update in myeloma kenneth anderson, md jerome lipper multiple myeloma center dana-farber cancer...
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Update in Myeloma
Kenneth Anderson, MD
Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute,
Harvard Medical SchoolBoston, 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
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
Placebo
Lenalidomide*10 mg/d with ↑↓ (5–15 mg)
Lenalidomide*10 mg/d with ↑↓ (5–15 mg)
RestagingRestagingDays 90Days 90––100100
RegistrationRegistration
A Phase III Randomized, Double-Blind Study of Maintenance Therapy With Lenalidomide (CC 5013) or Placebo Following Autologous Stem
Cell Transplantation for Multiple Myeloma
CRPRSD
Patient stratification based on diagnostic -2M and thalidomide and lenalidomide therapy during induction
Mel 200Mel 200
ASCTASCT
*provided by Celgene Corp, Summit, NJ
Randomization
McCarthy et al, ASH 2010 abstr 37
ResultsResults
• 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
ITT Analysis with a Median Follow-up from transplant of 17.5 months (p < 0.0001)
CALGB 100104,
follow up to 12/17/2009
Median TTP: 21.8mo
Median TTP: 42.3
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
ResultsResults• 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
Arm A=
Placebo
(N=307)
until relapse
Arm A=
Placebo
(N=307)
until relapse
Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line
Arm B=
Lenalidomide
(N=307)
10-15 mg/d until relapse
Arm B=
Lenalidomide
(N=307)
10-15 mg/d until relapsePrimary end-point: PFS.
Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide….
Phase III randomized, placebo-controlled trial
N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008
ASCT = autologous stem cell transplant. IFM = Intergroupe Francophone du Myelome.
Consolidation:
Lenalidomide alone 25 mg/day p.o.
days 1-21 of every 28 days for 2 months
Consolidation:
Lenalidomide alone 25 mg/day p.o.
days 1-21 of every 28 days for 2 months
Randomization: stratified according to Beta-2m, del13, VGPRRandomization: stratified according to Beta-2m, del13, VGPR
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 Criteriab Mc Nemar test
a IMW Criteriab Mc Nemar test
IFM 2005 02 : Responsea After Consolidation(n= 572)
IFM 2005 02 : Responsea After Consolidation(n= 572)Attal et al ASH 2010, abstr 310
IFM 2005-02 : PFS
. Arm A
N = 307
Arm B
N = 307P
Progression or Death 185 117
Median PFS post rando (m)
24 42
4-year post diag PFS
(or 3-year post rando)33% 60%
Hazard Ratio 1 0.5 < 10-8
Attal et al ASH 2010, abstr 310
IFM 2005-02 : PFS from randomization
P < 10-8
0.0
00
.25
0.5
00
.75
1.0
0
0 6 12 18 24 30 36 42
Placebo Revlimid
P < 10 -8
Rev (n =307)
Placebo (n = 307)
Median follow up: 34 m post rando, 44 m post diagMedian follow up: 34 m post rando, 44 m post diag
Attal et al ASH 2010, abstr 310
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%)
Febrile Neutropenia 0% 2% (1%)
Infections 5% (1%) 10% (1%)
DVT 0% 2% (0.3%)
Skin disorders 4% 6%
Fatigue 0% 1%
Peripheral Neuropathy 0.3% 0.7%
Hematologic malignancies (n)
2 10
Non hematologic malignancies (n)
1 6
Definitive Discontinuation for AE: placebo = 15% vs lenalidomide = 21%
Randomization
MM Stage II or III, Age 18–65
CAD + GCSF
3 x VAD
CAD + GCSF
3 x PAD
MEL 200 + PBSCT
In GMMG 2nd
MEL 200 + PBSCT
MEL 200 + PBSCT
In GMMG 2nd
MEL 200 + PBSCT
Thalidomide
maintenance 50 mg/day for
2 years
Allogeneic Tx
Bortezomib Maintenance
1.3 mg/m2 / 2 weeks for 2 years
Hovon Trial
Bortezomib 1.3 mg/m2i.v.
Doxorubicin 9 mg/m2
Dexameth 40 mg
Sonneveld et al ASH 2010 abstr 40
PAD vs VAD response
VAD arm % PAD arm % P-value
After induction
CR/nCR 5 11 0.002
≥VGPR 15 42 <0.001
≥PR 55 78 < 0.001
After HDM 1
CR/nCR 15 30 < 0.001
≥VGPR 36 61 <0.001
≥PR 77 88 < 0.001
On protocol
CR/nCR 34 49 <0.001
≥VGPR 55 76 0.001
≥PR 83 91 0.003
ResponseSonneveld et al ASH 2010 abstr 40
Response During Maintenance
VAD armThalidomide
%
PAD armBortezomib
%Response after HDM
≥ PR≥ VGPR≥ nCR
773615
886133
Change of Response during Maintenance
< PR → PR 4 1
< VGPR → VGPR 13 11
< nCR → nCR 12 13
< CR → CR 10 12
Sonneveld et al ASH 2010 abstr 40
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 del13/13q-
Bortezomib partly overcomes poor risk caused by t(4;14) and 17p-
After VAD/HSM/ASCT also additional responses are achieved with Thalidomide maintenance
BTD versus TDRANDOMIZATION
INDUCTION (three 21-d cycles)
VEL-THAL-DEX
• Vel 1.3mg/m2 twice weekly
• Thal 100200mg/day
• Dex 320mg/cycle
TRANSPLANTATION
• MEL 200
• Thal 100md/day
• Dex 160mg/cycle
• MEL 200
MAINTENANCE
• DEX
PBSC COLLECTION
• CTX
INDUCTION (three 21-d cycles)
THAL-DEX
• Thal 100200mg/day
• Dex 320mg/cycle
CONSOLIDATION (two 35-d cycles)
VEL-THAL-DEX
• Vel 1.3mg/m2 once weekly
• Thal 100mg/day
• Dex 320mg/cycle
CONSOLIDATION (two 35-d cycles)
THAL-DEX
• Thal 100mg/day
• Dex 320mg/cycle
Cavo et al, ASH 2010 abstr 42
INCREASED CR-nCR RATES WITH VTD COMPARED TO TD
31%
11%
52%
31%
55%
41%
62%
45%
P<0.0001 P<0.0001 P=0.0024 P=0.0002
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
• 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
Best Resp, n (%) All pts (N=66) Phase II (N=35)
CR 19 (29) 13 (37)
nCR 7 (11) 7 (20)
VGPR 18 (27) 6 (17)
PR 22 (33) 9 (26)
CR+nCR 26 (39) 20 (57) (90% CI) (29, 50) (42, 71)
CR+nCR+VGPR 44 (67) 26 (74) (90% CI) (56, 76) (59, 86)
At least PR 66 (100) 35 (100) (90% CI) (96, 100) (92, 100)
Richardson et al, Blood 2010Richardson 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 StudyNewly Diagnosed MM (SCT candidates)
RVDx3
RVD x 2
RVD x 5
Lenalidomide
Melphalan 200mg/m2* +
ASCT
Induction
Consolidation
Maintenance
CY (3g/m2) MOBILIZATIONGoal: 5 x106 cells/kg
RVDx3
CY (3g/m2)MOBILIZATIONGoal: 5 x106 cells/kg
Randomize
Collection
LenalidomideSCT at relapse
*Thromboprophylaxis randomization: aspirin vs low molecular weight heparin
R, lenalidomide; M, melphalan; d, dexamethasone; P, prednisone
MPRsix 28-day coursesM: 0,18 mg/Kg/d, days 1-4P: 2 mg/Kg/d, days 1-4R: 10 mg/d, days 1-21
MEL 200Two coursesM: 200 mg/m2 day -2Stem cell support day 0
1°RANDOMIZATION
2°RANDOMIZATION
MAINTENANCE28-day courses until relapseR: 10 mg/day, days 1-21
NO MAINTENANCE
Rd*four 28-day coursesR: 25 mg/d, days 1-21d: 40 mg/d, days 1,8,15,22
402 patients (younger than 65 years) randomized from 62 centers
Patients: Symptomatic disease, organ damage, measurable disease
MPR versus Mel 200mg/m2 x 2
Palumbo et al ASCO, 2010
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
Results
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
CR 10 (24) 10 (24) 7 (22) 8 (47) 35
MRD sampling
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)
Kumar et al, ASH 2010 abstr 621Kumar 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 621Kumar et al, ASH 2010 abstr 621
Combinations in the Upfront Treatment of MM
Stewart AK, Richardson PG, San Miguel JF Blood 2009
Best Resp, % (N=27)
sCR/CR/nCR 55
sCR 22
CR/nCR 33
≥VGPR 70
≥PR 96
Upfront Carfilzomib Rd
*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
Multiple Myelomameeting
eligibility criteria
High-dose melphalan (200 mg/m2) + autologous PBSC transplant
60 to 120 days
No eligible HLA-matched sibling donor
Non-myeloablative conditioningTBI 200 cGY
allogeneic PBSC transplant
High-dose melphalan (200 mg/m2) + autologous PBSC transplant
ObservationThalidomide
Dexamethasone x12 months.
Biologic assignment*
Eligible HLA-matched sibling donor
Randomization†
PRIMARY ENDPOINT : 3yr Progression Free Survival
BMT CTN 0102 Study SchemaBMT CTN 0102 Study Schema
HLA typing of all patients with siblings
*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.
† Randomization occurred once pts were assigned to auto-auto
Re
gis
te
rR
eg
ist
er
Krishan et al ASH 2010 abstr 41
Compliance with Interventions: Compliance with Interventions: Second Transplant and MaintenanceSecond Transplant and Maintenance
16 % 16 %Drop out
Rate
Auto-AutoN=436
Auto-AlloN=189
Received Second Transplant
N=156
Received Second Transplant
N=366
Thal-Dex Discontinuation at Day 365: 84%
Krishan et al ASH 2010 abstr 41
ResultsResults
• No difference in 3-year PFS and OS between auto-auto 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
VMPCycles 1-9Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
VMPTCycles 1-9Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4Thalidomide 50 mg/day continuously
RANDOMIZE
9 x 5-week cycles in both arms
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
Treatment schedule
MAINTENANCEBortezomib 1.3 mg/m2 IV: days 1,15Thalidomide 50 mg/day continuously
NO MAINTENANCE
Until relapse
* 66 VMP patients and 73 VMPT patients were treated with twice weekly infusions of BortezomibPalumbo et al ASH 2010 abstr 620
Best response rateBest response rate
% o
f p
atie
nts
% o
f p
atie
nts
CRCR VGPRVGPR PRPR
% o
f p
atie
nts
% o
f p
atie
nts
SDSD PDPD
90%
64%
42%
VMPT-VT (N=250)
0.007
0.001
<0.0001
P value
81%> PR
50%> VGPR
24%CR
VMP (N=253)
90%
64%
42%
VMPT-VT (N=250)
0.007
0.001
<0.0001
P value
81%> PR
50%> VGPR
24%CR
VMP (N=253)
VMPT VTVMP
2 42 6
3 1
1 7
1
0
5
1 0
1 5
2 0
2 5
3 0
3 5
4 0 42
2226
6
10
5
10
15
20
25
30
35
40
45
CRCR VGPRVGPR PRPR SDSD PDPDPalumbo et al ASH 2010 abstr 620
Progression-free survival / Time t next therapyMedian follow-up 32 months
3-years PFS Median PFS
VMP
VMPT
32% 27.4 months
51% 37.2 months
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60
Time (months)
Pat
ien
ts(%
)
HR 0.59
P < 0.0001
3-years PFS Median PFS
VMP
VMPT
32% 27.4 months
51% 37.2 months
3-years PFS Median PFS
VMP
VMPT
32% 27.4 months
51% 37.2 months
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60
Time (months)
Pat
ien
ts(%
)
HR 0.59
P < 0.0001
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60
Time (months)
Pat
ien
ts(%
)
HR 0.59
P < 0.0001
Time to next therapy48% Reduced Risk of Progression
3-years TNT Median TTNT
VMP
VMPT
51% 37.6 months
70% Not reached
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60
Time (months)
Pat
ien
ts(%
)HR 0.52
P < 0.0001
3-years TNT Median TTNT
VMP
VMPT
51% 37.6 months
70% Not reached
3-years TNT Median TTNT
VMP
VMPT
51% 37.6 months
70% Not reached
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60
Time (months)
Pat
ien
ts(%
)HR 0.52
P < 0.0001
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60
Time (months)
Pat
ien
ts(%
)HR 0.52
P < 0.0001
Progression-Free survival41% Reduced Risk of Progression
Palumbo et al ASH 2010 abstr 620
Efficacy and Toxicity by Bortezomibschedule
46.8 mg/m267.6 mg/m267.6Total planned dose
4%16%NAPN discontinuation
35%32%NAPFS @ 3 years
2%14%13%Grade 3-4
NA
44%
30%
VMP*(VISTA)
40 mg/m2
21%
23%
VMP once weekly N=190
Sensory PN
43%Any grade
41 mg/m2Total delivered dose
27%CR
VMP twice weekly N=63
**MateosMateos et al. J et al. J ClinClin OncolOncol 2010; 2010; PN: peripheral neuropathyPalumbo et al ASH 2010 abstr 620
Treatment discontinuationVMPT VT VMP
Discontinuation ratea, %
65 - 75 years of age 27 16
> 75 years of age 37 18
Median cumulative doseb-mg/m2
65 - 75 years of age 61 42
> 75 years of age 31 37
VMPT VT VMP
Discontinuation ratea, %
65 - 75 years of age 27 16
> 75 years of age 37 18
Median cumulative doseb-mg/m2
65 - 75 years of age 61 42
> 75 years of age 31 37
a Discontinuation due to AEsb 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
Induction: 21-day cyclesMaintenance: 35-day cycles
Cycles 1–4 Cycles 5–8
Vc: 1.6 mg/m2, days 1,8,15,22
Rest period:days 23–35
VcDVc: 1.3 mg/m2, days 1,4,8,11D: 20 mg, days 1,2,4,5,8,9,11,12
VcTDVc: 1.3 mg/m2, days 1,4,8,11T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5,8,9,11,12
VcMPVc: 1.3 mg/m2, days 1,4,8,11M: 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
RA
ND
OM
IZE
1:1
:1
Vc: 1.3 mg/m2, days 1,4,8,11D: 20 mg, days 1,2,4,5
Vc: 1.3 mg/m2, days 1,4,8,11T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5
Cycles 9–13
Interim analysis (IDMC)[ASH 2009]
Interim analysis (IDMC)[EHA 2010]
Niesvizky et al ASH 2010 abstr 619
Niesvizky et al ASH 2010 abstr 619
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
1
MP
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
PBO: 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 1-21Placebo
Placebo
Phase III Study Schema
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
RA
ND
OM
ISA
TIO
N
Double-Blind Treatment Phase
DiseaseProgression
Continuous LenalidomideTreatment
Lenalidomide
(25 mg/day) +/-
Dexamethasone
Open-Label Extension Phase
N = 459, 82 centers in Europe, Australia, and Israel
Stratified by age (≤ 75 vs > 75 years) and stage (ISS I/II vs III)
10 mg/daydays 1-21
Cycles (28-day) 1-9 Cycles 10+
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
Time (months)
Pat
ien
ts (
%)
HR 0.398 P < .0000001
Median PFS
MPR-R 31 months
MPR 14 months
MP 13 months
Median PFS
MPR-R 31 months
MPR 14 months
MP 13 months
Median follow-up 25 months
0 5 10 15 20 25 30 35 400
25
50
75
100
0 5 10 15 20 25 30 35 400
25
50
75
100
0 5 10 15 20 25 30 35 400
25
50
75
100
*Analysis based on data up to May 2010
HR 0.804P = .153
1
0 5 10 15 20 25 300
25
50
75
100
Time (months)
Pat
ient
s (%
)
0 5 10 15 20 25 300
25
50
75
100
0 5 10 15 20 25 300
25
50
75
100
Time (months)
Pat
ient
s (%
)
Landmark Analysis69% Reduced Risk of Progression
HR 0.314 P < .001
MPR-R
MPR
MPR-R
MPR
Lenalidomide Continuous TherapyMPR
Cycle 10
1
Adverse EventsDuring Induction & Maintenance
MPR-R(N = 150)
%
MPR(N = 152)
%
MP(N = 153)
%
Hematological (Grade 4)
Anemia 5 3 1
Febrile neutropenia 2 1 0
Neutropenia 36 32 8
Thrombocytopenia 13 14 4
Non-hematological (Grade 3/4)
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
MPR-R(N = 150)
%
MPR(N = 152)
%
MP(N = 153)
%
Hematological (Grade 4)
Anemia 5 3 1
Febrile neutropenia 2 1 0
Neutropenia 36 32 8
Thrombocytopenia 13 14 4
Non-hematological (Grade 3/4)
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
DVT, deep vein thrombosis; Cardiac disorder includes atrial fibrillation, myocardial ischemia, bradycardia; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome
*Based on updated data
Supportive Therapy
MRC Myeloma IX—
Trial Design
Intensive
ClodronateCVAD
Zoledronic acidCVAD
ClodronateC-TD
Zoledronic acidC-TD
MEL-200ASCT
–Thal +Thal
Non-intensive
ClodronateMP
Zoledronic acidMP
ClodronateC-TDa
Zoledronic acidC-TDa
MaxResponse
–Thal +Thal
Primary endpoints: PFS, OS, ORRSecondary endpoints: Time to first SRE, SRE incidence, Safety, and QoLZoledronic acid (4 mg IV q 3-4 wk); Clodronate (1,600 mg/d PO)
CVAD, cyclophosphamide (500 mg PO days 1, 5, and 15), vincristine (0.4 mg/d IV days 1-4), doxorubicin (9 mg/m 2/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/m 2), 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.
ISRCTN68454111
N = 1,960
RANDOMISATION RANDOMISATION
RANDOMISATION RANDOMISATION
Treatment continued until disease progression
47
Morgan et al ASH 2010 abstr 311
MRC Myeloma IX—
ZOLODRONIC vs CLODRONIC ACID
Endpoints (ZOL vs CLO)Primary: PFS, OS, and ORRSecondary: Time to first SRE, SRE incidence, and Safety
N = 1,960Patients with newly
diagnosed MM
(stage I, II, III)Clodronate (1,600 mg/d PO) +
intensive or non-intensive chemotherapy (n = 979)
Zoledronic acid (4 mga IV q 3-4 wk) + intensive or non-intensive chemotherapy
(n = 981)
Treatment continued at least until disease progression
Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS, overall survival, PFS, progression-free survival; PO, oral; SRE, skeletal-related event; ZOL, zoledronic acid.a Dose-adjusted for patients with impaired renal function, per the prescribing information.
48
Morgan et al ASH 2010 abstr 311
MRC Myeloma IX— ZOLODRONIC ACID Improved OS
and PFS vs CLODRONIC ACID
Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; ZOL, zoledronic acid.
a Cox model adjusted for chemotherapy, and minimization factors.
Riskreduction
Hazard ratio (ZOL versus CLO)0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
P value
.01180.842
16%
In favor of ZOL In favor of CLO
OS
.017912%0.883
PFS
• 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)
Morgan et al, ASH 2010 abstr 311Morgan et al, ASH 2010 abstr 311
Relapsed and Relapsed/Refractory Myeloma
51
Intravenous versus Subcutaneous Bortezomib
SC:Bortezomib 1.3 mg/m2, days 1, 4, 8, 11
If ≤PR after 4 cycles:Add 20 mg Dex, days 1, 2, 4, 5, 8, 9, 11, 12
SC:Bortezomib 1.3 mg/m2, days 1, 4, 8, 11
If ≤PR after 4 cycles:Add 20 mg Dex, days 1, 2, 4, 5, 8, 9, 11, 12
IV:Bortezomib 1.3 mg/m2, days 1, 4, 8, 11
If ≤PR after 4 cycles:Add 20 mg Dex, days 1, 2, 4, 5, 8, 9, 11, 12
IV:Bortezomib 1.3 mg/m2, days 1, 4, 8, 11
If ≤PR after 4 cycles:Add 20 mg Dex, days 1, 2, 4, 5, 8, 9, 11, 12
1
Eight 21-day cycles (plus 2 cycles if unconfirmed or delayed PR)
RANDOMIZE
2
• 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)
Moreau et al, ASH 2010 abstr 312
52
Primary Endpoint: Response After 4 Cycles (Single-Agent Bortezomib)
Response rate, %Bortezomib IV
(N=73)Bortezomib SC
(N=145)Relative risk
(95% CI)
ORR (CR + PR) 42 42 0.99 (0.71, 1.37)
CR 8 6
CR + nCR 14 12
PR 34 36
nCR 5 6
VGPR 3 4
≥VGPR (CR + nCR + VGPR) 16 17
Data shown for the response-evaluable population
Primary hypothesis of non-inferiority of ORR after 4 cycles clearly demonstrated
Moreau et al, ASH 2010 abstr 312
Hematology Laboratory Data
Grade 3/4, %Bortezomib IV
(N=74)Bortezomib SC
(N=147)
Hemoglobin 12 14
WBC 18 8
ANC 28 22
Platelets 23 18
Moreau et al, ASH 2010 abstr 312
Peripheral Neuropathy (PN)
Bortezomib IV
(N=74)
Bortezomib SC (N=148)
P-value*
Any PN event, % 53 38 0.04
Grade 2, % 41 24 0.01
Grade 3, % 16 6 0.03
Risk factors for PN, %
Grade 1 PN at baseline 28 23
Diabetes at baseline 11 13
Exposure to prior neurotoxic agents 85 86
*P-values are based on 2-sided Fisher’s exact test
Moreau et al, ASH 2010 abstr 312
Moreau et al, ASH 2010 abstr 312
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
59
Phase 1 (MTD)
Dose
2 mg
3 mg
4 mg
5 mg
Progressive disease (PD)
or no response aftercompletion of 4 cycles
POM therapy(QD on days 1-21 of
a 28 day cycle)
Option to add low-dose dex
(40 mg/wk)
Discontinue and follow-up for survival
and subsequent treatment
PD
Phase 2 (Open Label)
RA
ND
OM
IZA
TIO
N Arm A
POM (4 mg)+ low-dose dex
Arm B
POM (4 mg)
Option to add low-dose dex
(40 mg/wk)
Discontinue and follow-up for survival
and subsequent treatment
PD
PD
MM-002 Study SchemaPOM ± Low-Dose Dex in Relapsed and Refractory MM
Concomitant Medications: anti-coagulants, G-CSF use after Cycle 1, erythroid growth factors, bisphosphonates, transfusions with platelet, RBCs as clinically indicated .
Richardson et al, ASH 2010 abstr 864
MM-002: Phase 1 POM ± Low-Dose Dex in Relapsed and Refractory MM
Best Response & Clinical Outcome (Evaluable Ptsa [n=28])
60
• 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)
14
33 27 29 2114
27
43
25
40
10
20
30
40
50
60
70
80
2 mg (n = 3) 3 mg (n = 7) 4 mg (n = 11) 5 mg (n = 7) Total (N = 28)
Ev
alu
ab
le P
ts (
%)
CR PR MR
≥ PR: 33%≥ MR: 33% ≥ PR: 14%
≥ MR: 29%b
≥ PR: 27%≥ MR: 55%b
≥ PR: 29%≥ MR: 71%b
≥ PR: 25%≥ MR: 50%
a. Includes eligible, treated and evaluable for efficacy assessment; b. Discrepancies in totals due to roundingc. 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)
Richardson et al, ASH 2010 abstr 864
61
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
Pomalidomide/Dexamethasone Therapy for Relapsed/Refractory MM
Pomalidomide 2 or 4 mg daily continuous, days 1-28
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
28 day cycle
Lacy et al ASH 2010, abstr 987
Response Rates
2 mgN=35
4 mg N=35
Confirmed Response Rate (>PR)
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
49% 40%
Lacy et al ASH 2010 abstr 987
2mg (n=35) 4mg (n=35)
Median time to response 1 mo (range: 1-4) 1.7mo (range: 1-6)
Duration of response* 12 mo (95%CI: 11-NA) NA
Survival at 6 Months 78% (95%CI: 65-94) 69% (95%CI: 53-89)
CI: confidence interval; mo: month; NA: not attained* Kaplan Meier
Patient Outcomes Lacy et al ASH 2010 abstr 987
Conclusions
• 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
Lacy et al ASH 2010 abstr 987
• 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
66
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.
Elotuzumab: BackgroundRichardson et al, ASH 2010 abstr 864
67
Randomized Phase 2 Study Schema
• 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
Response Assessments
CYCLE 1 CYCLE 2 CYCLE 3
1 8 15 221 8 15 22 1 8 15 221 8 15 22
CYCLE 5
1 8 15 22
CYCLE 6
1 8 15 22 28
Dexamethasone
Lenalidomide
Elotuzumab
Dosing
Cycle day: 1 8 15 221 8 15 22 1 8 15 221 8 15 22 1 8 15 22 1 8 15 22 28
CYCLE 1 CYCLE 2 CYCLE 3 CYCLE N-1 CYCLE NCYCLE 4
daily dosedaily dose daily dose daily dosedaily dose daily dose
Richardson et al, ASH 2010 abstr 864
Cycle
1 D
ay 2
2
Basel
ine
Cycle
1 D
ay 2
2
Basel
ine
Cycle
1 D
ay 2
20
20
40
60
80
100
% O
ccu
pan
cy o
f C
S1
by
Elo
tuzu
mab
on
CD
45d
im/C
D13
8+ B
M c
ells
CD138+, 10 mg/kg, n=24
CD138+, 20 mg/kg, n=18
Basel
ine
Cycle
1 D
ay 2
2
Basel
ine
0
20
40
60
80
100
% O
ccu
pan
cy o
f C
S1
by
Elo
tuzu
mab
on
CD
45d
im/C
D38
+ B
M c
ells
CD38+, 10 mg/kg, n=24
CD38+, 20 mg/kg, n=18
68
CS1 Saturation on CD38+ and CD138+ in Patient BM MM Cells
Richardson et al, ASH 2010 abstr 864
69
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
1. Lonial S et al. ASCO 2010; Abstract 8020 (Oral). 2. Lonial S et al. ASH 2010; Abstract 1936.
Richardson et al, ASH 2010 abstr 864
0 4 8hp-Akt
Akt
Bortezomib
Bortezomib
caspase ↑ Akt ↑
anti-apoptosis
Perifosine
apoptosis
C PB P+B
p-JNK1/2
caspase-8
CFPARP
CF
C: controlB: Bortezomib (10 nM)P: Perifosine (5 μM)
8h
Akt Inhibitor Perifosine Enhances Bortezomib-Induced Cytotoxicity in MM Cells
0
20
40
60
80
100
120
0 5 7.5Bortezomib (nM)
% c
on
tro
l
24hPerifosine (μM)
057.5
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)
• Grade 3/4 AEs in ≥ 5%: thrombocytopenia, neutropenia, anemia
Clinical trial of Bortezomib and perifosine versus Bortezomib in relapsed MM ongoing for FDA approval
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
Richardson P, et al. ASH 2009
Protein
protein aggregates(toxic)
UbUb
UbUb
26S proteasome
UbUb
Ub Ub
Ub
Aggresome
Panibinostat,vorinostat
dynein
UbUb
dynein
MicrotubuleAutophagy
Bortezomib
Ub Ub
Ub
Lysosome
HDAC6
HDAC6
HDAC6
Ub
Ub
Blockade of Ubiquinated Protein Catabolism
Hideshima et al, Clin Cancer Res;2005; 11: 8530Catley et al, Blood 2006; 108: 3441-9.
Panobinostat + Bortezomib EfficacySan Miguel et al, ASCO 2010
Res
pons
e R
ate
(%)
0
10
20
30
40
50
60
70
80
90
100
All (N = 47) BTZ refractory (n = 15)
MR
PR
VGPR
CR
70%70%
60%60%
HDAC6 Inhibitors Enhances Cytotoxicity Induced by Proteasome Inhibitors
0
20
40
60
80
100
120
0 nM 2.5 nM 5 nM Carflizomib 5 nM
Bortezomib
% c
on
tro
l
Tub 0 uM
Tub 0.3 uM
Tub 1 uM
Tub 3 uM
WT161 0 uM
WT161 0.3 uM
WT161 1 uM
WT161 3 uM
Luc+
Myeloma cells
Luc-
Stromal cells
Myeloma +
Stromal cells
Biolum signal No signal Biolum signal
High-Throughput Screening of MM with High-Throughput Screening of MM with BMSCs to Define Optimal CombinationsBMSCs to Define Optimal Combinations
McMillin et al. Nat Med 2010; 16: 483.
%
Su
rviv
al%
S
urv
ival
% S
urv
ival
% S
urv
ival
% S
urv
ival
% S
urv
ival
0.00.0 0.50.5 1.01.0 1.51.5 2.02.000
2525
5050
7575
100100
No BMSCsNo BMSCs
+HS-5 stroma+HS-5 stroma
Dex (uM)Dex (uM)
DexDex
00 1010 2020 3030 4040 5050 606000
2525
5050
7575
100100
Doxo (ng/mL)Doxo (ng/mL)
No BMSCsNo BMSCs
+HS-5 stroma+HS-5 stroma DoxoDoxo
No BMSCsNo BMSCs
+HS-5 stroma+HS-5 stroma
00 1010 2020 3030 404000
2525
5050
7575
100100
PS-341 (nM)PS-341 (nM)
BortezomibBortezomib
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.