Transcript Overall Survival 3-year

Maintenance Therapy in Myeloma
Myeloma Canada National
Conference
Donna E. Reece, M.D.
Princess Margaret Hospital
24 September 2011
Maintenance Therapy in Myeloma
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Older term derived from childhood acute leukemia
therapy
In the past, most cancers not treated with maintenance
“Maintenance” therapy defined as
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May be hard to distinguish from “consolidation” therapy
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…any treatment administered after the completion of
induction therapy in patients whose disease is either
responsive or non-progressive at that time, with the goal of
prolonging survival…
Defined as relatively intensive, short-term post-ASCT therapy
Maintenance can be used after ASCT or non-transplant
therapy
Maintenance Therapy in Myeloma
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Maintenance therapy has been tried in myeloma in
previous years
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BUT we only had melphalan, steroids and VAD as anti-myeloma
tools
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Older maintenance trials showed limited benefit from
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Melphalan maintenance not effective and too hard on normal marrow
Interferon
Steroids
What has changed?
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Availability of more effective myeloma drugs
Availability of oral drugs
Better understanding of side-effects and their management
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Weekly and/or subcutaneous bortezomib
Maintenance after ASCT
ASCT
ASCT
No
maintenance Relapse
Maintenance
with drug “A”
Use drug “A”
Relapse
?Longest Time in Remission?
?Best Overall Survival?
Use other
drugs
Phase III Maintenance Therapy Trials in
Myeloma
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Thalidomide
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Lenalidomide
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7 randomized studies
Different doses and duration of thalidomide; some used
steroids
Different control arms
2 randomized trials of low-dose lenalidomide 10 mg/day
One gave 2 months of “consolidation” with full-dose
lenalidomide first
Bortezomib
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2 randomized trials
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One used bortezomib before ASCT as well
Second is in progress
Thalidomide Maintenance Trials
Author/Year
N
Thalidomide dose
(mg)
/duration
Attal/2006
597
Thal 200 (median dose)
vs obs /progression
+
+
Spencer/2006
243
Thal 200 + pred vs pred/
12 months
+
+
Maiolino/2008
212
Thal 200 + dex vs dex/
12 months
+
NS
Barlogie/2006*
668
Thal 400/
progression
+
NS
Thal 100/
progression
+/-
Morgan/2008*
--
Progression- Overall
free
Survival
Survival
(+ in highrisk)
NS
(if optimal
relapse Rx)
Lokhorst/2010*
550
Thal 50/ progression
+
-
Stewart/2010
325
Thal 200 + pred vs obs/
48 months
+
NS
Thalidomide Maintenance Trials: Summary
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Thalidomide maintenance prolongs PFS
BUT peripheral neuropathy and other side-effects limit
the dose and duration of maintenance
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Quality of life negatively impacted
Benefit on survival variable
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Most patients cannot tolerate it much beyond a year
Likely in part related to availability of “good” therapy when the
disease progresses
Summary of Phase III Trials of
Lenalidomide Maintenance after ASCT
Author/Year
N
Pre-ASCT induction # ASCT
PFS/TTP
Median
(months)
Attal/2010
(IFM 2005-02)
614
VAD or
Velcade + dex
1 or 2
McCarthy/2010
(CALBG
100104)
568
Lenalidomide 32%
Bortezomib 42%
Thalidomide 16%
1
42
24
3-year
(%)
Lenalidomide 60%*
Observation 33%
42.3 Lenalidomide ~50%*
21.8 Observation ~25%
Attal M, et al. ASCO 2010; abstract #8018; McCathy PL, et al. ASCO 2010; abstract #8017.
Overall Survival
3-year
(%)
Lenalidomide
Observation
81%
81%
Lenalidomide
Observation
~80%
~80%
24 mo
0.00
21.9 mos
0.25
0.50
39.6 mo
IFM 2005-01
42 mo
0.75
CALGB100104
1.00
Lenalidomide Maintenance
Effect on PFS
0
6
12
18
Placebo
Progression Free Survival (PFS)
McCathy PL, et al. Haematologica 2011; 96 (Suppl 1): S23.
24
30
36
42
Revlimid
Event Free Survival (EFS)
Attal M, et al. ASCO 2010; abstract #8018.
Lenalidomide Maintenance
Overall Survival Benefit?
IMF 2005-02
0.00
0.25
0.50
0.75
1.00
CALGB 100104
0
6
12
18
Placebo
Median follow-up of 28 mos. P=0.018
McCathy PL, et al. Haematologica 2011; 96 (Suppl 1): S23.
24
30
36
Revlimid
No significant difference
Attal M, et al. ASCO 2010; abstract #8018.
42
Significant Toxicity with Lenalidomide
Maintenance Phase III Trials
Toxicity
IMF 2005-02
CALGB
Len
Placebo
Len
Placebo
Low neutrophils
(WBC)
43%
14%
43%
9%
Low platelets
12%
6%
13%
4%
Fever + low WBC
2%
0.1%
6%
2%
Documented
Infection
10%
4%
16%
5%
Discontinuation of
lenalidomide
6%
4%
13%
2%
N=23
(6.8%)
N=6
(1.6%)
N=18
(6.5%)
N=4
(2.6%)
2º malignancy
Attal M, et al. ASCO 2010; abstract #8018; McCarthy PL, et al. ASCO 2010; abstract #8017; Attal M, personal
communications; IMWG Feb 2011.
Secondary Cancers with Lenalidomide
Maintenance: Considerations
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Small increase in incidence, but.....
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No increase when lenalidomide used for relapsed myeloma
Other drugs/agents may predispose to second cancers
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IFM study counted skin cancers
CALGB study had several cases even before starting drug
Prolonged oral alkylating agents
XRT
Other chemotherapy drugs
Plasma cell disorders themselves have a slightly higher risk
of leukemia
AWARENESS and monitoring
Myeloma is the main wolf barking at the door!
Future Directions and Answers: CTN Trial
VRD x 3
Melphalan 200
mg/m2
+ ASCT
SC collection
CY + G-CSF
Melphalan 200
mg/m2
+ ASCT
Melphalan 200
mg/m2
+ ASCT
Len maintenance
Melphalan 200
mg/m2
+ ASCT
VRD
consolidation
Randomized Trial
VAD +Thalidomide Maintenance vs Bortezomib in
Induction and Maintenance
Phase III Trial of VAD or PAD Induction with Thalidomide vs
Bortezomib Maintenance: HOVON MM 65/GMMG-HD4
PFS
3-year PFS 48% vs 42%
Sonneveld P, et al. ASH 2010: abstract 40.
Overall Survival
3-year OS 78% vs 71%
Maintenance Therapy in Myeloma
Summary and Conclusions
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Median PFS after ASCT has improved without
maintenance using better induction
Maintenance with novel agents further improves PFS
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Toxicity issues are critical
PFS is 3 ½ years with lenalidomide maintenance
Overall survival results are improved in some studies of
thalidomide, lenalidomide and bortezomib maintenance
Bortezomib maintenance under further investigation
Decisions regarding maintenance will be influenced by
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Incidence of toxicity such as 2º cancers
Outcome after myeloma progression
Identification of subgroups most likely to benefit
Funding