Transcript Myeloma Updates ASH 2011 Annual Meeting Steve Smith OHSU Knight Cancer Institute Center for Hematologic Malignancies [email protected].

Myeloma Updates
ASH 2011 Annual Meeting
Steve Smith
OHSU Knight Cancer Institute
Center for Hematologic Malignancies
[email protected]
What was new is now old…
 long-term data on novel agent + chemo combinations
 2nd generation immunomodulators, proteasome
inhibitors
Will chemotherapy combinations be replaced by
multitargeted therapies?
Overview: Progress in MM
 Overall survival rates improving
• in younger patients
 Almost 800 ASH abstracts in multiple myeloma
• about 10x more than a decade ago
  understanding of pathbiology
• of the malignant plasma cell and microenvironment
ASH 2011:
• nontransplant (elderly) regimens: longer follow-up
• second generation novel agents
• “multitargeted” strategies
MM Survival Trends
Patients > 65 years at Diagnosis*
1.0
1.0
0.9
0.9
Overall Surv vi al (proport io n)
Overall Sur v vi al (proport o
i n)
Patients < 65 years at Diagnosis*
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
Time Since Diagnosis (months)
Time Since Diagnosis (months)
*Swedish Registry data.
1950 – 1959
1960 – 1969
1970 – 1979
1980 – 1989
1990 – 1999
2000 – 2005
Turesson I, et al. J Clin Oncol. 2009;28:830-834.
Newly Diagnosed, Patients SCT Ineligible
MPT1
N = 129
VMP2
N = 337
MPR3
N = 153
MPR-R4
N = 152
VTP5
N = 130
CR
16%
30%
11%
16%
27%
> VGPR
29%
Not reported
33%
32%
37%
> PR
69%
71%
68%
77%
81%
PFS
21.8 mo
TTP: 24.0 mo
14 mo
31 mo
23 mo
Median follow-up
31.8 mo
36.7 mo
25 mo
25 mo
22 mo
MPT: melphalan, prednisone, thalidomide; VMP: bortezomib, melphalan, prednisone; MPR: melphalan,
prednisone, lenalidomide; MPR-R: MPR with maintenance lenalidomide; VTP: bortezomib, thalidomide,
prednisone.
1Palumbo
A, et al. Blood. 2008;112:3107-3114;
MV, et al. Blood. 2009;114(22). Abstract 3859;
3,4Palumbo A, et al. Blood. 2010;116(21). Abstract 622 and Abstract 566;
5Mateos MV, et al. Blood. 2009;114(22). Abstract 3.
2Mateos
VISTA Final Analysis
 (Velcade) as Initial Standard Therapy in Multiple
Myeloma= VISTA
 updated OS analysis of VISTA after 5 years
median follow-up
 randomized, international, phase III clinical trial
Newly Diagnosed/SCT ineligible
VISTA Final Analysis
Newly Diagnosed/SCT ineligible
VISTA Final Analysis
 5-year OS
• VMP vs MP: 46.0% vs 34.4%
• 13.3-month increase in OS
 OS benefit in most subgroups
• sex, race, geographic region, β2-microglobulin level, and
albumin level
 OS benefit not observed for high-risk cytogenetics
• OS benefit initially observed in VMP arm diminished when patients received
second-line therapy (included bortezomib in 60% of MP pts)
Newly Diagnosed/SCT ineligible
MPRR: Italian intergroup study MM-015
ASH 2011: 41 month f/u

MM-015: MPR with or without maintenance lenalidomide, vs MP in upfront SCT
ineligible pts
Newly Diagnosed/SCT ineligible
Italian Intergroup MM-015
PFS benefit to lenalidomide maintenance
Landmark Analysis: PFS After Cycle 9
MPR-R vs
Patients (%)
100
MPR
75
HR 0.314
Log rank P < 0.001
50
25
0
0
5
Newly Diagnosed/SCT ineligible
10
15
20
Time (months)
25
30
Palumbo A, et al. Blood. 2009;114(22). Abstract 613;
Palumbo A, et al. European Hematology Association 15th Congress. 2010. Abstract 566.
MM-015: Outcomes in Overall Population
 Continued lenalidomide significantly improves PFS vs placebo
• PFS benefit extended through patient subgroups in landmark analysis
⁻ Age (65-75 vs > 75 yrs), response (PR vs ≥ VGPR), ISS stage (I/II vs III)
• No effect on OS or TTP with maintenance lenalidomide
Outcome
MPR-R
(n = 152)
MPR
(n = 153)
MP
(n = 154)
Median PFS, mos
 HR vs MP
 P value vs MP
31
0.395
< .001
14
0.796
.135
13
4-yr OS, %
 HR vs MP
 P value vs MP
59
0.898
.579
58
1.089
.648
58
TTP
 HR vs MP
0.337
0.826
Palumbo A, et al. ASH 2011. Abstract 475.
MM-015: Grade 4 Toxicities during induction and
maintenance
Adverse Events, %*
Induction Therapy
Maintenance
Therapy
MPR
MP
MPR-R
MPR
•Neutropenia
32
7
2
0
•Thrombocytopenia
7
4
4
3
•Anemia
2
2
3
1
•Febrile neutropenia
0
0
0
0
Grade 4 hematologic
events
Newly
1. é J etDiagnosed/SCT
al. Br J Haematol. ineligible
1998;102:1115-1123.
Palumbo A, et al. ASH 2011 Abstract 475
MM-015: Second Malignancies
Second
Malignancies,
Incidence Rate/100
Patients/Yr
Total invasive
second primary
malignancies
Hematologic
malignancies
Solid tumors
Nonmelanoma
skin cancer
Newly Diagnosed/SCT ineligible
MPR-R
(n = 150)
MPR
(n = 152)
MP
(n = 153)
3.04
2.57
0.98
1.75
1.54
0.24
1.26
1.28
0.74
0.50
1.29
1.50
1. é J et al. Br J Haematol. 1998;102:1115-1123.
Palumbo A, et al. ASH 2011 Abstract 475
Relapsed / Refractory Disease
Patients Relapsing and Refractory to Bortezomib and
Thalidomide or Lenalidomide
100%
80%
60%
40%
20%
0%
0
12
24
Months
36
48
N
Events (n)
Median
Overall Survival
291
173
9 months
Event-Free Survival
291
222
5 months
60
Kumar, et al. Haematologica. 2010;95(suppl 2). Abstract 376.
The Next Generation…
 2nd generation immunomodulatory agents
 2nd generation proteasome inhibitors
 HDAC Inhibitors
 Monoclonal antibodies
 Alkylating agents
 Other proteasome inhibitors
 Heat shock protein inhibitors
 PI3K / AKT inhibitor
 mTOR inhibitors
Carfilzomib: second-generation proteasome inhibitor
 Administered IV
• First 2 days of each week, for 3 weeks (repeated monthly)
 Active in heavily pretreated MM patients
 Mild neuropathy seen but uncommon (< 20%)
• Severe neuropathy (grade 3-4): <2%
•
Toxicity
⁻ Myelosuppression, fatigue, URI/ PNA, infusion reactions
 ≈ 15% grade 3-4 anemia, thrombocytopenia, and neutropenia
PX-171-003-A1: Siegel DS, et al. Blood. 2010;116(2). Abstract 985;
PX-171-004 Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099;
Wang ASH 2009 Abstract 302.
Niesvizky R, et al. Blood. 2010;116(2). Abstract 619.
Carfilzomib: Phase II Rel/Ref MM
ASH 2011: Single-Agent Carfilfzomib, rel/ref MM (PX-171-004):
Final results from the bortezomib-naive group
 n = 129
 Treated for up to 12 cycles
 Data from 2 cohorts presented
1- Carfilzomib 20 mg/m2 (n=59)
2- Carfilzomib 20 mg/m2 for cycle 1, then
(n=70)
Rel/Ref MM

to 27 mg/m2 for cycles 2-12
Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813
Carfilzomib phase II PX-171-004: Baseline characteristics
Carfilzomib
20 mg/m2
(n = 59)
Carfilzomib
20/27 mg/m2
(n = 70)
65 (38-82)
65.5 (45-85)
3.5 (0.7-24.4)
3.6 (0.7-12.2)
49
55
2 (1-4)
2 (1-4)
Refractory to most
recent therapy, %
66
64
Prior Stem cell
transplantation (%)
80
67
Cyto or FISH =
Unfavorable (%)
15
14
Characteristic
Median age, yrs (range)
Median yrs from diagnosis
(range)
Neuropathy, %
Median previous
treatments, n (range)
Rel/Ref MM
Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813
Carfilzomib phase II PX-171-004: Response Data
Carfilzomib
20 mg/m2
(n = 59)
Carfilzomib
20/27 mg/m2
(n = 67)*
ORR, %
42
52
CR
VGPR
PR
Median time to response,
mos
Median PFS, mos
Median duration of f/u,
mos
3
14
25
2
27
24
1.0
1.9
8.2
NR
23.2
13.8
Outcome
Rel/Ref MM
Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813
Carfilzomib phase II PX-171-004: Conclusions
 In bortezomib-naïve rel/ref MM pts, combined ORR 48%
• Potential dose-response relationship
 No increase in neuropathy risk with carfilzomib in pts with
history of, or pre-existing, neuropathy
• PNP is
⁻ Mostly mild to moderate severity , not dose limiting
 Grade 3/4 adverse events in 80% of patients- primarily
hematologic
⁻ Generally reversible
 AE’s led to treatment discontinuation in 16% of patients
Rel/Ref MM
Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813
ASH 2011: Phase 2 results
 Carfilzomib + len + dex
Upfront, SCT-eligible
Upfront, SCT-eligible
Upfront, SCT-eligible
Upfront, SCT-eligible
Upfront, SCT-eligible
Upfront, SCT-eligible
MLN9708 Phase I Study: ASH 2011
 MLN9708, PO proteasome inhibitor
 Phase I study
 relapsed/refractory MM (N = 56)
⁻ Dose-escalation phase (n = 26)
⁻ Expansion phase (n = 36; 6 from dose-escalation cohort)
⁻ 27% to 32% refractory to bortezomib on last previous therapy
 MLN9708 dosing
⁻ Starting 0.24 mg/m2, increased to 2.23 mg/m2 on Days 1, 4, 8, 11 of a
21-day cycle for up to 12 cycles
• 46 patients evaluable for response
Richardson PG, et al. ASH 2011. Abstract 301.
Rel/Ref MM
MLN9708 Phase I Study: Safety and Response
 MTD 2.0 mg/m2
• 32% of patients required dose reductions due to adverse events
⁻ Mainly thrombocytopenia, neutropenia, and rash
⁻ 9% of patients discontinued treatment due to adverse events
 Grade 3/4 adverse events: thrombocytopenia (34%), neutropenia
(14%), fatigue (9%), rash (9%)
• No grade 3 /4 neuropathy
 15% (n = 7) patients achieved response
• Durable disease control up to 15.9 mos
• Majority (61%) of remaining patients reached SD, durable for up to 12.9
mos
Richardson PG, et al. ASH 2011. Abstract 301.
Rel/Ref MM
MLN9708 + Len + Dex: Phase I/II Combination
 Open-label, multicenter, dose-escalation phase I/II trial
•
Primary endpoints: safety, MTD, recommended phase II dose
⁻ Secondary endpoints: MLN2238 pharmacokinetics, treatment response
 Previously untreated MM (n = 15 to date)
 Treatment: 28-day cycles for up to 12 mos
⁻ MLN9708: started at 1.68 mg/m2, increased in 33% increments based DLT
⁻ Dex: 40 mg/day on Days 1, 8, 15, 22
⁻ Lenalidomide: 25 mg/day on Days 1-21
Berdeja JG, et al. ASH 2011. Abstract 479.
Upfront, SCT-eligible
MLN9708 + Len + Dex Phase I/II: outcomes
 Responses observed in all patients (N =15), generally in cycle 1
• CR (n = 4), VGPR (n = 5), and PR (n = 6)
 No DLT observed up to 2.23 mg/m2 MLN9708
• Recommended phase II dose: 2.23 mg/m2/wk
 Well tolerated
• Grade 1 peripheral neuropathy (n = 3)
• Grade 3: vomiting (n = 2), deep vein thrombosis (n = 2), anemia (n = 2),
rash (n = 2)
• Grade 4: thrombocytopenia (n = 1)
Berdeja JG, et al. ASH 2011. Abstract 479.
Upfront, SCT-eligible
Final topic…
Relapsed/novel agents:
Multitargeted combinations
Update on Multiple Myeloma
clinicaloptions.com/oncology
VANTAGE 088: Study Design

International, multicenter, double-blind, randomized phase III trial[1]
– Vorinostat: HDAC inhibitor active when combined with bortezomib in phase I and II
trials[2-4]
21-day cycles
Relapsed/
refractory MM
patients with PD following
most recent therapy
(N = 637)
1-3 previous therapies;
bortezomib sensitive
Bortezomib 1.3 mg/m2
on Days 1, 4, 8, 11 +
Vorinostat 400 mg/day
on Days 1-14
(n = 317)
Bortezomib 1.3 mg/m2
on Days 1, 4, 8, 11 +
Placebo
(n = 320)
PD or
unacceptable
toxicity
Primary endpoint: PFS
Secondary endpoints:
OS, TTP, ORR, safety
1. Dimopoulos MA, et al. ASH 2011. Abstract 811. 2. Weber D, et al. ASCO 2008. Abstract 871.
3. Badros A, et al. Clin Cancer Res. 2009;15:5250-5257. 4. Siegel DS, et al. ASH 2011. Abstract 480.
Rel/Ref MM
Update on Multiple Myeloma
clinicaloptions.com/oncology
VANTAGE 088: PFS, OS, and Response
 PFS significantly prolonged with addition of vorinostat to bortezomib
– No difference in median OS (data not yet mature)
Bortezomib + vorinostat (n = 315)
Bortezomib + placebo (n = 320)
PFS (IAC)
Response Rate (%)
Patients With PFS (%)
100
7.63 vs 6.83 mos
HR: 0.774 (95% CI:
0.64-0.94; P = .01)
80
60
40
20
0
0
5
10
15
Mos
20
25
Dimopoulos MA, et al. ASH 2011. Abstract 811.
70 P < .0001
60
50
40
30
20
10
0
ORR CR
Response (IAC)
MR
VGPR PR
Response Type
SD
Rel/Ref MM
Update on Multiple Myeloma
clinicaloptions.com/oncology
PANORAMA-2: Study Design
 Panobinostat: potent, investigational HDAC inhibitor
– Combination with bortezomib active in relapsed/refractory MM
– ORR: 80% (overall population); 50% (bortezomib-refractory subset)[1]
 Current study evaluated efficacy of panobinostat with bortezomib plus
dexamethasone in relapsed bortezomib-refractory MM patients (N =
55)[2]
Phase I: 8 x 3-wk cycles
– Single-arm phase II trial
– Primary endpoint: ORR
Panobinostat 20 mg on Days 1, 3, 5, 8, 10, 12 +
Bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11 +
Dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12
Phase II (for patients with clinical benefit after phase I):
6-wk cycles until PD
Panobinostat 20 mg on Days 1, 3, 5, 8, 10,
12, 22, 24, 26, 29, 31, 33 +
Bortezomib 1.3 mg/m2 on Days 1, 8, 22, 29 +
Dexamethasone 20 mg on Days 1, 2, 8, 9, 22, 23, 29, 30
1. San Miguel J, et al. 2011 EHA. Abstract 0314. 2. Richardson PG, et al. ASH 2011. Abstract 814.
Rel/Ref MM
Update on Multiple Myeloma
clinicaloptions.com/oncology
PANORAMA-2: Response and Safety

Responses were rapid, often within 1-2 cycles
Response Rate, %
Panobinostat + Bortezomib + Dexamethasone
(n = 55)
ORR (CR + nCR + PR)
 CR
0
 nCR
4
 PR
25
Clinical benefit (ORR + MR)
 MR
VGPR

29
49
20
6
Most frequent grade 3/4 events: thrombocytopenia (53%), anemia (16%),
neutropenia (12%)
– Peripheral neuropathy (24%) was grade 3/4 in only 1 patient (2%)
– Fatigue (63%) was grade 3/4 in 16%; generally manageable with dose reduction
Richardson PG, et al. ASH 2011. Abstract 814.
Rel/Ref MM
Update on Multiple Myeloma
clinicaloptions.com/oncology
PANORAMA-2: Conclusions
 Combination of investigational HDAC inhibitor
panobinostat with bortezomib active[1]
– Effective even in this heavily pretreated, bortezomibrefractory MM patient set
 Treatment relatively well tolerated[1]
– Grade 3/4 myelosuppression manageable with dose
reduction or interruption
– Infrequent grade 3/4 peripheral neuropathy
 Lower toxicity with this dose schedule (1 wk rest period
between cycles) vs previously observed in phase I trial[2]
1. Richardson PG, et al. ASH 2011. Abstract 814. 2. San Miguel J, et al. 2011 EHA. Abstract 0314.
Rel/Ref MM
On the horizon
 Improving outcomes for lenalidomide/bortezomibrefractory patients
 maximizing clinical benefit
• disease control using maintenance? drug holiday? Multitargeted
combinations?
 Active clinical trials:
• Novel agents, orally administered
• MLN+rev+dex upfront
• optimal ASCT regimen? CTN 0702:
⁻ tandem len maintenance
⁻ single len+bort+dex consolidation len maintenance
⁻ single len maintenance
Acknowledgements
Myeloma Program at OHSU:
•
•
•
•
Emma Scott, MD ([email protected])
Anne Kratz, RN
Richard Maziarz, MD ([email protected])
All other MD, RN, PA/NP, admin staff at OHSU
Slides
• Rachid Baz, MD (Moffitt Cancer Center, Tampa, FL)
• Clinical Care Options (clinicaloptions.com)
• educational concepts group
(www.educationalconcepts.net)
(Extra slides)
(Extra slides)
Consolidation after ASCT- already presented in Paris 2011…
 CALGB 100104
• OS benefit to len maintenance after ASCT (90 vs 83%
OS at 28 months, p=.02)
• TTP benefit 48 mo vs 31 mo
• second malignancies higher (n=15 vs 6)
 IFM 2005- clear PFS benefit (42 vs 22 mo),
second malignancies higher, study halted
 both: higher cumulative grade 3-4 PMN with
maintenance, more 2nd malignancies…
Update on Multiple Myeloma
clinicaloptions.com/oncology
QuiRedex: Study Design
 Multicenter, open-label, randomized phase III trial
– Evaluated new treatment regimen for smoldering MM vs current standard
of care
Maintenance
Induction
Patients with
high-risk
smoldering MM
9 x 28-day cycles
28-day cycles
Lenalidomide 25 mg/day on
Days 1-21 +
Dexamethasone 20 mg/day on
Days 1-4, 12-15
Lenalidomide
10 mg/day on Days 1-21
(Low-dose dexamethasone
added at time of
biologic progression)
2 yrs
(N = 126)
No Treatment
No Treatment
Primary endpoint: TTP to symptomatic MM
Secondary endpoints: response, duration of response, safety and tolerability, PFS, OS
Mateos MV, et al. ASH 2011. Abstract 991.
Update on Multiple Myeloma
clinicaloptions.com/oncology
QuiRedex: TTP to Symptomatic MM and
OS
 Significant increase in TTP with vs without treatment
Proportion of
Patients Alive
1.0
Lenalidomide + dexamethasone
No treatment
0.8
0.6
Median TTP
Lenalidomide/dexamethasone: NR
No treatment: 23 mos
HR: 6.0 (95% CI: 2.9-12.6; P < .0001)
Median follow-up: 32 mos (range: 12-49)
0.4
0.2
0
0
5
10 15 20 25 30 35 40 45
Mos From Inclusion
 Significantly prolonged OS with vs without treatment
– Median 3-yr OS (from study inclusion): 93% vs 76%; P = .04
– Median 5-yr OS (from diagnosis): 94% vs 79%; P = .03
Mateos MV, et al. ASH 2011. Abstract 991.
Update on Multiple Myeloma
clinicaloptions.com/oncology
QuiRedex: Safety
 3 cases of second primary malignancies reported in treatment arm
Adverse Event, %
Lenalidomide + Dexamethasone
(n = 57)
No Treatment
(n = 62)
Grade 1/2
Grade 3
Grade 1/2
Anemia
28
2
--
Neutropenia
20
5
--
Thrombocytopenia
13
2
--
Asthenia
20
7
11
Constipation
18
--
2
Diarrhea
24
2
4
Rash
33
4
--
Paresthesias
5
--
--
Tremor
13
--
2
Infection
46
6
26
Deep vein thrombosis
5
--
Mateos MV, et al. ASH 2011. Abstract 991.
Alternative Bortezomib Regimens
Regimen
N
ORR
CR
Grade 1/2
PN
> Grade 3
PN
CyBorD
Twice weekly btz
Once weekly btz
33
30
88%
93%
39%
40%
64%
56%
6%
0%
VMPT-VT
Twice weekly btz
Once weekly btz
63
190
86%
85%
35%
30%
29%
19%
14%
2%
Btz: bortezomib; PN: peripheral neuropathy; CyBorD: cytarabine, bortezomib, dexamethasone;
VMPT-VT: bortezomib, melphalan, prednisone, thalidomide followed by maintenance bortezomib
and thalidomide.
Reeder CB, et al. ASH Annual Meeting Abstracts. 2009;114(22):616;
Palumbo A, et al. ASH Annual Meeting Abstracts. 2010;116(21):620.
Bort- Alternative Modes of Administration
IV Bortezomib
N = 73
SC Bortezomib
N = 145
P
ORR after 8 cycles
CR
> VGPR
52%
12%
25%
52%
10%
25%
NS
NS
NS
Median TTP
1-year OS
Any grade 3/4 AE
PN
Any grade
> grade 3
9.4 months
77%
70%
10.4 months
73%
57%
0.39
NR
NR
53%
16%
38%
6%
0.04
0.03
IV: intravenous; SC: subcutaneous; CR: complete response; VGPR: very good partial response; TTP: time
to progression; OS: overall survival; AE: adverse event; PN: peripheral neuropathy.
Moreau P, et al. Blood. 2010;116(21). Abstract 312.