Multiple Myeloma: Where are we heading with novel agents

1
Multiple Myeloma Where are we heading with
novel agents?

• Dr Graham Jackson
• Royal Victoria Infirmary, Newcastle Upon Tyne

2
Combinations therapies in Multiple Myeloma

• Treatment Opportunities

induction
relapse
M-COMPONENT
High-dose
remission
3
1st line Multiple Myeloma therapy
4
Thalidomide in 1st line Multiple Myeloma therapy
5
GIMEMA - Newly diagnosed MM gt65 yrs
MPT (n129) Melphalan 4mg/m2 on days 1-7/month
for 6 courses Prednisone 40mg/m2 on days
1-7/month for 6 courses Thalidomide 100mg/day
continuously until relapse
Randomise
Patients with newly diagnosed Multiple Myeloma
N255
MP (n126) Melphalan 4mg/m2 on days 1-7/month for
6 courses Prednisone 40mg/m2 on days 1-7/ month
for 6 courses
Palumbo A et al. Lancet 2006 367825-831.
6
MPT in Elderly Patients With MM Response
MP, (n126)
P value
MPT, (n129)
Response
lt0.001
7
28
CR nCR
2
16
CR
5
12
nCR
45
60
PR
47
lt0.001
76
ORR
lt0.001
13.6
29.2
Median EFS mths
NS
64
80
OS at 36 mths
PR (gt50), nCR (IF), CR (IF-)
Palumbo A et al. Blood. 2005106 abstract 779
7
MPT vs MP in Elderly MM Patients Event-Free and
Overall Survival
Adapted with permission from Palumbo A et al.
Lancet 2006 367 825
8
IFM 99-06 Newly diagnosed MM 65-75 years
MP (n191) 12 Courses at 6-week intervals
3
Randomise
Patients with untreated, symptomatic Multiple
Myeloma N436
MP-Thal (n124) MP Thal at the maximum
tolerated dose, but lt400mg/day
2
MEL 100-based treatment (n121) VADx2, CTX 3mg/m2
and 2 courses of MEL 100mg/m2
2
All patients received Clodronate Melphalan 0.25
mg/kg Prednisone 2 mg/kg
Facon et al. Lancet 2007 370 1209-18
9
IFM 99-06
PFS
OS
1
1
MP-T vs MP, Plt0.0001 MP-T vs MEL100, Plt0.0002
MP-T vs MP, P0.0006 MP-T vs MEL100, P0.02
0.8
0.8
0.6
0.6
Proportion of surviving patients
Proportion of progression-free surviving patients
0.4
0.4
0.2
0.2
0
0
0
12
24
36
48
60
72
0
12
24
36
48
60
72
84
Time from randomization (month)
Time from randomization (month)
Facon et al. Lancet 2007 370 1209-18
10
IFM 01-01 Newly Diagnosed MM Pts gt75 yrs
gt75y (med 78.4y) Newly Diagnosed
MPPlacebo
12 courses, 6 weekly
MPThal 100mg
n150
n200
Melphalan 0.2 mg/kg/d Day 1-4 Prednisone 2
mg/kg/d Day 1-4
Interim Analyses
Clodronate was given to all pts No
anti-coagulant prophylaxis was given
11
IFM 01-01 Progression-Free Survival (PFS) and
Overall Survival (OS)
200 Pts, Median follow-up time 24 months
PFS
OS
Survival Distribution Function
Survival Distribution Function
Time from randomization (months)
Time from randomization (months)
Log-Rank test p0.001
Log-Rank test p0.05
12
MP vs. MPT
IFM best response at 12 months GIMEMA response
after 6 months nCr
Palumbo et al. Lancet 2006367825-831 Facon et
al. Lancet 20073701209-1218 Hulin, ASCO 2007
13
Myeloma IX responses intensive arm
14
Bortezomib in 1st line Multiple Myeloma therapy
15
VISTA Assessment with melphalan and prednisone
VMP Cycles 1-4 Bortezomib 1.3mg/m² IV days 1,
4, 8, 11, 22, 25, 29, 32 Melphalan 9mg/m² and
prednisone 60mg/m² days 1-4 Cycles 5-9
Bortezomib 1.3mg/m² IV days 1, 8, 22,
29 Melphalan 9mg/m² and prednisone 60mg/m² days
1-4
RANDOMI ZE
9 x 6-week cycles (54 weeks) in both arms
MPCycles 1-9 Melphalan 9mg/m² and prednisone
60mg/m² days 1-4

• In MM patients previously untreated who were not
  candidates for HDT-ASCT
• Patients Symptomatic MM/ end organ damage with
  measurable disease
• 65 yrs or lt65yrs and not transplant eligible

Weber D. Protocol CC-5013-MM-009. Dimopoulos M.
Protocol CC-5013-MM-010.
16
VISTA Response to Treatment
measured in serum or urine by centralised
laboratory
Bladé et al. Br J Haematol 1998 1021115-23
17
VISTA Time to progression
18
VISTA Overall Survival
19
VISTA Grade 3/ 4 Adverse Events ()
20
Lenalidomide Studiesin 1st line Multiple Myeloma
21
SWOG-S0232 lenalidomide plus dexamethasone in
newly diagnosed MM
Induction therapy
Maintenance therapy
Repeat courses every 35 days up to 3 courses in
the absence of PD or unacceptable toxicity
If PR, CR, SD on induction, repeat courses every
28 days until progression/relapse
Lenalidomide 25 mg/day p.o., days
128 Dexamethasone 40 mg/day p.o., days 14,
912, 1720 (n 250)
Lenalidomide 25 mg/day p.o., days
121 Dexamethasone 40 mg/day p.o., days 14, 1518
Newly diagnosed, untreated MM (N 500)
PD (unblinded induction)
PD (unblinded induction)
Placebo 25 mg/day p.o., days 128 Dexamethasone
40 mg/day p.o., days 14, 912, 1720 (n 250)
Placebo p.o., days 121 Dexamethasone 40 mg/day
p.o., days 14, 1518
End-points progression-free survival, response
rate, overall survival.
National Cancer Institute. www.cancer.gov/search/V
iewClinicalTrials.aspx?cdrid 306449versionHealt
hProfessionalprotocolsearchid1341055.
22
SWOG S0232 Response Rate
85
plt0.002

55
22
4
JA Zonder et al. Blood 2007110(11)Abstract 77.
gt 75 reduction in M-Protein
23
S0232 Progression Free Survival
Len-Dex
p0.002
Dex
JA Zonder et al. Blood 2007110(11)Abstract 77.
24
Phase III NDMM trials
84
82
80
76
Patients,
76
71
71
61

CR Rate VGPR Not Reported
25
Proposed phase III UK wide first line treatment
protocol Myeloma XI

• Will compare CTD/CTDa induction (Myeloma IX) with
  CRD/CRDa as initial therapy for patients with
  multiple myeloma.
• Sub optimal response will be offered vel/dex
• Eligible patients will be offered stem cell
  transplant

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Maintenance therapy
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Little Rock Data

• 668 patients
• 4 cycles of chemotherapy Thal 400mg v none
• Transplants x 2 Thal 200mg v none
• 3 cycles of consolidation Thal 200mg v None
• Maintenance interferon dex Thal 100mg v none
  then interferon Thal 50 mg v none

41
Little Rock Data

• 668 patients
• Thalidomide v No Thalidomide
• CR Rate 62 v 43
• 5yr EFS 56 v 44
• 5yr OFS 65 v 65
• Survival from relapse 1.1yrs v 2.7yrs

42
Relapse therapy - Velcade
43
APEX Treatment plan
Randomization
Dexamethasone
Bortezomib
Induction
4 cycles
8 cycles
1.3 mg/m2 IV push Days 1, 4, 8, 11 Q3W cycle
40 mg po Days 14, 912, 1720 Q5W cycle
Maintenance
3 cycles
5 cycles
1.3 mg/m2 IV push Days 1, 8, 15, 22 Q5W cycle
40 mg po Days 14 Q4W cycle
273 treatment days
280 treatment days
Richardson et al. N Engl J Med 20053522487
44
Bortezomib or High-dose Dexamethasone for
Relapsed Multiple Myeloma
Overall Response Rates
Richardson et al. N Eng J Med 2005
3522487-2498 Richardson et al. ASH 2005 abs
2547
45
APEX Outcome
1-year survival (n 669)
Time to progression (n 669)
Richardson et al. N Engl J Med 20053522487
46
APEX Treatment-emergent grade 3 AEs reported
by 5 of patients
Bortezomib (n 331)
Dexamethasone (n 332)
Hyperglycemia
Pneumonia
Dyspnea
Fatigue

Diarrhea
Peripheral neuropathy
Anemia
Neutropenia
Thrombocytopenia
Richardson et al. N Engl J Med 20053522487
47
Fast initial response to Bortezomib

• Median time to response 1.2 mos (range 30127)
• Median time to initial response within the first
  2 cycles
• 86 of responding pts (CR PR) achieved first
  response within 4 cycles

Cycle 1
Cycle 511
Time to initial response to Bortezomib in APEX
13 pts (10)
19 pts(14)
Cycle 4
20 pts(15)
49 pts(36)
Cycle 2
34 pts(25)
Cycle 3
Richardson et al. Blood 2005 106 (Abstract
2547) Poster at ASH 2005
48

APEX
Updated Results of APEX Trial

• Time to max serum M-protein reduction in
  responding bortezomib pts

20 responding pts achieved max M-protein
reduction in cycle 8 or later
Richardson P, et al. ASH 2005, abstract 2547
49
APEX
Updated Results of APEX Trial

• SURVIVAL

Overall and 1-Year Survival
P.0272

• Bortezomib continues to demonstrate superior
  survival despite gt 62 of HD dex pts crossing
  over to bortezomib
• Median OS 29.8 months vs 23.7
• 1-year survival rate 80 vs 67

Richardson P, et al. ASH 2005, abstract 2547
50
Treatment with Bortezomib at first relapse
compared with later therapy in APEX

• Bortezomib is more effective when used earlier in
  
• treatment course

Richardson et al. EHA 2006 (Abstract 0224)
51
Clinical Benefit by Response Type
Months (median)
50 (16) patients achieved CR/nCR 93 (28)
achieved a PR
52
Comparison with equivalent data from the APEX
study
Morris et al. IMW 2007, PO-624
53
Myeloma X Relapse Trial (Intensive)

• Eligibility
• MM previously treated with std chemo auto SCT
  (in or out of MRC IX)
• Requiring therapy for PD following plateau (18
  mo from 1st transplant)

Registration
54
Second Relapse ? Revlimid
55
Relapsed/ Refractory Myeloma Phase III study
design
Beginning with cycle 5, dexamethasone is reduced
to 40 mg on days14 only, every 28 days.
Weber D. Protocol CC-5013-MM-009. Dimopoulos M.
Protocol CC-5013-MM-010.
56
MM-009/010 pooled analysis prior therapies
Rev/Dex
Placebo/Dex
80
73
70
58
58
60
42
Patients ()
40
36
20
8
8
0
Bort
Thal
Dex
SCT
Weber et al. Blood 2007110Abstract 412, Oral
Session.
57
MM-009/010 pooled analysis update
Weber et al. Blood 2007110Abstract 412.
58
MM-009/ MM-010 pooled analysis
70
61
60
PR
50
CR/
nCR
40
Response Rate ()
plt0.001
30
24
22
20
CR15
CR2
CR/nCR24
10
3
CR/nCR 3.4
0
Rev/
Dex
Dex
Median Duration of Response 16 Months
Weber et al. Blood 2007110Abstract 412, Oral
Session.
59
MM-009/010 pooled analysis Time to Progression
Rev/Dex
100
Dex
75
Patients ()
50
Median 11.2 months
p lt 0.001
25
Median 4.7 months
0
0
5
10
15
20
25
30
Time to progression (months)
Weber et al. Blood 2007110Abstract 412, Oral
Session.
60
Response and TTP at 1st relapse
80
65
70
PR
58
60
CR/nCR
50
Response Rate ()
40
33
26
30
20
20
20
10
5
3
0
Rev/Dex
Dex
Rev/Dex
Dex
n124
n124
n229
n227
TTP (med. mos)
4.7
9.6
4.7
14.5
plt0.05
OS (med. mos)
27.3
33.3
33.6
39.1
Weber et al. Blood 2007110Abstract 412, Oral
Session
61
Median Survival continues to extend since gt50
pts remain alive
Rev/Dex
Patients ()
P0.021
Dex alone (47 crossed over to Lenalidomide)
p-value from log-rank testData up to January
2007
Overall survival (months)
Weber et al. Blood 2007110Abstract 412, Oral
Session
62
Rev/ Dex Vs Dex Control with 47 Crossover Vs
Historical Expectations
14.9 months
1. Ishak et al. British Journal of Haematology
2008 Abstract 327, Oral Presentation 2. Weber
et al. Blood 2007110Abstract 412, Oral Session.
63
Conclusions

• Myeloma therapy is improving all the time
• Good evidence that novel agents can improve
  outcome if included in initial therapy
• Sequencing of drugs dictated by NICE
• What about differing sub-groups?
• Renal failure
• Del chr 13
• 4.14 translocation