Transcript Update in Myeloma Kenneth Anderson, MD Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute, Harvard Medical School Boston, MA.

Update in Myeloma
Kenneth Anderson, MD
Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute,
Harvard Medical School
Boston, MA
Integration of Novel Therapy Into
Myeloma Management
Bortezomib, Lenalidomide, Thalidomide,
Doxil
Target MM in the BM microenvironment
to overcome conventional drug
resistance in vitro and in vivo
Effective in Relapsed/Refractory MM
Effective as Induction/First-line Therapy
Effective in Consolidation/ Maintenance
Integration of Novel Therapy Into
Myeloma Management
Six FDA/EMEA Drug Approvals
in Last Five Years
Median survival prolonged from 3-7 years
(especially in younger patients)
Three phase III trials of novel agents
ongoing for FDA approval
Newly Diagnosed
Stem Cell Transplant Eligible
A Phase III Randomized, Double-Blind Study of Maintenance Therapy
With Lenalidomide (CC 5013) or Placebo Following Autologous Stem
Cell Transplantation for Multiple Myeloma
Registration
S-D Stage 1-3, < 70 years
> 2 cycles of induction
Attained SD or better
 1 yr from start of therapy
> 2 x 106 CD34 cells/kg
Restaging
Days 90–100
Randomization
Placebo
Mel 200
ASCT
CR
PR
SD
McCarthy et al, ASH 2010 abstr 37
Lenalidomide*
10 mg/d with
↑↓ (5–15 mg)
*provided by Celgene
Corp, Summit, NJ
Patient stratification based on diagnostic -2M and thalidomide and
lenalidomide therapy during induction
Results
• TTP was defined as disease progression or death due to
any cause
• TTP was calculated from day 0 of ASCT
• Of 231 lenalidomide patients, 46 have experienced an
event (progression or death)
• Of 229 placebo patients, 95 have experienced an event
(p < 0.0001)
• Estimated hazard ratio of 0.40, thus a 60% reduction in
the risk of disease progression with lenalidomide
McCarthy et al, ASH 2010 abstr 37
Median TTP: 42.3
Median TTP: 21.8mo
CALGB 100104,
follow up to 12/17/2009
ITT Analysis with a Median Follow-up from
transplant of 17.5 months (p < 0.0001)
Results
• Maintenance therapy with lenalidomide when compared to
placebo will significantly prolong time to disease progression
• Currently, there is no difference in OS at a median follow-up of
1.5 years post-ASCT
• Lenalidomide prolonged TTP within patient stratification by high
and low β2M, and prior thalidomide or lenalidomide induction
therapy
• Lenalidomide maintenance produced some hematologic toxicity,
but this was not severe with dropouts due to all AEs at 12%
McCarthy et al, ASH 2010 abstr 37
Results
• 86 of ~ 110 eligible placebo patients started lenalidomide therapy
• As of November 2010, 122 lenalidomide patients and 86 placebo
patients remain on lenalidomide
• 25 new malignancies reported so far
– 4 before randomization
– 15 of 231 on lenalidomide arm
– 6 of 229 on the placebo arm
• Of the 25 new malignancies, there are 5 cases of AML/MDS
– 2 MDS cases did not receive lenalidomide
– Of 3 MDS/AML lenalidomide pts, 1 received breast cancer therapy in the past
McCarthy et al, ASH 2010 abstr 37
IFM 2005-02: Study design
Attal et al ASH 2010, abstr 310
Phase III randomized, placebo-controlled trial
N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008
Patients < 65 years, with non-progressive disease,  6 months after ASCT in first line
Randomization: stratified according to Beta-2m, del13, VGPR
Consolidation:
Lenalidomide alone 25 mg/day p.o.
days 1-21 of every 28 days for 2 months
Arm A=
Arm B=
Placebo
Lenalidomide
(N=307)
(N=307)
until relapse
10-15 mg/d until
relapse
Primary end-point: PFS.
Secondary end-points: CR rate, TTP, OS, feasibility of long-term
lenalidomide….
ASCT = autologous stem cell transplant.
IFM = Intergroupe Francophone du Myelome.
IFM 2005 02 : Responsea After Consolidation
(n= 572)
Attal et al ASH 2010, abstr 310
PRE
POST
p value b
CR (IF -)
14%
20%
<0.0001
≥ VGPR
58%
67%
<0.0001
a
IMW Criteria
b Mc Nemar test
IFM 2005-02 : PFS
Attal et al ASH 2010, abstr 310
Arm A
N = 307
Arm B
N = 307
Progression or Death
185
117
Median PFS post rando
(m)
24
42
33%
60%
1
0.5
.
4-year post diag PFS
(or 3-year post rando)
Hazard Ratio
P
< 10-8
IFM 2005-02 : PFS from randomization
0.75
1.00
Attal et al ASH 2010, abstr 310
0.25
0.50
Rev (n =307)
Placebo (n = 307)
P < 10 -8
P < 10-8
0.00
Median follow up: 34 m post rando, 44 m post diag
0
6
12
18
Placebo
24
30
Revlimid
36
42
Grade 3-4 Adverse Events during
treatment
AE (grade 4)
Arm A
Arm B
Anemia
2% (1%)
4% (2%)
Thrombocytopenia
6% (2%)
12% (5%)
Neutropenia
14% (3%)
43% (11%)
0%
2% (1%)
5% (1%)
10% (1%)
DVT
0%
2% (0.3%)
Skin disorders
4%
6%
Fatigue
0%
1%
0.3%
0.7%
Hematologic malignancies (n)
2
10
Non hematologic malignancies (n)
1
6
Febrile Neutropenia
Infections
Peripheral Neuropathy
Definitive Discontinuation for AE: placebo = 15% vs lenalidomide =
21%
Hovon Trial
Sonneveld et al ASH 2010
abstr 40
MM Stage II or III, Age 18–65
Randomization
3 x PAD
3 x VAD
CAD + GCSF
MEL 200 + PBSCT
Thalidomide
maintenance
50 mg/day for
2 years
1.3 mg/m2
i.v.
Doxorubicin
9 mg/m2
Dexameth
40 mg
CAD + GCSF
MEL 200 + PBSCT
In GMMG 2nd
Bortezomib
MEL 200 + PBSCT
Allogeneic
Tx
In GMMG 2nd
MEL 200 + PBSCT
Bortezomib
Maintenance
1.3 mg/m2 / 2 weeks
for 2 years
Response
Sonneveld et al ASH 2010 abstr 40
VAD arm %
PAD arm %
P-value
CR/nCR
5
11
0.002
≥VGPR
15
42
<0.001
≥PR
55
78
< 0.001
CR/nCR
15
30
< 0.001
≥VGPR
36
61
<0.001
≥PR
77
88
< 0.001
CR/nCR
34
49
<0.001
≥VGPR
55
76
0.001
≥PR
83
91
0.003
After induction
PAD vs VAD response
After HDM 1
On protocol
Response During Maintenance
Sonneveld et al ASH 2010 abstr 40
VAD arm
Thalidomide
%
PAD arm
Bortezomib
%
≥ PR
≥ VGPR
≥ nCR
Change of Response
during Maintenance
77
36
15
88
61
33
< PR → PR
4
1
< VGPR → VGPR
13
11
< nCR → nCR
12
13
< CR → CR
10
12
Response after HDM
Conclusions
Bortezomib based treatment improves PFS (median 36 m vs 27 m)
and OS (median not reached) in patients with newly diagnosed
transplant candidates
Bortezomib maintenance is well tolerated and induces additional
responses in patients including nCR/CR
Bortezomib treatment overcomes poor risk caused by creatinin > 2
mg/dL and del13/13qBortezomib partly overcomes poor risk caused by t(4;14) and 17pAfter VAD/HSM/ASCT also additional responses are achieved with
Thalidomide maintenance
BTD versus TD
RANDOMIZATION
INDUCTION (three 21-d cycles)
INDUCTION (three 21-d cycles)
VEL-THAL-DEX
THAL-DEX
• Vel 1.3mg/m2 twice weekly
• Thal 100200mg/day
• Thal 100200mg/day
• Dex 320mg/cycle
• Dex 320mg/cycle
PBSC COLLECTION
• CTX
TRANSPLANTATION
Cavo et al, ASH 2010 abstr 42
• MEL 200
CONSOLIDATION (two 35-d
cycles)
•
Thal 100md/day
•
Dex 160mg/cycle
• MEL 200
CONSOLIDATION (two 35-d cycles)
THAL-DEX
VEL-THAL-DEX
• Vel 1.3mg/m2 once weekly
• Thal 100mg/day
• Thal 100mg/day
• Dex 320mg/cycle
• Dex 320mg/cycle
MAINTENANCE
• DEX
INCREASED CR-nCR RATES WITH VTD COMPARED TO TD
P<0.0001
P<0.0001
P=0.0024
P=0.0002
62%
55%
52%
45%
41%
31%
31%
11%
EBMT criteria (with added nCR and VGPR categories)
Cavo et al, ASH 2010 abstr 42
Results
• By comparison with TD, VTD as induction and
consolidation therapy incorporated into double ASCT
 significantly increased the rates of CR, CR-nCR
and VGPR after induction, autotransplants and
consolidation
 significantly improved the probability to achieve a
molecular remission
 completely overcame the high risk of progression
or death related to t(4;14)
 significantly extended TTP and PFS
Cavo et al, ASH 2010 abstr 42
Upfront Revlimid Velcade Dexamethasone
Best Resp, n (%)
All pts (N=66)
Phase II (N=35)
CR
nCR
VGPR
PR
CR+nCR
19 (29)
7 (11)
18 (27)
22 (33)
26 (39)
13 (37)
7 (20)
6 (17)
9 (26)
20 (57)
(90% CI)
(29, 50)
(42, 71)
44 (67)
26 (74)
(56, 76)
(59, 86)
66 (100)
35 (100)
(96, 100)
(92, 100)
CR+nCR+VGPR
(90% CI)
At least PR
(90% CI)
• Response improvement seen in 42/56 pts (75%) from C4–8 and 20/38 pts
(53%) beyond C8
• Median (range time to best overall response) was 2.1(0.6,20) mos
Richardson et al, Blood 2010
Conclusions
• RVD highly effective for previously untreated MM
 100% response rate (≥PR) without ASCT
 CR/nCR (52%) and ≥VGPR (74%)
• Estimated 24-mo PFS of 68% and OS of 95% with
RVD ± ASCT
• Very good tolerability
 Manageable toxicities
 Only 2% G3 sensory PN, 6% DVT; no treatment-related
mortality
Richardson et al, Blood 2010
IFM/DFCI 2009 Phase 3 Study
Newly Diagnosed MM (SCT candidates)
Randomize
RVDx3
CY (3g/m2)
MOBILIZATION
Goal: 5 x106 cells/kg
Induction
Collection
RVDx3
CY (3g/m2)
MOBILIZATION
Goal: 5 x106 cells/kg
Melphalan
200mg/m2* +
ASCT
Consolidation
RVD x 5
RVD x 2
Maintenance
Lenalidomide
Lenalidomide
SCT at relapse
MPR versus Mel 200mg/m2 x 2
 402 patients (younger than 65 years) randomized from 62 centers
 Patients: Symptomatic disease, organ damage, measurable
disease
Rd*
four 28-day courses
R: 25 mg/d, days 1-21
d: 40 mg/d, days
1,8,15,22
1°
R
A
N
D
O
M
I
Z
A
T
I
O
N
MPR
six 28-day courses
M: 0,18 mg/Kg/d, days 14
P: 2 mg/Kg/d, days 1-4
R: 10 mg/d, days 1-21
MEL 200
Two courses
M: 200 mg/m2 day -2
Stem cell support day
0
2°
R
A
N
D
O
M
I
Z
A
T
I
O
N
NO
MAINTENANCE
MAINTENANCE
28-day courses until
relapse
R: 10 mg/day, days 1-21
Palumbo et al ASCO, 2010
*Thromboprophylaxis randomization: aspirin vs low molecular weight
heparin
R, lenalidomide; M, melphalan; d, dexamethasone; P, prednisone
Results
MPR
MEL200
P value
CR
13%
16%
0.82
> VGPR
55%
53%
0.63
PFS @ 14 months
86%
86%
0.49
OS @ 14 months
96%
98%
0.13
Palumbo et al ASCO, 2010
EVOLUTION STUDY: MRD negativity
across arms
Response by
algorithm (overall
population), n (%)
VDCR
(n = 42)
VDR
(n = 42)
VDC
(n = 32)
VDC-mod
(n = 17)
TOTAL
10 (24)
10 (24)
7 (22)
8 (47)
35
Patients ≥CR providing
MRD sample, n (%)
10 of 10
(100)
7 of 10
(70)
4 of 7
(57)
7 of 8
(88)
28
Patients ≥CR MRD –ve,
n (%)
5 of 10
(50)
6 of 7
(85)
0 of 4 (0)
2 of 7 (29)
13 of 28
(46)
CR
MRD sampling
Kumar et al, ASH 2010 abstr 621
EVOLTION: Conclusions
• VDC (mod) and VDR active with reasonable toxicity
profile
• VDCR and VDC (initial) do not appear to have any
advantages over VDR and VDC (mod) in efficacy or
toxicity
• Phase III studies should compare RVD and VDC
(mod) to assess VGPR, MRD-negative CR and PFS
Kumar et al, ASH 2010 abstr 621
Combinations in the Upfront Treatment of MM
Stewart AK, Richardson PG, San Miguel JF Blood 2009
Upfront Carfilzomib Rd
Best Resp, %
sCR/CR/nCR
sCR
CR/nCR
≥VGPR
≥PR
(N=27)
55
22
33
70
96
*As of data cutoff date: 12 November 2010,
4 patients not evaluable for response
(2 did not complete 1 cycle, 2 response not yet
confirmed)
Jakubowiak et al, ASH 2010 abstr 862
BMT CTN 0102 Study Schema
Multiple Myeloma
meeting
eligibility criteria
High-dose melphalan (200 mg/m2)
+ autologous PBSC transplant
HLA typing of all patients
with siblings
Biologic assignment*
Eligible HLA-matched
sibling donor
60 to 120 days
Non-myeloablative conditioning
TBI 200 cGY
allogeneic PBSC transplant
Register
*Biologic assignment
occurred when HLA-typing
results were available. The
time range from prior to first
transplant to at most 30 days
after first transplant.
No eligible HLA-matched
sibling donor
High-dose melphalan (200 mg/m2)
+ autologous PBSC transplant
Randomization†
† Randomization occurred
once pts were assigned to
auto-auto
Observation
Thalidomide
Dexamethasone
x12 months.
PRIMARY ENDPOINT : 3yr Progression Free Survival
Krishan et al ASH 2010 abstr 41
Compliance with Interventions:
Second Transplant and Maintenance
Auto-Allo
N=189
Auto-Auto
N=436
16 %
Received
Second Transplant
N=366
Thal-Dex
Discontinuation
at Day 365: 84%
Drop out
Rate
16 %
Received
Second Transplant
N=156
Krishan et al ASH 2010 abstr 41
Results
• No difference in 3-year PFS and OS between autoauto or auto-allo for the standard risk group (vs high
risk).
• Potential benefits of graft-versus-myeloma were
offset by increased TRM.
• Thal-Dex maintenance did not improve PFS or OS,
due to poor tolerability or compliance.
Krishan et al ASH 2010 abstr 41
Newly Diagnosed
Stem Cell Transplant Ineligible
Treatment schedule
 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
9 x 5-week cycles in both arms
NO MAINTENANCE
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
* 66 VMP patients and 73 VMPT patients were treated with twice weekly infusions of Bortezomib
Palumbo et al ASH 2010 abstr 620
Best response rate
VMP (N=253)
VMPT-VT (N=250)
P value
CR
24%
42%
<0.0001
> VGPR
50%
64%
0.001
> PR
81%
90%
0.007
40
VMP
31
30
VMPT  VT
35
26
% of patients
% of patients
42
40
35
25
45
24
20
17
15
10
30
26
25
22
20
15
10
5
1
6
5
1
0
0
CR
VGPR PR
SD
PD
CR
VGPR
PR
SD
PD
Palumbo et al ASH 2010 abstr 620
Progression-free survival / Time t next therapy
Median follow-up 32 months
Progression-Free survival
Time to next therapy
41% Reduced Risk of Progression
48% Reduced Risk of Progression
3-years PFS
VMPT
Median PFS
51%
Median TTNT
VMPT
70%
Not reached
VMP
51%
37.6 months
37.2 months
1.00
VMP
3-years TNT
32%
1.00
27.4 months
0.75
0.50
HR 0.59
P < 0.0001
0.25
0.00
Patients (%)
Patients (%)
0.75
HR 0.52
0.50
P < 0.0001
0.25
0.00
0
10
20
30
40
Time (months)
50
60
0
10
20
30
40
50
Time (months)
Palumbo et al ASH 2010 abstr 620
60
Efficacy and Toxicity by Bortezomib
schedule
VMP*
(VISTA)
VMP
twice weekly N=63
VMP
once weekly N=190
CR
30%
27%
23%
PFS @ 3 years
NA
32%
35%
Any grade
44%
43%
21%
Grade 3-4
13%
14%
2%
PN discontinuation
NA
16%
4%
Total planned dose
67.6
67.6 mg/m2
46.8 mg/m2
Total delivered dose
NA
41 mg/m2
40 mg/m2
Sensory PN
*Mateos et al. J Clin Oncol 2010; PN: peripheral neuropathy
Palumbo et al ASH 2010 abstr 620
Treatment discontinuation
VMPT  VT
VMP
65 - 75 years of age
27
16
> 75 years of age
37
18
65 - 75 years of age
61
42
> 75 years of age
31
37
Discontinuation ratea, %
Median cumulative doseb-mg/m2
a
b
Discontinuation due to AEs
Cumulative dose of bortezomib
Palumbo et al ASH 2010 abstr 620
Weekly Bortezomib Maintenance Therapy After
Bortezomib-Based Induction Regimens in Elderly
Newly Diagnosed Multiple Myeloma Patients
Niesvizky et al ASH 2010 abstr 619
Induction: 21-day cycles
Cycles 1–4
Cycles 5–8
RANDOMIZE 1:1:1
VcD
Vc: 1.3 mg/m2, days 1,4,8,11
D: 20 mg, days 1,2,4,5,8,9,11,12
VcTD
Vc: 1.3 mg/m2, days 1,4,8,11
T: 100 mg, days 1–21
D: 20 mg, days 1,2,4,5,8,9,11,12
Maintenance:
35-day cycles
Cycles 9–13
Vc: 1.3 mg/m2, days 1,4,8,11
D: 20 mg, days 1,2,4,5
mg/m2,
Vc: 1.3
days 1,4,8,11
T: 100 mg, days 1–21
D: 20 mg, days 1,2,4,5
Vc: 1.6 mg/m2,
days 1,8,15,22
Rest period:
days 23–35
VcMP
Vc: 1.3 mg/m2, days 1,4,8,11
M: 9 mg/m2, days 1,2,3,4 of every other cycle
P: 60 mg/m2, days 1,2,3,4 of every other cycle
Interim analysis (IDMC)
[ASH 2009]
Interim analysis (IDMC)
[EHA 2010]
Summary
• All three regimens (VcD, VcTD, VcMP) were active in elderly patients
with newly diagnosed MM
 Grade ≥3 AEs, serious AEs, PN and study discontinuations due to AEs
were highest in the VcTD arm
• Maintenance with single-agent Vc post induction was well tolerated
 Compared with post-induction rates, the rates of all-grade and grade ≥3
PN did not increase substantially in all three treatment arms
• Vc maintenance resulted in increased ≥VGPR rates in all three arms
• PFS appeared similar between the treatment arms in the ITT
population
 Median follow up 13.4 months (ITT population)
 Patients continue to be followed for progression and survival status
Niesvizky et al ASH 2010
abstr 619
Phase III Study Schema
N = 459, 82 centers in Europe, Australia, and Israel
Open-Label
Extension Phase
Double-Blind Treatment Phase
RANDOMISATION
Cycles (28-day) 1-9
MPR-R
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
MPR
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
MP
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
PBO: days 1-21
Cycles 10+
Continuous Lenalidomide
Treatment
10 mg/day
days 1-21
Placebo
Disease
Progression
Lenalidomide
(25 mg/day)
+/Dexamethasone
Placebo
Stratified by age (≤ 75 vs > 75 years) and stage (ISS I/II vs III)
M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System.
1
Progression-Free Survival*
All Patients
60% Reduced Risk of Progression
Median PFS
Patients (%)
100
75
MPR-R
31 months
MPR
14 months
MP
13 months
50
HR 0.398
P < .0000001
25
HR 0.804
P = .153
0
0
5
10
15
20
25
Time (months)
30
35
40
Median follow-up 25 months
*Analysis based on data up to May 2010
1
Landmark Analysis
69% Reduced Risk of Progression
MPR
Lenalidomide Continuous Therapy
100
MPR-R
MPR
Patients (%)
75
HR 0.314
50
P < .001
25
0
0
Cycle 10
5
10
15
20
Time (months)
25
30
1
Adverse Events
During Induction & Maintenance
MPR-R
(N = 150)
%
MPR
(N = 152)
%
MP
(N = 153)
%
Anemia
5
3
1
Febrile neutropenia
2
1
0
Neutropenia
36
32
8
Thrombocytopenia
13
14
4
Infections
11
15
9
Pulmonary embolism
2
2
0
DVT
3
5
<1
Fatigue
6
2
3
Peripheral neuropathy
0
0
1
Rash
5
5
<1
Cardiac disorder
<1
1
3
Solid tumors
<1
3
1
AML
2
1
0
MDS
<1
1
0
Hematological (Grade 4)
Non-hematological (Grade 3/4)
DVT, deep vein thrombosis; Cardiac disorder includes atrial fibrillation, myocardial ischemia,
bradycardia; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome
*Based on updated data
1
Supportive Therapy
MRC Myeloma IX—
Trial Design
Morgan et al ASH 2010 abstr 311
Intensive
N = 1,960
Non-intensive
RANDOMISATION
Clodronate
CVAD
Zoledronic acid
CVAD
Clodronate
C-TD
RANDOMISATION
Zoledronic acid
C-TD
Clodronate
MP
Zoledronic acid
MP
Clodronate
C-TDa
MEL-200
ASCT
Max
Response
RANDOMISATION
RANDOMISATION
–Thal
+Thal
–Thal
Zoledronic acid
C-TDa
+Thal
Treatment continued until disease progression
Primary endpoints: PFS, OS, ORR
Secondary endpoints: Time to first SRE, SRE incidence, Safety, and QoL
Zoledronic acid (4 mg IV q 3-4 wk); Clodronate (1,600 mg/d PO)
ISRCTN68454111
CVAD, cyclophosphamide (500 mg PO days 1, 5, and 15), vincristine (0.4 mg/d IV days 1-4), doxorubicin (9 mg/m2/d days 1-4), dexamethasone (40 mg/d PO days 1-4,
13-15 q 3 wk); C-TD, cyclophosphamide (500 mg PO days 1, 9, and 15), thalidomide (100-200 mg/d), dexamethasone (40 mg/d PO days 1-4, 12-15 q 3 wk);
C-TDa is C-TD except thalidomide 50-200 mg/d, dexamethasone 20 mg/d days 1-4, 15-18 q 4 wk; MP, melphalan (7 mg/m2), prednisolone (40 mg) PO for 4 days;
Thal, thalidomide (50 mg/d); PFS, progression-free survival; ORR, overall response rate; OS, overall survival, SRE, skeletal-related event; QoL, quality of life.
47
MRC Myeloma IX—
ZOLODRONIC vs CLODRONIC ACID
Morgan et al ASH 2010 abstr 311
N = 1,960
Patients with newly
diagnosed MM
(stage I, II, III)
R
A
N
D
O
M
I
S
A
T
I
O
N
Zoledronic acid (4 mga IV q 3-4 wk) +
intensive or non-intensive chemotherapy
(n = 981)
Treatment continued at least until disease
progression
Clodronate (1,600 mg/d PO) +
intensive or non-intensive chemotherapy
(n = 979)
Endpoints (ZOL vs CLO)
Primary: PFS, OS, and ORR
Secondary: Time to first SRE, SRE incidence, and Safety
Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS,
48 PFS, progression-free survival; PO, oral; SRE, skeletal-related event; ZOL, zoledronic acid.
overall survival,
a Dose-adjusted for patients with impaired renal function, per the prescribing information.
MRC Myeloma IX— ZOLODRONIC ACID Improved OS
and PFS vs CLODRONIC ACID
• ZOL significantly reduced relative risk of death by 16% vs CLO
(HR = 0.842; 95% CI = 0.736, 0.963; P = .0118)
• ZOL prolonged OS by 5-5 mos (p=0.04)
P value
16%
.0118
12%
.0179
0.842
OS
0.883
PFS
0
Risk
reduction
0.2
0.4
0.6
0.8
1
1.2
1.4
Hazard ratio (ZOL versus CLO)
In favor of ZOL
1.6
1.8
2
In favor of CLO
Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; OS, overall survival; PFS,
progression-free survival; ZOL, zoledronic acid.
a
Morgan et al, ASH 2010 abstr 311
Cox model adjusted for chemotherapy, and minimization factors.
Relapsed and
Relapsed/Refractory Myeloma
Intravenous versus Subcutaneous
Bortezomib
• Non-inferiority design
 60% retention of the IV treatment effect by ORR after 4 cycles of
treatment
 2:1 randomization SC vs IV (N=222)
 Stratification : ISS stage, number of prior lines of therapy (1 vs >1)
• 53 centers in 10 countries (Europe, Asia, and South America)
SC:
Bortezomib 1.3 mg/m2, days 1, 4, 8, 11
R
A
N
D
O
M
I
Z
E
2
1
If ≤PR after 4 cycles:
Add 20 mg Dex, days 1, 2, 4, 5, 8, 9, 11,
12
Eight 21-day cycles
(plus 2 cycles if unconfirmed or
delayed PR)
IV:
Bortezomib 1.3 mg/m2, days 1, 4, 8, 11
If ≤PR after 4 cycles:
Add 20 mg Dex, days 1, 2,51
4, 5, 8, 9, 11,
12
Moreau et al, ASH
2010 abstr 312
Primary Endpoint: Response After
4 Cycles (Single-Agent Bortezomib)
Moreau et al, ASH 2010 abstr 312
Bortezomib IV
(N=73)
Bortezomib SC
(N=145)
Relative risk
(95% CI)
42
42
0.99 (0.71, 1.37)
CR
8
6
CR + nCR
14
12
PR
34
36
nCR
5
6
VGPR
3
4
16
17
Response rate, %
ORR (CR + PR)
≥VGPR (CR + nCR + VGPR)
Data shown for the response-evaluable population
 Primary hypothesis of non-inferiority
of ORR after 4
52
cycles clearly demonstrated
Hematology Laboratory Data
Moreau et al, ASH 2010 abstr 312
Grade 3/4, %
Bortezomib IV
(N=74)
Bortezomib SC
(N=147)
Hemoglobin
12
14
WBC
18
8
ANC
28
22
Platelets
23
18
Peripheral Neuropathy (PN)
Moreau et al, ASH 2010 abstr 312
Bortezomib IV
(N=74)
Bortezomib SC
(N=148)
Pvalue*
Any PN event, %
53
38
0.04
Grade 2, %
41
24
0.01
Grade 3, %
16
6
0.03
Grade 1 PN at baseline
28
23
Diabetes at baseline
11
13
Exposure to prior neurotoxic agents
85
86
Risk factors for PN, %
*P-values are based on 2-sided Fisher’s exact test
Conclusions
• The efficacy of bortezomib was similar by SC and IV
administration in patients with relapsed MM
 similar PK (systemic exposure) and PD (proteasome
inhibition) profiles
• SC administration has an improved safety profile
 significantly fewer all-grade, grade 2, and grade 3 PN
events
• SC administration had acceptable local tolerability
Moreau et al, ASH 2010
abstr 312
MM-002 Study Schema
POM ± Low-Dose Dex in Relapsed and Refractory MM
Phase 1 (MTD)
Richardson et al, ASH 2010 abstr 864
Dose
POM therapy
(QD on days 1-21 of
a 28 day cycle)
2 mg
Progressive disease (PD)
3 mg
or no response after
completion of 4 cycles
Option to add
low-dose dex
(40 mg/wk)
4 mg
PD
Discontinue
and follow-up
for survival
and
subsequent
treatment
5 mg
RANDOMIZATION
Phase 2 (Open Label)
Arm A
POM (4 mg)
+ low-dose dex
Arm B
POM (4 mg)
PD
PD
Option to add
low-dose dex
(40 mg/wk)
Discontinue
and follow-up
for survival
and
subsequent
treatment
Concomitant Medications: anti-coagulants, G-CSF use after Cycle 1, erythroid growth
factors, bisphosphonates, transfusions with platelet, RBCs as clinically indicated .
59
MM-002: Phase 1
POM ± Low-Dose Dex in Relapsed and Refractory MM
Best Response & Clinical Outcome
Richardson et al, ASH 2010 abstr 864
(Evaluable Ptsa [n=28])
CR
PR
MR
Evaluable Pts (%)
80
≥ PR: 27%
≥ MR: 55%b
70
60
50
40
≥ PR: 29%
≥ MR: 71%b
≥ PR: 33%
≥ MR: 33%
≥ PR: 14%
≥ MR: 29%b
≥ PR: 25%
≥ MR: 50%
43
27
25
30
20
14
33
27
10
29
21
14
4
0
2 mg (n = 3)
•
•
•
•
•
3 mg (n = 7)
4 mg (n = 11)
5 mg (n = 7)
Total (N = 28)
Best response (≥ PR) to POM alone: 18%
Median time to best responsec: 16.1 wks
Median DOR: 20.1 wks (assessed for responders only)
Median PFS: 20.1 wks (95% CI: 12.0, 36.0)
Median OS: 79.6 wks (95% CI: 61.9, NE)
a. Includes eligible, treated and evaluable for efficacy assessment; b. Discrepancies in totals due to rounding
c. Response rates based on EBMT criteria; includes pts on POM alone (n=9), pts who had dex added for SD (n=7), and
pts who had dex added for PD (n=12)
60
MM-002: Conclusions
POM ± Low-Dose Dex in Relapsed and Refractory MM
• Manageable toxicity profile in heavily pretreated pts
 MTD: 4 mg days 1-21 of 28-day cycle
 Most common hematologic G 3/4 AE: myelosuppression
• Low incidence of G 3/4 PN and DVT
• Responses in heavily pretreated relapsed and refractory pts
 Median lines of prior therapy: 6 in Phase 1; 5 in Phase 2
 Phase 1:
• ≥PR: 25%; ≥MR: 50%
• Median DOR: 20.1 wks
• Median PFS: 20.1 wks
• Median OS: 79.6 wks
 Phase 2:
• ≥PR 25%; ≥MR 38%
• Median DOR not reached
Richardson et al, ASH 2010 abstr 864
61
Pomalidomide/Dexamethasone Therapy
for Relapsed/Refractory MM
Lacy et al ASH 2010, abstr 987
Pomalidomide 2 or 4 mg daily continuous, days 1-28
28 day
cycle
Dexamethasone 40 mg days 1, 8, 15, 22
Aspirin 325 mg daily
After 2 cycles, if NR or if progression, pomalidomide dose could be
increased to 4 mg/day in the 2 mg cohort
Response Rates
Lacy et al ASH 2010 abstr 987
2 mg
N=35
4 mg
N=35
9 (26%)
9 (26%)
CR
0
1
VGPR
5
3
PR
4
5
MR
8
5
SD
13
12
PD
2
8
NE
3
1
Confirmed Response
Rate (>PR)
49%
40%
Patient Outcomes
Lacy et al ASH 2010 abstr 987
Median time to response
Duration of response*
Survival at 6 Months
2mg (n=35)
4mg (n=35)
1 mo (range: 1-4)
1.7mo (range: 1-6)
12 mo (95%CI: 11-NA)
NA
78% (95%CI: 65-94)
69% (95%CI: 53-89)
CI: confidence interval; mo: month; NA: not attained
* Kaplan Meier
Conclusions
Lacy et al ASH 2010 abstr 987
• Pom/Dex in MM refractory to lenalidomide and bortezomib
•
•
•
•
•
- 40-49% >MR, DOR 12 months
- 69-78% OS at 6 months
Median time to response 1 - 2 month
Toxicity is manageable at both dose levels and primarily
neutropenia
ORR similar at both dose levels
Effective in high risk patients
Ongoing study of 4 mg for 21 of 28 days
Elotuzumab: Background
Richardson et al, ASH 2010 abstr 864
• Elotuzumab (HuLuc63) is a humanized monoclonal
•
•
IgG1 antibody targeting human CS1, a cell surface
glycoprotein1,2
CS1 is highly and uniformly expressed on MM cells1–3
 Restricted expression on NK cells
 Little to no expression on normal tissues
 Clinical trial of Elotuzumab in MM achieved SD
In a MM xenograft mouse model, the antitumor activity
of elotuzumab was enhanced by the addition of
lenalidomide4
MM, multiple myeloma; NK, natural killer.
1. Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784. 2. Tai YT et al. Blood. 2008;112:1329-1337.
3. van Rhee F et al. Mol Cancer Ther. 2009;8:2616-2624. 4. Lonial S et al. Blood. 2009;114:432.
66
Randomized Phase 2 Study Schema
Response Assessments
Richardson et al, ASH 2010 abstr 864
Elotuzumab
CYCLE 11
CYCLE
Dosing
Lenalidomide
Cycle day:
CYCLE 22
CYCLE
daily dose
1
8
15
CYCLE 33
CYCLE
daily dose
22
1
8
15
daily dose
22
1
8
15
CYCLE N-1
5
CYCLE
CYCLE 4
daily dose
22
1
8
15
CYCLE 6
CYCLE
N
daily dose
22
1
8
15
daily dose
22
1
8
15
22
Dexamethasone
• Pts randomized to receive elotuzumab 10 or 20 mg/kg IV, in combination with
lenalidomide 25 mg PO and low-dose dexamethasone 40 mg PO wkly (28-day
cycles)
• Treatment continued until PD or unacceptable toxicity
• Premedication regimen (30–60 mins prior to elotuzumab infusion)




Methylprednisone 50 mg IV
Diphenhydramine 25–50 mg PO or IV (or equivalent)
Ranitidine 50 mg IV (or equivalent)
Acetaminophen 650–1000 mg PO
67
28
CD38+, 10 mg/kg, n=24
CD38+, 20 mg/kg, n=18
100
80
60
40
20
0
% Occupancy of CS1 by Elotuzumab on
CD45dim/CD138+ BM cells
% Occupancy of CS1 by Elotuzumab on
CD45dim/CD38+ BM cells
CS1 Saturation on CD38+ and CD138+ in
Patient BM MM Cells
CD138+, 10 mg/kg, n=24
CD138+, 20 mg/kg, n=18
100
80
60
40
20
0
Richardson et al, ASH 2010 abstr 864
68
Elotuzumab/Len/Dex
• Well tolerated
 Gr 3/4 AEs >10%: neutropenia (14%), lymphopenia (14%),
thrombocytopenia (13%)
 Premedication mitigates infusion reactions
• ORR
 Phase 1: 82%1,2
 Phase 2: 81% ORR, 37% VGPR/CR
• 10 mg/kg elotuzumab is recommended Phase 3 dose
 Activity (90% ORR, 42% VGPR/CR), safety, and CS1 saturation
similar to 20 mg/kg
 High ORR in β2M ≥3.5 mg/L, prior thalidomide and median ≥2
prior therapies
• Phase 3: Randomized Trial of Lenalidomide/Dexamethasone
With or Without Elotuzumab in Relapsed or Refractory MM in
2011
Richardson et al, ASH 2010 abstr 864
1. Lonial S et al. ASCO 2010; Abstract 8020 (Oral). 2. Lonial S et al. ASH 2010; Abstract 1936.
69
Akt Inhibitor Perifosine Enhances
Bortezomib-Induced Cytotoxicity in MM Cells
Bortezomib
Bortezomib
0
Akt ↑
caspase ↑
Perifosine
4
8h
p-Akt
Akt
apoptosis anti-apoptosis
8h
C
B
P P+B
p-JNK1/2
120
24h
Perifosine (μM)
0
5
7.5
% control
100
caspase-8
CF
PARP
CF
C: control
B: Bortezomib (10 nM)
P: Perifosine (5 μM)
80
60
40
20
0
0
5
7.5
Bortezomib (nM)
Hideshima et al. Blood 2006; 107: 4053-52
Perifosine/Bortezomib ± Dexamethasone in
Relapsed/Refractory Myeloma: Phase I/II
• Long-term follow-up results of phase I/II study (N = 73)
Patients
ORR, %
Median TTP, mo (range)
Median OS, mo
All
38
6.4 (5.3-7.1)
> 22.5
• Bort relapsed
55
8.8 (6.3-11.2)
> 25
• Bort refractory
32
5.7 (4.3-6.4)
16
• Grade 3/4 AEs in ≥ 5%: thrombocytopenia, neutropenia,
anemia
Clinical trial of Bortezomib and perifosine versus
Bortezomib in relapsed MM ongoing for FDA approval
Richardson P, et al. ASH 2009
Blockade of Ubiquinated Protein Catabolism
Protein
Ub
Ub
Ub
protein aggregates
(toxic)
Ub
Ub
26S proteasome
Ub
HDAC6
Ub
Panibinostat,
vorinostat
Ub
Bortezomib
HDAC6
dynein
Ub
HDAC6
dynein
Microtubule
Ub
Aggresome
Ub Ub
Lysosome
Ub Ub
Ub
Ub
Autophagy
Hideshima et al, Clin Cancer Res;2005; 11: 8530
Catley et al, Blood 2006; 108: 3441-9.
Panobinostat + Bortezomib Efficacy
San Miguel et al, ASCO 2010
100
90
Response Rate (%)
80
70
70%
60%
60
MR
50
PR
40
30
VGPR
20
10
CR
0
All (N = 47)
BTZ refractory (n = 15)
HDAC6 Inhibitors Enhances Cytotoxicity
Induced by Proteasome Inhibitors
120
Tub 0 uM
Tub 0.3 uM
100
Tub 1 uM
Tub 3 uM
% control
80
WT161 0 uM
WT161 0.3 uM
60
WT161 1 uM
WT161 3 uM
40
20
0
0 nM
2.5 nM
Bortezomib
5 nM
Carflizomib 5 nM
High-Throughput Screening of MM with
BMSCs to Define Optimal Combinations
% Survival
100
75
Dex
50
No BMSCs
+HS-5 stroma
25
0
0.0
0.5
1.0
1.5
2.0
Dex (uM)
Luc+
Luc-
Myeloma +
Myeloma cells
Stromal cells
Stromal cells
% Survival
100
No BMSCs
+HS-5 stroma
75
Doxo
50
25
0
0
10
20
30
40
50
60
Doxo (ng/mL)
No signal
Biolum signal
100
% Survival
Biolum signal
Bortezomib
75
No BMSCs
+HS-5 stroma
50
25
0
McMillin et al. Nat Med 2010; 16: 483.
0
10
20
PS-341 (nM)
30
40
Conclusions and Future Directions
1.
Combination novel therapy represents a new treatment paradigm
in MM targeting the tumor cell in its microenvironment which has
markedly improved OR, CR, EFS and OS.
2.
Ongoing oncogenomic and proteomic studies are informing
clinical protocol design and identifying novel therapeutic targets.
3.
Rationally-designed combination therapies (IMiDs, proteasome
inhibitors, HDAC inhibitors, and MoAbs) will achieve durable CR
in the majority of pts
4.
Genomics will allow for improved patient classification and
personalized medicine in MM.