SWOG Protocol S0232:
Dex +/- Lenalidomide for
Previously Untreated Myeloma
Zonder JA, Crowley JJ, Hussein MA,
Bolejack V, Abidi MH, Moore Sr. DF,
Whittenberger BF, Durie BGM, Barlogie B
Abstract #77, 49th Annual ASH meeting, Atlanta, GA
Disclosures for J. Zonder, MD
In compliance with ACCME policy, ASH requires the following disclosures to the session audience:
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Celgene, Millennium, Cephalon
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Speaker Engagements
Celgene, Millennium
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th 49
Presentation includes discussion of the following off-label use of lenalidomide and bortezomib
(initial treatment of multiple myeloma)
Background: Initial Therapy
No "Standard Therapy" exists for NDMM
· MP (T)
· VAD (DVd)
· Thal-Dex
· Pulse Dex
· Vel-Dex (Dox)
Small minority achieve CR, none cured
· ASCT improves CR rate, possibly survival
Background: Initial Therapy
No "Standard Therapy" exists for NDMM
· MP (T or V)
· VAD (DVd)
· Thal-Dex
· Pulse Dex
· Vel-Dex (Dox)
Small minority achieve CR, none cured
· ASCT improves CR rate, possibly survival
Current goal: Increase CR/nCR while
minimizing therapy-related toxicity
Background: Len-Dex in RRMM
1.0
Len/Dex (11.2 mo)
0.9
0.8
Dex (4.7 mo)
0.7
Patients
0.6
of
0.5
0.4
0.3
Proportion
P<0.001
0.2
MM-009/010:
0.1
Time to Progression
0.0
0
2.5
5
7.5
10
12.5
15
17.5
20
22.5
Time to Tumor Progression (mo)
Weber D, et al. N Engl J Med 2007;357(21):2133
Dimopoulos M, et al. N Engl J Med 2007;357(21):2123
Background:Phase II Len-Dex vs NDMM
CR
n = 34
PR
ASCT or
SD
Cont. Current Rx
Len 25 mg/day x 21d
Pulse Dex 40 mg/day*
ASA 325 mg/d
PD
*Days 1-4, 9-12, 17-20
Off Protocol
×4 cycles
>nCR/VGPR: 38% (ORR: 91%)
2-yr PFS (No ASCT): 59%
2-yr OS (No ASCT): 90%
Rajkumar SV, et al. Blood. 2005;106:4050
Lacy MQ, et al. Mayo Clin Proc. 2007;82:1179
SWOG S0232: Study Design
Induction Therapy
Maintenance Therapy
Three 35-day courses
Repeat q 28 days until PD
Len 25 mg/d x 28 days
Len 25 mg/d x 21 days
Dex 40 mg d 1­4, 9-12, 17-20
Dex 40 mg d 1­4, 14-18
(n=100)
Untreated
MM
(n=198**)
PD
PD
n=40
Placebo 25 mg/d x 28 days
Placebo 25 mg/d x 21 days
Dex 40 mg d 1­4, 9-12, 17-20
Dex 40 mg d 1­4, 14-18
(n=98)
ASA 325 mg/day required
**Protocol closed after early interim analysis by DSMC.
Eligibility
Ineligible for/declining immediate ASCT
No prior therapy (<4 d dex allowed)
Adequate renal, hepatic function
Measurable disease
· Serum M-Protein >1000 mg/dL
· Urine light chain >500 mg/24 hr
Age >18 yrs
Performance Status 0-2 (3 if due to MM)
Stratification
PS 0-1 vs 2-3
ISS stage I vs II vs III
Patient Status
198 pts
* As of July
18th, 2007
LD
D
Ineligible
Ineligible
100 pts
98 pts
19 pts
12 pts
No difference
in Age, Race,
Gender, ISS, PS
61 resp eval
72 resp eval
81 pts
86 pts
74 tox eval
82 tox eval
41 pts
58 pts
Off-Study
40 pts
28 pts
Off-Study
Patient Status
198 pts
* As of July
18th, 2007
LD
D
Ineligible
Ineligible
100 pts
98 pts
19
31 pts
12 pts
23: missing / out of window baseline M-protein
61 resp
7:
eval
concurrent medical illness / recent
72
other resp eval
cancer
81 pts
86 pts
74 tox
1:
eval
required companion study not open
82 tox eval
41 pts
58 pts
Off-Study
40 pts
28 pts
Off-Study
Response to Therapy
CR
PR
LD
Dex
X-over
SD
PD
10%
15%
38%
62%
84%
55%
49%
70%
53%
22%
15%
4%
p = 0.001
S0232: Progression Free Survival
Len-Dex
p=0.002
Dex
Len-Dex
Dex
S0232: Overall Survival
p=NS
Len-Dex
Dex
Outcomes after Cross-over to LD
100%
100%
PFS
OS
80%
80%
72% at 1 yr
62% at 1 yr
60%
60%
40%
40%
20%
20%
12-Month
12-Month
Deaths / N Estimate
Events / N Estimate
All
8 / 32
72%
All
11 / 32
62%
0%
0%
0
6
12
18
0
6
12
18
Months After Crossover Registration
Months After Crossover Registration
Major Adverse Events
LD (%)
Dex (%)
Gr.3-4 PLTs
4.2
2.4
Gr.3-4 ANC
13.8
2.4 p=0.010
Gr.3-4 Hgb
8.3
9.8
Infections (all)
51.4
28 p=0.003
Infections (Gr.3-5)*
18.9
9.8
Hyperglycemia (any)
51.4
57.3
Depression (any)
33.3
20.7
*One participant on LD arm had a Grade 5 (lethal) infection
Thrombotic Events
LD
Dex
TEEs
20
25
12
7 p = 0.089
no ASA
6
0
on ASA
14
12
After X-over
5
Summary and Discussion
LD much more active than Dex vs NDMM
· Higher ORR and CR
· High 1-yr OS rate both arms ( with Dex?)
· Effective salvage with cross-over
Toxicity is manageable but not trivial
· Grade 3-4 neutropenia , but not PLTs, Hgb
· Non-neutropenic Infections more common
Thrombosis rates remained high on ASA
· ASA compliance, other risk factors not known
· Decreased Dex dose may clot incidence
· Optimal prophylaxis not known (?LMWH)
Acknowledgements
Southwest Oncology Group
· Dana Sparks and Larissa Rios (Coordinators)
· Jason McCoy and Antje Hoering (Biostats)
· Harry Erba, MD (Executive Committee Liaison)
Karmanos Cancer Institute
· Charles Schiffer, MD
· Multiple Myeloma Research Team
Participating Investigators and Patients