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                                                            The Mediterranean School ofOncology
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, 20-21 Novembre, 2009
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Multiple Myeloma
ASL TORINO 902.000 people
INCIDENCE 1974 5.9/100.000 2002
8.9/100.000Median age at diagnosis 69.4
years
Regione Piemonte, Assessorato Sanità 2006,15
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Survival outcomes for multiple myeloma
Age at diagnosis Years Mortality Ratio
Increased ratio 0-40 1.00 (ref.) 41-50
1.27 27 51-60 1.50 18 61-70 1.96
31 71-80 2.42 23 81 3.40 40
60 years ? 4-year survival 70 years ? 3-year
survival
Kristinsson SY, et al. J Clin Oncol.
2007251993-9.
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OS From Time of Diagnosis in 6-yr Intervals
Based on Date of Diagnosis
Kumar SK et al. Blood. 2008 111 2516
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MP vs Dexamethasone-Based Regimens (IFM 95-01
Trial)

• 488 patients aged 65-75 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 109 110 109 101
PR? (Plt0.001) 51 74 40 42
CR (PNS) 1 3 1 1
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
Plt0.001 for pts not receiving Melphalan
Facon T et al. Blood. 2006 1071292
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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 14, 1518
  even d 14),
• Melphalan 0.25 mg/kg/d (d 14) prednisone 2
  mg/kg, d 14, q 46 wks

Ludwig H, et al. Blood. 2009 13(15)3435-42.
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Summary of MPT phase 3 trials in the upfront
setting
Regimen n CRPR () 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 1123107-14
Thal/MP vs MP vs MEL 100 191 124 121 76 35 65 13 2 18 27.5m 17.8m 19.4m 51.6m 33.2m 38.3m Facon, et al.Lancet 2007 370120918
Thal/MP vs MP (gt75y) 113 116 62 31 7 1 24.1m 19m 45.3m 27.7m Hulin, et al.J Clin Oncol 2009 273664-70
Thal/MP vs MP 363 total 42 28 6 3 20m 18m 29m 33m Gulbrandsen et al. EHA 2008 (Abstract 209)
Thal/MP vs MP 152 149 66 47 2 2 EFS 13m vs 9m PFS 13m vs 10m 37m 30m Wijermans et al. ASH 2008 (Abstract 649)
CR nCR
Thal doses 200400 mg
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.
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Grade 3-4 Adverse Events
P .0002
P .0001
P .03
P .009
P .006
MPT 4 infection, 2 cardiac, 3 progression
MP 1 infection, 1 progression
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MRC Myeloma IX study

• 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)
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Efficacy
  CTDa (n120) MP (n113)
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

Although thalidomide maintenance may improve PFS,
there is no demonstrable benefit on OS
Morgan et al. ASH 2007 (Abstract 3593)
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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 ß2-microglobulin, albumin, region

VMP Cycles 14 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 14 Cycles 59 Bortezomib
1.3 mg/m2 IV d 1,8,22,29 Melphalan 9 mg/m2 and
prednisone 60 mg/m2 d 14
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 19 Melphalan 9 mg/m2 and prednisone
60 mg/m2 d 14
San Miguel et al. N Engl J Med 200835990617
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VISTA New Engl J Med data
Responses according to EBMT criteria1
Time to progression
100
VMP n337 MP n331 p-value
ORR (PR) 71 35 lt10-6
CR 30 4 lt10-6
PR 40 31
MR 9 22
SD 18 40
90
80
70
60
50
40
30
20
10
0
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 lt10-10
Time to CR 4.2 5.3 lt10-10
Median DOR, months
All responders 19.9 13.1
Patients achieving CR 24.0 12.8
Medians shown for responding patients p-values
based on total study population
1. Bladé et al. Br J Haematol 19981021115-23.
San Miguel et al. N Engl J Med 200835990617
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VISTA Overall Survival36 reduced risk of
death on VMP
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
0.0032
San Miguel et al. ASH 2008 (abstract 650)
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VISTA Update ASH 2008
VMP MP
Time to next therapy 28.1 months 19.2 months HR0.53, Plt0.000001
Treatment-free interval 16.6 months 8.4 months HR0.54, Plt0.00001

• Subsequent therapy
• Patients can be successfully treated with
  subsequent immunomodulatory-based therapy and can
  also be retreated with bortezomib (CR 4-10 PR
  44-55)

VMP MP
Bortezomib 16 43
Thalidomide 49 44
Lenalidomide 19 6
San Miguel et al. ASH 2008 (abstract 650)
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VISTA Adverse events
VMP (n340) VMP (n340) MP (n337) MP (n337)
AE, Grade 3 Grade 3 Grade 4 Grade 3 Grade 4
Neutropenia 29 29 11 23 15
Thrombocytopenia 20 20 18 16 15
Anemia 16 16 3 20 8
GI 19 19 1 5 0
Peripheral sensory neuropathy 13 13 lt1 0 0
Fatigue 7 7 1 2 0
Asthenia 6 6 lt1 3 0
Pneumonia 5 5 2 4 1
Herpes zoster 4 4 0 2 0

• 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)
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VMP vs VTP in newly diagnosed elderly patients
with MMPETHEMA/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, N260 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 14 Cycles 2-6 (5-week
cycles) Bortezomib 1.3 mg/m2 IV d
1,8,15,22 Melphalan 9 mg/m2 and prednisone 60
mg/m2 d 14
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 14 Cycles 2-6
(5-week cycles) Bortezomib 1.3 mg/m2 IV d
1,8,15,22 Thalidomide 100 mg/d and prednisone 60
mg/m2 d 14
Mateos et al. ASH 2008 (abstract 651)
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VMP vs VTP in newly diagnosed elderly patients
with MMPETHEMA/GEM study
VMP (n130) VTP (n130)
ORR 81 81
CR IF- 22 27
CR IF 19 10
PR 40 44
Median time to first response 1.6 months 1.6 months
Median time to CR 4.4 months 4.9 months
2-year TTP 72 68
2-year OS 90 90
Mateos et al. ASH 2008 (abstract 651)
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VMP vs VTP in newly diagnosed elderly patients
with MMPETHEMA/GEM study
G3 Adverse events VMP (n80) VTP (n87) P
Neutropenia 34 19 0.009
Thrombocytopenia 21 9 0.01
Non-hematological AEs 25 32 0.04
Cardiac toxicity 0 7
Thromboembolic events lt1 4
Peripheral neuropathy 5 9
Treatment discontinuation 8 17
Deaths 4 4

• 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)
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VMPT vs VMP in elderly patients with newly
diagnosed MMGIMEMA 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 lt65 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
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)
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VMPT vs VMP in elderly patients with newly
diagnosed MMGIMEMA study
VMPT (N177) VMP (N177) P value
CR 35 21 0.06
gt VGPR 51 42 lt 0.0001
TTNT _at_ 3 years 80 78 0.30
PFS _at_ 3 years 71 56 0.13
OS _at_ 3 years 90 89 0.81
Palumbo et al. ASH 2008 (abstract 652)
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VMP vs VMPTGrade 3-4 Hematologic Adverse Events
VMPT
VMP
of patients
Palumbo et al. ASH 2008 (abstract 652)
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VMP vs VMPTGrade 3-4 Non Hematologic Adverse
Events
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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 200835990617 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) 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 Not reported in abstract All patients CR (IF-) 21 CR PR 82 Subgroup bortezomib weekly CR (IF-) 20 (CR PR not reported)
VMPT vs VMP Palumbo et al. ASH 2008 (abstract 652) From March 2007 Nine 5-week cycles Bortezomib 1.3 mg/m2, d 1, 8, 15, 22 45 weeks 36 bortezomib injections Not reported in abstract All patients CR (IF-) 21 CR PR 82 Subgroup bortezomib weekly CR (IF-) 20 (CR PR not reported)
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 Not reported in abstract CR (IF-) 22 CR PR 81
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Phase I/II trial of MPR in newly diagnosed MM
Median age 71 years (range, 5777)
Cohort Lenalidomide, mg/day Melphalan, mg/kg/day Prednisone, mg/kg/day
1 (n 6) 5 0.18 2
2 (n 6) 5 0.25 2
3 (n 6 15) 10 0.18 2
4 (n 6 15) 10 0.25 2
Every 46 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. 200725 4459
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Newly Diagnosed MM Patients MPR vs MPT Response
Rates
MPR Cohort 3 (0.18-10) Best Response n21
MPT Best Response n129
70
60
50
48
40
33
30
24
24
19
Proportion of patients
20
10
0
0
0
CR
VGPR
PR
MR
SD
PD
Historical control Palumbo et al, Lancet 2006
5.4 of response not available
Palumbo A, et al. J Clin Oncol. 200725 4459
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Newly Diagnosed MM Patients MPR vs MPT EFS and
OS
R-MP median follow-up 14.6 months (10.8-21.8)
N53
MPT median follow-up 17.6 months (0.23-44.3)
N129
OS
EFS
RMP
RMP
MPT
MPT
Proportion of patients
Proportion of patients
p0.046
p0.053
Months
Months
Historical control Palumbo et al, Lancet 2006
Palumbo A, et al. J Clin Oncol. 200725 4459
27
Grade 34 Adverse Events Cohort 3 (0.18-10) vs
MPT
MPR n21
MPT n129
Neutropenia
Thrombocytopenia
Anemia
Cutaneous
Infections
Cardiac
Thrombosis
Early deaths
of patients
Historical control, Lancet 2006
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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

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PAD induction plus reduced-intensity ASCT plus
lenalidomide consolidation/maintenance in elderly
patients

• Patients (n102)
• aged 6575 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)
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Results
After PAD After tandem MEL100 ASCT After LP Consolidation
CR 13 41 53
VGPR 59 88 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
  ß2-microglobulin levels (p0.10), presence of
  chromosome 13 deletion (p0.5) or t(414)
  (p0.61)

Palumbo et al. JCO 2009 (in press)
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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)
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Therapeutic AlgorithmLevel of Evidence 1b (gt 1
Randomized Trial)
Diagnosis
gt 65 years

1 randomized trial
MP
TD
gt
5 randomized trials
MP
MPT
gt
MPV
MP
1 randomized trial
MPR
MP
under evaluation
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Factors Affecting Preference for MPNovel
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

Duration of treatment 6 cycles
San Miguel JF. Presented at 11th International
Myeloma Workshop June 2530, 2007 Kos, Greece
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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