Multiple Myeloma:

1
Multiple Myeloma

• Upfront studies

Antonio Palumbo
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Levels of Evidence/Grades of Recommendation
Levels of Evidence Levels of Evidence
Ia Evidence obtained from meta-analysis of randomised controlled trials
Ib Evidence obtained from ?1 randomised controlled trial
IIa Evidence obtained from ?1 well-designed, non-randomised study, including phase II trials and case control studies
IIb Evidence obtained from ?1 other type of well-designed, quasi-experimental study, ie, studies without planned intervention, including observational studies
III Evidence obtained from well-designed, non-experimental descriptive studies. Evidence obtained from meta-analysis, randomised controlled trials, or phase II studies which are published only in abstract form
IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
Grades of Recommendation Grades of Recommendation
Grade A Evidence level Ia, Ib
Grade B Evidence level IIa, IIb, III
Grade C Evidence level IV
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Transplant

• Patients lt 65 years

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Total Therapy (TT) Trials Treatment Schema
Phase TT1 TT2 TT3
Randomization ? Thal (400 mg/day) ?
Induction
ASCT 1 MEL200 MEL200 MEL200
ASCT 2 MEL200 MEL140 TBI if ltPR MEL200 BEAM if ltPR MEL200
Consolidation None DCEP/CAD VDT-PACE
Maintenance IFN-a IFN-a ( D in 1st yr) 1st yr with VTD 2nd yr with TD
Barlogie B et al. Blood. 19999355 Shaughnessy
J Jr et al. Br J Haematol. 200312044 Barlogie
B et al. Blood. 2005106337a abstract 1154
5
TT1 vs TT2 (No Thal) Response
Parameter TT1, TT2 (Thal), P Value
n 231 345
CR, 43 41 NS
5-yr cont CR, 45 32 lt0.001
5-yr EFS, 43 28 lt0.001
5-yr OS, 62 57 0.11
Median f/u, yr 11.5 3.5
Barlogie B et al. Blood. 19999355 Shaughnessy
J Jr et al. Br J Haematol. 200312044 Barlogie B
et al. Blood. 20061072633
6
TT2
Response Thal Thal P value
n 345 323
CR, 43 62 lt0.001
5-yr EFS, 44 56 0.01
5-yr OS, 63 68 0.90
Overall SAEs gtGrade 2 Thal () Thal () P value
n 337 314
DVT or PE, 17 30 lt0.001
Syncope 44 56 lt0.001
Peripheral neuropathy 17 27 lt0.001
Barlogie B et al. New Engl J Med. 20063541021
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TT3 vs TT2 Thal
Parameter TT3 (n162) TT2 ( Thal) (n323) P Value
Median time to completion of 1st transplant, mo 3 5 lt0.001
Median time to completion of 2nd transplant, mo 5 10 lt0.001
Completed 1st transplant, 92 89 NS
Completed 2nd transplant, 78 68 0.028
Probability of nCR at 12 mo, 81 64 0.001
Median number CD34/kg (? 106) 27 20 lt0.001
Treatment-related mortality at 12 mo 4 6 NS
TT3 vs TT2 Thal Significantly less DVT,
febrile neutropenia, somnolence, PN, and
dizziness, but significantly more anorexia and
renal insufficiency
Barlogie B et al. Blood. 2005106337a abstract
1154
8
New Drugs as induction for Autologous /
Allogeneic transplant

• VDT-PACE as induction regimen
• stem cell mobilization after Cycle 1
• stem cell collection after 1 VTD-PACE gt2 VTD
  PACE
• TT3 compares favorably to TT2 as historical
  control
• nCR 16 after 1 cycle VTD-PACE
• nCR 26 after 2 cycles VDT-PACE
• nCR 40 after first MEL200
• nCR 80 after second MEL200
• Estimated CR rate 80 for TT3 (MEL200 Tal
  Vel)
• 60 for TT2 (MEL200 Tal)
• 40 for TT1 (MEL200)

Bartlogie et al. ASH 2004 Abstract 538
9
Autologous followed by Allogeneic Transplantvs
Tandem Autologous transplant
Autologous Auto-Allogeneic
Transplant-related mortality 4 11
Complete Remission 26 54
Progression-free survival _at_ 3 yrs 41 75
Overall survival _at_ 3 yrs 58 83
Bruno B, Blood. 200510618a, abstract 46.
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Maintenance With Thalidomide AfterASCT for MM
(IFM 99-02)
mo 3Randomized if no progression (n593 as of
6/05)
Arm A No maintenance therapy(n200)
Patients with stage 1, 2, or 3 MM lt65 yr oldNo
prior therapy 0 or 1 risk factor (n780)
VAD regimen (vincristine, doxorubicin, and
dexamethasone) 34 cycles
Melphalan,140 mg/m2, and ASCT
Melphalan,200 mg/m2and ASCT
Arm B Pamidronate, 90 mg/mo(n196)
Arm C Pamidronate, 90 mg/mo Thalidomide, 100
mg/day (n201)
Attal M et al. Blood. 2005106335a abstract
1148
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IFM 99-02 Results
Endpoint Arm A No Maintenance Arm B Pam Arm C Thal/Pam P Value
Patients, n 200 196 201
Response Rate ?90,
After VAD 15 15 16
At randomization 45 47 50
After randomization 55 57 68 0.03
Events, 48 47 36 0.04
Median EFS, mo 38 38 gt48
4-yr EFS, 37 35 50 0.003
4-yr OS, 78 74 87 0.04
P0.01 for arm B vs arm C Attal M et al. Blood.
2005106335a abstract 1148
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Standard treatment

• Patients gt 65 years

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MP vs Dexamethasone-Based Regimens (IFM 95-01
Trial)

• 488 patients aged 65-75 yr randomised 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. 2005 Sep 20 Epub ahead of
print
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Thalidomide
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Thalidomide/Dexamethasone vs Dexamethasone in
Newly Diagnosed MM
Phase III ECOG E1A00 Study Design
CR/PR/stable
Newly diagnosed MM (n207)
? 4 cycles
Any progression
Administered as 4-wk cycle All patients received
monthly pamidronate or zoledronic acid No DVT
prophylaxis Rajkumar SV et al. J Clin Oncol.
200624431
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Thalidomide/Dexamethasone vs Dexamethasone Best
Response Within 4 Cycles
Endpoint Thal/Dex (n99) Dex (n100)
Response rate, 63 41
Adjusted response rate, 72 50
CR, 4 0
Median time to response (range), mo 1.1 (0.74.1) 1.1 (0.72.9)
Disease progression within first 4 mo, 2 5
P0.0017
Based on ITT, ?50 reduction in serum and urine
M protein, or ?90 reduction in urine M protein
if only urinary protein was evaluable for
response Allowing for use of serum M protein
when a measurable urine M protein was unavailable
at follow-up Rajkumar SV et al. J Clin Oncol.
200624431
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Thalidomide/Dexamethasone vs Dexamethasone
Specifically Monitored Adverse Events
Adverse Event Thal/Dex, n () (n102) Dex, n () (n102) P value
DVT grade 3 17 (17) 3 (3) lt0.001
Rash grade 3 4 (4) 0 (0)
Sinus bradycardia grade 3 1 (1) 0 (0)
Neuropathy grade 3 7 (7) 4 (4)
Any toxicity grade 4 35 (34) 18 (18)
Total 46 (45) 21 (21) lt0.001
Deaths within 4 cycles Thal/Dex, 7 Dex, 11
Rows do not add to total as patients could have
more than 1 of these adverse events Rajkumar SV
et al. J Clin Oncol. 200624431
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MPT vs MP in Elderly Patients With MM
Phase III Randomized, Controlled Trial
MPT arm (median age 72) Melphalan, 4 mg/m2 (7
days/mo) Prednisone, 40 mg/m2 (7
days/mo) Thalidomide, 100 mg/d (continuously)
(n129)
Newly diagnosed MM patients, aged gt65 yr (n255)
? ? 6 courses
MP arm (median age 72) Melphalan, 4 mg/m2 (7
days/mo) Prednisone, 40 mg/m2 (7 days/mo) (n126)
Thalidomide dose reduced to 50 if grade 2
toxicity enoxaparin prophylaxis added to
protocol December 2003 No. of patients with 6
mo follow-up Palumbo A et al. Lancet. 2006367825
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MPT vs MP in Elderly Patients With MM Response
Response MPT, (n129) MP, (n126) P Value
CR nCR 27.9 7.2
CR 15.5 2.4
nCR 12.4 4.8
PR 60.4 45.2
ORR 76.0 47.6
2-yr EFS 54 27 0.0006
3-yr OS 80 64 NS
gt936 mo 89 70 0.03
PR (gt50), nCR (IF), CR (IF)
Palumbo A et al. Lancet. 2006367825
20
MPT vs MP in Elderly Patients With MM
Event-Free Survival and Overall Survival
EFS 49 ? in risk of event for MPT
OS 65 ? in risk of death at gt9 mo for MPT
1.0
09
MPT
08
MP
07
06
Proportion of Patients
05
04
03
02
HR 0.68 (95 CI 0.381.22) P0.19
01
0
6
0
12
18
24
12
18
24
0
6
30
Months
Months
Number at risk
Number at risk
MPT
129
106
70
43
26
MPT
129
111
79
52
38
20
MP
126
97
49
21
111
72
42
27
10
MP
126
13
Adapted with permission from Palumbo A et al.
Lancet. 2006367825
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MPT vs MP in Elderly Patients With MM Grade 3/4
AEs
P0.001
P0.001
P0.01
Patients,
Palumbo A et al. Lancet. 2006367825
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MPT in Elderly Patients With MM Thromboembolic
Events

• MPT with no prophylaxis (n65)
• 56.9 (37/65) grade 3/4 adverse events
• 16.9 (11/65) thromboembolism
• MPT enoxaparin (40 mg/day for 4 mo) (n64)
• 39.1 (25/64) grade 3/4 adverse events
• 3.1 (2/64) thromboembolism
• Both patients had evidence of thromboembolism
  within 2 mo of discontinuing enoxaparin

P0.042 comparing MPT with MP P0.005
comparing MPT with MP
Palumbo A et al. Lancet. 2006367825
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MP vs MPT and MP vs Mel 100 in Newly Diagnosed
Elderly MM Patients
IFM 99-06 Trial Design
MP arm (n191) Standard MP 12 courses at 6-wk
intervals
3
2
MPT arm (n124) MP Arm Thal at MTD but ?400
mg/day, stopped at end of MP
Newly diagnosed MM patients 6575 yr (N436 as
of 5/05)
1o endpoint OS
2
MEL 100 arm (n121) VAD ? 2 cyclophosphamide 3
g/m2 G-CSF PBSC harvest (melphalan, 100 mg/m2
PBSC G-CSF) ? 2
All patients received clodronate Facon T et al.
Blood. 2005106230a abstract 780
24
MP vs MPT and MP vs Mel 100 in Newly Diagnosed
Elderly MM Patients Response
MPT
PFS
OS
MP
MEL 100
Fraction
Fraction
Time From Inclusion, mo
Time From Inclusion, mo
Treatment PFS, mo P value OS, mo P value
MP 17.2 1.5 30.3 5.8
MPT 29.5 3.6 gt56
MEL 100 19.0 1.3 38.6 3.0
lt0.0001
0.0008
0.0001
0.014
Third interim analysis (May 1, 2005) median
follow-up time (SEM) 32.21.8 mo Facon T et
al. Blood. 2005106230a abstract 780
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Lenalidomide
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Lenalidomide and Dexamethasone for Newly
Diagnosed MM Response
EBMT Response Category No. of Responders, n ()
PR 31 (91)
CR 2 (6)
nCR/VGPR 11 (32)
PR 18 (53)
MR 2 (6)
SD 1 (3)
Adequate stem cells were obtained in all patients
who underwent ASCT
n34
Rajkumar SV et al. Blood. 20051064050
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Phase II Trial of Lenalidomide and Dexamethasone
for Newly Diagnosed MM
SCT planned off treatment
CR/PR/Stable at 4 mo
Lenalidomide 25 mg/day days 121, 28-day cycle
Dex 40 mg/day days 14, 912, 1720, 28-day
cycle Aspirin daily for DVT prophylaxis
Newly diagnosed MM (n34)
No SCT remain on treatment at MD discretion
Progressive disease off treatment
Progressively reduced for AEs to 15, 10, and 5
mg Progressively reduced for AEs to 40 mg/day
for 4 days q 2 wk, 40 mg/day for 4 days q 4 wk,
and 20 mg/day for 4 days q 4 wk 80 mg/day or 325
mg/day at MD discretion

Rajkumar SV et al. Blood. 20051064050
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Phase I/II Trial of Lenalidomide, Prednisone,and
Melphalan (RMP) in Newly Diagnosed MM
Median age 71 yr ( range, 5777)
Cohort Melphalan (mg/kg/day) Lenalidomide (R) (mg/day) Prednisone (mg/kg/day)
1 (n6) 0.18 5 2
2 (n6) 0.25 5 2
3 (n21) 0.18 10 2
4 (n21) 0.25 10 2
day
1 2 3 4
21
Melphalan
Prednisone
Lenalidomide
q 46 wk for maximum of 9 cycles ASA (100 mg/day)
given as DVT prophylaxis
Palumbo A et al. Blood. 2005106231a abstract
785
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RMP in Newly Diagnosed Patients Response vs MPT
N37
N76
N20
N76
of patients
60
63
51
33
10
1CR
Cycle 1
Cycle 3
Palumbo A et al. Oral presentation at ASH Annual
Meeting December 10-13, 2005 Atlanta, GA
30
RMP in Newly Diagnosed Patients Toxicities
Grade 3 toxicities seen in cohorts 3 and 4 only
Hematologic
Non-hematologic
Cohort 3 (0.18/10) (n21)
Cohort 4 (0.25/10) (n17)
Palumbo A et al. Presented at ASH Annual
Meeting December 10-13, 2005 Atlanta, GA
31
Bortezomib
32
(No Transcript)
33
Reduced Dose PAD Combination TherapyNewly
Diagnosed Patients

• Patients n20
• Treatment Induction 4, 21 day cycles prior to
  transplant
• Bortezomib 1.0 mg/m2 days 1,4, 8, 11
• Adriamycin 9 mg/m2 IV push days 1-4
• Dexamethasone 40 mg PO - Cycle 1 d 1-4, 8-11,
  15-18
• Cycle 2 4 d 1-4
• PBSC harvested followed by HD Mel (MEL200) and
  PBSCT

Popat R, et al. ASH 2005,Abstract 2554
1Oakervee et al., Br J. Haematol 2005 129 755-762
SLIDE 33
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Study of VTD in Newly Diagnosed MM Followed by
Early Intensive Therapy

• T 100 mg/day ? q 7 days to 200 mg/day, D 20
  mg/m2 days14, 912, and 1720, bortezomib (V)
  1.3 mg/m2 (15 patients), 1.5 mg/m2 (11 patients)
  and 1.6 mg/m2 (10 patients)
• LMWH or warfarin to keep INR between 2.0 and 3.0
• Response rates
• Stringent criteria (gt75 ? in serum M protein
  and/or gt99 ? in urine M protein) was 78 (19
  CR)
• Standard criteria (gt50 ? in serum M protein
  and/or gt90 ? in urine M protein) was 92
• 30 higher by either criteria with VTD than TD
  (Plt0.01)
• No added benefit of bortezomib gt1.3 mg/m2
• Side effects were mild and reversible (DVT in 2
  patients, grade 3 neuropathy in 3 patients,
  serious infections in 3 patients)
• After median of 4 mo, HDT-supported ASCT
  successful in 22 patients
• Primary resistant disease responsive in 4/6
  patients
• PR converted to CR in 3/13 patients
• 3 patients intensified in CR

Wang M et al. Blood. 2005106231a abstract 784
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Phase I/II Study of V-MP in Untreated MM
Patients ?65 yr
n60 median age 74 (range, 6585)
day
1 2 3 4 5 8 11
22 25
29 32
B
B
B
B
B
B
B
B
Melphalan
9 mg/m2
Prednisone
60 mg/m2
Four 6-wk cycles followed by five 5-wk cycles 2
sequential doses of B (1.0 and 1.3 mg/m2) tested
(6 patients each) to define MTD in combination
with MP. Expanded at MTD to 60 patients. 53
evaluable for response
Toxicity, Grade 3 Grade 4
Neutropenia 26 13
Thrombocytopenia 33 13
Infection 12 2
Peripheral neuropathy 13 2
of patients
Mateos MV et al. Blood. 2005106232a abstract
786
36
Bortezomib, Melphalan, Prednisone, and
Thalidomide (V-MPT) in Advanced MM
Median age 68 (range, 3879)
Cohort Melpahalan (mg/m2) po Prednisone (mg/m2) po Thalidomide (mg/day) po Bortezomib (mg/m2) IV
1 (n10) 6 60 100 1.0
2 (n10) 6 5 100 1.3
3 (n10) 6 10 100 1.6
day
1 2 3 4 5
15 22
35
Melphalan
Prednisone
Thalidomide
q 35 days for 6 cycles
DLT grade 4 neutropenia for 7 days grade 4
other hematologic grade 3 non-hematologic
Palumbo A et al. Blood. 2005106717a abstract
2553
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Phase III trial Study Design
Day 1 cycle 3
28 days after CTX
60 days after MEL200
Blood Samples for coagulation study
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Phase III Study Design
9 V-MP courses
No maintenance
250 pts
random
diagnosis
Maintenance with Velcade and Thalidomide
9 V-MPT courses
250 pts
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Treatment Schedule

• Induction nine 6-week courses

1 2 3 4 8 11
22 25 29
32 42
Velcade 1.3 mg/sqm biweeky couses 1-4 weekly
courses 5-9
Melphalan 9 mg/sqm
Prednisone 60 mg/sqm

• Maintenance

Thalidomide 50 mg daily continuously Velcade
1,3 mg/sqm/2 weeks.
No maintenance therapy is scheduled for patients
randomized to control arm
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Phase III Study Design
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Treatment Administrated
Drug Dose Duration Duration
gt 65 yr lt 65 yr
Enoxaparin 40 mg/day 6 months 9 weeks (or until Thal will be administered)
Warfarin 1.25 mg/day 6 months 9 weeks (or until Thal will be administered)
Cardioaspirin 100 mg/day 6 months 9 weeks (or until Thal will be administered)
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Phase III Study Design
4 PAD courses
2 CY courses
2 MEL100 courses
Maintenance with Revlimid
Consolidation with Revlimid and Prednisone
43

Treatment Schedule

• Induction 4 PAD courses

1 4 8 11 15
18
28
Peg-Doxorubicine 30mg/sqm
Velcade 1.3 mg/sqm
Dexamethasone 40 mg QD
Cycle 1
Cycle 1
Cycle 1-4

• Consolidation 4 28 days RP courses (within 6
  months after ASCT)

1
21
28
Revlimid 25 mg QD
Prednisone 50 mg each other day

• Manteinance R 28-days courses until
  progression

Revlimid 10 mg QD
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GIMEMA ongoing trials
lt 60 years
60-70 years
gt 65 years
Dexamethasone Velcade Thalidomide CY PBPC
Dexamethsone Doxorubicin Velcade
9 cycles MP Velcade Thalidomide
No Transplant
MEL 100 ASCTransplant
MEL 200 ASCTransplant
Dexamethasone Velcade Talidomide
Lenalidomide Dexamethasone
Talidomide Velcade