true in pts aged 72,
but not in pts < 72.
Ludwig H, et al. Blood (15):

7. Summary of MPT phase 3 trials in the upfront setting
Regimen n
CR+PR (%)
CR (%)
PFS/EFS OS
Reference
Thal/MP vs MP
129
126 76 48 16 4
21.8
14.5
45m
47.6m
Palumbo et al. Blood 2008; 112:
Thal/MP vs MP vs
MEL 100
191
124
121 35 65 13 2 18
27.5m
17.8m
19.4m
51.6m
33.2m
38.3m
Facon, et al. Lancet 2007; 370:1209–18
Thal/MP vs
MP (>75y)
113
116 62 31 7 1
24.1m
19m
45.3m
27.7m
Hulin, et al. J Clin Oncol 2009; 27:
Thal/MP* vs MP
363 total 42 28 6† 3†
20m
18m
29m
33m
Gulbrandsen et al. EHA 2008 (Abstract 209)
152
149 66 47
EFS 13m vs 9m
PFS 13m vs 10m
37m
30m
Wijermans et al. ASH 2008 (Abstract 649)
ITALIAN: Patients treated with MPT showed higher response rate and longer EFS. PR were 76% for MPT and 47.6% for MP, including nCR of 27.9% and 7.2% respectively. After a median follow-up of 17.6 months, the 2 year EFS rate was 54% in MPT and 27% in MP arm (p=0.0006). The 3 years OS rate was 80% for MPT and 64% for MP (p=0.19).
FRENCH: Median PFS times were 17.1 months for MP, 27.6 months for MPT, and 19.4 months for MEL100. The PFS time was significantly longer in the MPT group than in the MP group (P<0.001), but no significant difference was noted between MP and MEL100 groups (P=0.09). PFS for MPT was significantly better than that for MEL100 (P=0.001)
The favorable PFS time in the MPT group translated into a significant benefit in terms of OS. Median OS times were 32.2 months for MP, 53.6 months for MPT, and 38.6 months for MEL100. The OS time was significantly longer for MPT than MP (P=0.001), and there was a trend towards better survival comparing MEL100 to MP (P=0.09). MPT was also significantly superior to MEL100 in terms of OS (P=0.001)
*Thal doses: 200–400 mg
†CR + nCR
In 5/5 studies, MPT was superior to MP in terms of PFS and/or TTP.
In 2/5 studies, MPT was superior to MP in terms of OS.

8. Grade 3-4 Adverse Events P = .0002 P = .0001 P = .03 P = .009 P = .006
The MPT safety profile did not differ significantly from the initial report.
Grade 3–4 adverse events were reported in fifty-five per cent of MPT patients and in twenty-two per cent of MP patients.
The most frequent grade 3–4 adverse events were hematologic, infections, cardiac, thromboembolism and neurologic events. After the introduction of enoxaparin prophylaxis grade 3-4 thromboembolism was reported in 3 patients. Two of these patients had evidence of thromboembolism within 2 months after the discontinuation of enoxaparin. No late thrombormbolic events were reported.
Grade 3-4 neurological toxicity was reported in fourteen per cent of patients. Peripheral neuropathy was the most frequent neurological adverse event, observed in ten per cents of patients.
P = .006
*MPT: 4 infection, 2 cardiac, 3 progression
MP: 1 infection, 1 progression

9. MRC Myeloma IX study Thalidomide maintenance:
Non-intensive arm: MP vs. attenuated CTD prior to maintenance randomization
Thalidomide maintenance:
initiated at the end of induction in the non-intensive arm; 100mg daily until relapse
median age 73 non-intensive
Morgan et al. ASH 2008 (abstract 656)

10. Efficacy
CTDa
(n=120) MP
(n=113) CR
22.5% 6%
≥VGPR
47.5%
9.5%
≥ PR
82.5%
49%
Intensive pathway: significant benefit of maintenance in patients with less than a VGPR post initial induction (p=.007)
PFS difference did not translate into survival benefit because survival after progression in PR patients receiving maintenance thalidomide was poor (p=.002)
Non-intensive pathway: similar but less pronounced effect of thalidomide maintenance on PFS
Intensive pathway: significant benefit of maintenance in patients with less than a VGPR post initial induction (p=.007)
PFS difference did not translate into survival benefit because survival after progression in PR patients receiving maintenance thalidomide was poor (p=.002)
Trend for longer survival in patients with longer recovery time (time between stopping thalidomide and progression) (p=.056)
Non-intensive pathway: similar but less pronounced effect of thalidomide maintenance on PFS
Consolidation effect of thalidomide rather than a maintenance effect in this setting
Impact of maintenance in different cytogenetic subgroups
PFS and OS in patients with del17p significantly worse in thalidomide maintenance group
Although thalidomide maintenance may improve PFS, there is no demonstrable benefit on OS
Morgan et al. ASH 2007 (Abstract 3593) 10

11. 9 x 6-week cycles (54 weeks) in both arms
VISTA: VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone
Randomized, international, phase III trial of VMP vs MP in 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 R A N D O M I Z E
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
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 11

12. VISTA: New Engl J Med data
Responses according to EBMT criteria1
Time to progression
VMP
n=337 MP
n=331
p-value
ORR (≥PR)
71%
35%
<10-6 CR
30% 4% PR
40%
31% MR 9%
22% SD
18%
100
VMP: 24.0 months (83 events)
MP: 16.6 months (146 events)
HR=0.483, P< 3 6 9 12 15 18 21 24 27
VMP MP 90 80 70 60 50 40 30 20 10
Time to response and duration of response
Time (months)
VMP MP
p-value
Median time to response, months
Time to first response*
1.4
4.2
<10-10
Time to CR*
5.3
Median DOR, months
All responders
19.9
13.1
Patients achieving CR
24.0
12.8
7 patients in each group not evaluable: either not treated (n=5) or found to have no measurable disease at baseline by central laboratory assessment (n=9), despite having met eligibility criterion of measurable disease by local laboratory evaluation
P-values shown for comparisons of EBMT response rates; calculated by stratified Cochran Mantel-Haemszel chi-squared test
ORR by International Uniform Response Criteria including patients in response at last assessment (but unconfirmed) was 78% with VMP (12 additional patients) and 40% with MP (4 additional patients). Of 79 patients (23%) with stable disease by International Uniform Response Criteria, 4 (1%) were immunofixation-negative, and 19 (6%) had >50% reduction in M-protein in serum and/or urine; however, these patients were not recorded as PR because they did not fulfill all of the criteria, mainly because the confirmatory test was missing. Furthermore, 38 (11%) patients either had 25-49% reductions in M-protein or met the EBMT criteria for MR for non-secretory disease. Accordingly, only 18 (7%) patients were ‘true’ non-responders.
*Medians shown for responding patients; p-values based on total study population
1. Bladé et al. Br J Haematol 1998;102:
San Miguel et al. N Engl J Med 2008;359:906–17 12

13. VISTA: Overall Survival ~36% reduced risk of death on VMP
Median follow-up 16.3 months
VMP: not reached (45 deaths)
MP: not reached (76 deaths)
HR = 0.607, p =
VMP MP
UPDATE AT ASH 2008
Median follow-up 25.9 months
VMP: median OS not reached (75 deaths); 3-year OS rate = 72%
MP: median OS not reached (111 deaths); 3-year OS rate = 59%
HR = 0.644, p =
San Miguel et al. ASH 2008 (abstract 650) 13

14. VISTA Update – ASH 2008 VMP MP Time to next therapy 28.1 months
HR=0.53, P<
Treatment-free interval
16.6 months
8.4 months
HR=0.54, P<
Subsequent therapy:
Patients can be successfully treated with subsequent immunomodulatory- based therapy and can also be retreated with bortezomib (CR 4-10%; PR %)
VMP MP
Bortezomib
16%
43%
Thalidomide
49%
44%
Lenalidomide
19% 6%
San Miguel et al. ASH 2008 (abstract 650)

15. VISTA: Adverse events VMP (n=340) MP (n=337) AE, % Grade 3 Grade 4
Neutropenia 29 11 23 15
Thrombocytopenia 20 18 16
Anemia 3 8 GI 19 1 5
Peripheral sensory neuropathy 13
<1
Fatigue 7 2
Asthenia 6
Pneumonia 4
Herpes zoster
Herpes zoster more frequent with VMP (14% vs 4%)
Rate with VMP only 3% among patients receiving antiviral prophylaxis
Peripheral neuropathy was manageable and reversible
79% of PN events improved (≥1 grade), median of 1.9 months
60% of PN events completely resolved, median of 5.7 months
San Miguel et al. ASH 2008 (abstract 650) 15

16. VMP vs VTP in newly diagnosed elderly patients with MM PETHEMA/GEM study
Randomized, phase III trial of VMP vs VTP in previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT
age ≥65 yrs, N=260 pts
VMP
Cycle 1 (6-week cycle)
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 2-6 (5-week cycles)
Bortezomib 1.3 mg/m2 IV: d 1,8,15,22 R A N D O M I Z E
VTP
Cycle 1 (6-week cycle)
Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32
Thalidomide 100 mg/d and prednisone 60 mg/m2: d 1–4
Cycles 2-6 (5-week cycles)
Bortezomib 1.3 mg/m2 IV: d 1,8,15,22
Mateos et al. ASH 2008 (abstract 651) 16

17. VMP vs VTP in newly diagnosed elderly patients with MM PETHEMA/GEM study
VMP (n=130)
VTP (n=130)
ORR
81%
CR IF-
22%
27%
CR IF+
19%
10% PR
40%
44%
Median time to first response
1.6 months
Median time to CR
4.4 months
4.9 months
2-year TTP
72%
68%
2-year OS
~90%
Mateos et al. ASH 2008 (abstract 651)

18. VMP vs VTP in newly diagnosed elderly patients with MM PETHEMA/GEM study
≥G3 Adverse events
VMP (n=80)
VTP (n=87) P
Neutropenia
34%
19%
0.009
Thrombocytopenia
21% 9%
0.01
Non-hematological AEs
25%
32%
0.04
Cardiac toxicity 7%
Thromboembolic events
<1% 4%
Peripheral neuropathy 5%
Treatment discontinuation 8%
17%
Deaths
Conclusions
Similar efficacy in the two arms
Modified VMP regimen (weekly schedule after cycle 1; only six cycles) is well tolerated
Reduced incidence of PN
Thalidomide may not be the partner of choice for combination with bortezomib
Mateos et al. ASH 2008 (abstract 651)

19. VMPT vs VMP in elderly patients with newly diagnosed MM GIMEMA study
511 patients (older than 65 years) randomized from 58 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 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
Median age 71 y; 30% >75 y; Median KPS 80%; 63% IgG; 33% B2M > % albumin < 35 g/L
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
* 61 VMP patients and 70 VMPT patients were treated with biweekly infusions of Bortezomib
Palumbo et al. ASH 2008 (abstract 652) 19

20. VMPT vs VMP in elderly patients with newly diagnosed MM GIMEMA study
VMPT (N=177)
VMP (N=177)
P value CR
35%
21%
0.06
> VGPR
51%
42%
<
3 years
80%
78%
0.30
3 years
71%
56%
0.13
3 years
90%
89%
0.81
Palumbo et al. ASH 2008 (abstract 652)

21. VMP vs VMPT Grade 3-4 Hematologic Adverse Events
Palumbo et al. ASH 2008 (abstract 652)
% of patients

22. VMP vs VMPT Grade 3-4 Non Hematologic Adverse Events
% of patients
VMPT
VMP

23. Overview of planned and actual bortezomib doses in phase 3 trials
Study
Bortezomib schedule
Planned treatment
Actual bortezomib treatment received
Responses in VMP groups
VISTA
San Miguel et al. N Engl J Med 2008;359:906–17
Four 6-week cycles
1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32
Five 6-week cycles
1.3 mg/m2, d 1, 8, 22, 29
54 weeks:
52 bortezomib injections
Median number of treatment cycles administered: 8 (46 weeks) in VMP group:
48 injections
CR (IF-): 30%
CR + PR: 71%
VMPT vs VMP
Palumbo et al. ASH 2008 (abstract 652)
Not reported in abstract
All patients:
CR (IF-): 21%
CR + PR: 82%
Subgroup – bortezomib weekly:
CR (IF-): 20%
(CR + PR: not reported)
From March 2007:
Nine 5-week cycles
Bortezomib 1.3 mg/m2, d 1, 8, 15, 22
45 weeks:
36 bortezomib injections
VMP vs VTP
Mateos et al. ASH 2008 (abstract 651)
One 6-week cycle
1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, 32
Five 5-week cycles
1.3 mg/m2, days 1, 8, 15, 22
31 weeks:
28 bortezomib injections
CR (IF-): 22%
CR + PR: 81% 23

24. Phase I/II trial of MPR in newly diagnosed MM
Median age 71 years (range, 57–77)
Cohort
Lenalidomide, mg/day
Melphalan, mg/kg/day
Prednisone, mg/kg/day
1 (n = 6) 5
0.18 2
2 (n = 6)
0.25
3 (n = ) 10
4 (n = )
Lenalidomide
Melphalan
Prednisone
Day
In this phase I/II study 54 pts (median age 71 years) were enrolled to receive 9 cycles of lenalidomide (5-10 mg/day for 21 days) plus melphalan ( mg/kg for 4 days) and prednisone (2 mg/kg for 4 days) every 4 weeks followed by maintenance therapy with lenalidomide alone (10 mg/day for 21 days every month). Four different dose-levels were tested to define the maximum tolerated dose (MTD). Aspirin (100 mg/day) was administered as antithrombotic prophylaxis.
Lenalidomide 10 mg/day for 21 days and melphalan 0.18 mg/kg for 4 days monthly was defined as the MTD.
Every 4–6 weeks for maximum of 9 cycles.
Aspirin (100 mg/day) given as DVT prophylaxis.
MTD = Mel 0.18 mg/kg + Lenalidomide 10 mg/day
Palumbo A, et al. J Clin Oncol. 2007:25: 4459

25. Newly Diagnosed MM Patients MPR vs MPT: Response Rates
Cohort 3 ( )
Best Response
n=21
MPT
Best Response
n=129*
Proportion of patients
37% 70 60 50
48% 40 33 30
After MPR treatment, at the MTD, the best response was higher than in the historical
control treated with MPT. Notably in the MPR study, no stable or progressive disease
was reported, with all patients achieving at least a MR. 24 24 19
Proportion of patients 20 10 CR
VGPR PR MR SD PD
Palumbo A, et al. J Clin Oncol. 2007:25: 4459
*Historical control – Palumbo et al, Lancet 2006
5.4% of response not available

26. Newly Diagnosed MM Patients MPR vs MPT: EFS and OS
R-MP: median follow-up 14.6 months ( ) [N=53]
MPT: median follow-up 17.6 months ( ) [N=129]*
EFS OS
RMP
RMP
MPT
Proportion of patients
Proportion of patients
MPT
The 1-year EFS was 92.3% in the MPR group and 78% in the MPT group. The 1-year OS
was 100% in the MPR study and 87.4% in the MPT study.
Median follow up was similar in both groups: 14.6 months for MPR survivors and
17.6 months for MPT. Even though this comparison was not randomized, and these data
should be judged with caution, both EFS and OS in the MPR group showed
a borderline increase in comparison with the MPT group.
p=0.046
p=0.053
Months
Months
Palumbo A, et al. J Clin Oncol. 2007:25: 4459
*Historical control – Palumbo et al, Lancet 2006

27. Grade 3–4 Adverse Events Cohort 3 (0.18-10) vs MPT MPT [n=129]*
MPR [n=21]
Neutropenia
Thrombocytopenia
Anemia
Cutaneous
Infections
Cardiac
Thrombosis
Early deaths
% of patients
*Historical control, Lancet 2006

28. Conclusions Novel agents are changing the scenario in elderly
MPT and VMP have been shown to be superior over MP (and MEL100)
Initial results suggest a high efficacy for MPR
Response rates with novel agents in elderly patients are comparable to previous outcomes with ASCT in younger patients
Role of maintenance needs further studies

29. PAD induction plus reduced-intensity ASCT plus lenalidomide consolidation/maintenance in elderly patients
Patients (n=102)
aged 65–75 years
Treatment
Induction (four 21-day PAD cycles)
Bortezomib 1.3 mg/m2 days 1, 4, 8, 11
Pegylated-lyposomal-doxorubicin 30 mg/m2 day 4
Dexamethasone 40 mg days 1-4, 8-11, 15-18
Intensification: tandem Melphalan 100 mg/m2 (MEL100) + ASCT
Consolidation: 4 28-day LP cycles (Lenalidomide 25 mg days 1-21 plus, Prednisone 50 mg every other day)
Maintenance: Lenalidomide (10 mg days 1-21 every 28 day)
Palumbo et al. JCO 2009 (in press)

30. After LP Consolidation
Results
After PAD
After tandem MEL100 + ASCT
After LP Consolidation CR
13%
41%
53%
≥ VGPR
59%
88%
≥ PR
94%
Not available
100%
Median follow-up: 14 months
1-year PFS 92%
1-year TTP 97%
1-year OS 92%
PFS not significantly affected by β2-microglobulin levels (p=0.10), presence of chromosome 13 deletion (p=0.5) or t(4;14) (p=0.61)
Palumbo et al. JCO 2009 (in press)

31. Results Most frequent grade 3/4 adverse events
During PAD:
thrombocytopenia (13%)
neutropenia (11%)
infections (18%)
gastrointestinal toxicities (12%)
peripheral neuropathy (11%)
deep vein thrombosis (6%)
During LP consolidation:
neutropenia (18%)
thrombocytopenia (6%)
infections (6%)
deep vein thrombosis (6%)
PAD induction regimen followed by reduced-intensity ASCT, Lenalidomide as consolidation and maintenance is a highly effective regimen in elderly patients
Palumbo et al. JCO 2009 (in press)

32. Therapeutic Algorithm Level of Evidence 1b (> 1 Randomized Trial)
Diagnosis
> 65 years = TD MP
1 randomized trial
>
MPT MP
5 randomized trials
On the basis of these recently results we can now change the therapeutic algorithm for elderly myeloma patients. MP remains the starting point for the development of combination therapies. Five randomized studies strongly support the use of MPT as the current standard of care for older patients. Preliminary results from the VISTA trial are encouraging for the VMP combination, while the MPR regimen is still under evaluation in a larger international randomized phase III trials. The results of these ongoing trials will likely define the new standard for elderly myeloma patients.
>
MPV MP
1 randomized trial
MPR MP
under evaluation

33. Factors Affecting Preference for MP–Novel Combination*
Consolidate data MPT
Antecedent or risk of DVT MPV
Antecedent PN MPR
Renal insufficiency MPV
Distance from hospital MPR or MPT
Poor patient accomplishment MPV
Cost MPT
Factors Affecting Preference for MP–Novel Combination
Choice of MPT, MPV, or MPR may be influenced by several factors
MPT has the largest dataset demonstrating benefit and has the lowest cost
MPV may be considered for patients with a history or risk of DVT, those with renal insufficiency, or those with poor patient accomplishment. “Patient accomplishment” refers to those patients who, due to cultural or psychological conditions, may not take the medicines appropriately at home
MPR may be considered for patients with antecedent peripheral neuropathy
Oral thalidomide or lenalidomide (MPT or MPR) may be preferable to IV bortezomib (MPV) for patients who live a distance from the hospital
The duration of treatment peraphs could be reduced from the standard 12 months of MP to 6 cycles of these more active combinations
San Miguel JF. Presented at: 11th International Myeloma Workshop; June 25–30, 2007; Kos, Greece
*Duration of treatment: 6 cycles
San Miguel JF. Presented at: 11th International Myeloma Workshop; June 25–30, 2007; Kos, Greece

34. EMN01
Newly diagnosed symptomatic MM patients ≥ 65 years of age or younger not eligible for SCT
INDUCTION
660 pts
ARM A (220 pts)
Rd X 9 courses
ARM B (220 pts)
MPR X 9 courses
ARM C (220 pts)
CPR X 9 courses
Maintenance
Maintenance
Maintenance
ARM A1 R
ARM A2 RP
ARM B1 R
ARM B2 RP
ARM C1 R
ARM C3 RP