U.S. Cooperative Group Studies
> 65 yrs/Non-transplant Candidates
ECOG
SWOG
UPFRONT
Trials in Elderly/ Non-SCT Candidates
MPT vs MP vs Mel1001
MPT longer med.PFS
MPT longer med.OS (58.6 vs 33.2 vs 38.3 mos)
MPR-R vs MPR vs MP2
MPR-R higher overall response (77% vs 50% MP)
MPR-R faster response (median 2 mos.)
MPR-R highest 2 yr PFS (55% vs 16% for MP)
VMP vs MP3
VMP longer med. PFS (24mos vs 16.6 mos)
VMP higher OS @ 2 yrs (82.6% mos vs 69.5%)
1Facon et al. Lancet. 2007;370:1209-1218.
2
3
Palumbo et al, ASH 2010: abstract 320
San Miguel et al, N Engl J Med. 2008;359:906-17
MM Induction Trials in Elderly/Non-SCT
ECOG
Lenalidomide - low-dose dexamethaone
(Ld) Vs. Lenalidomide high-dose
dexamethasone (LD)
All pts: Ld higher I yr OS (96%) than LD (87%)
2 yr OS (87%) Vs (75%)
>65 yrs: Ld higher I yr OS (94%) than LD (83%)
Rajkumar et al. Lancet Oncol: 11(1):29-37, 2010.
Current Questions to Consider in Non-transplant
Patients with Newly Diagnosed MM
· What are the best IMiD and bortezomib-based regimens for
patients not proceeding to AuSCT?
· Where does quality of life fit in?
· Can we identify optimal regimens for subgroups?
2
ECOG:E1A06: MPT Vs MPR
Cycles (28-day) 1-12
Maintenance Cy 13 +
PFS
Thalidomide
MPT
Overall Survival
Maintenance Tx
M: 9 mg/m2/d, days 1-4
100 mg/day,
P: 100 mg/d, days 1-4
days 1-28
Response
T: 100 mg/day po, days 1-28
(n=277/304)
ORR
Enteric coated ASA 325 mg /d
ASA 325mg/d
PR
Disease
VGPR
progression:
nCR
TION
Off
CR
Study
MPR
Toxicity
M: 5 mg/m2/d, days 1-4
Lenalidomide
Maintenance Tx
P: 100 mg/d, days 1-4
TC classification
R: 10 mg/d days 1-21
10 mg/day,
Enteric coated ASA 325mg/d
days 1-28
RANDOMIZA
QOL: - FACT-nTX
ASA 325mg/d
- by response
- by MM
Stratified by ISS Stage (I/II Vs III) and Age (<65 or >65)
attributes
M, melphalan; P, prednisone; T thalidomide; R, lenalidomide
Stewart et al ECOG EA1A06
3
Elderly Untreated MM: UPFRONT Phase 3b Trial:
Community-based Trial of 3 Bortezomib-based Regimens
Induction q 3 wk x 8 cycles
VcD
V: 1.3 mg/m2 IV d1,4,8,11
D: 20 mg po d1,2,4,5,8,9,11,12(cyc1-4)
d1,2,4,5(cyc5-8)
Maintenance
(n=502)
q 35d x 5 cycles
VcTD*
TION
V: 1.3 mg/m2 IV d1,4,8,11
Vc Maintenance
D: 20 mg po d1,2,4,5,8,9,11,12(cyc1-4)
V: 1.6 mg/m2 IV d1,8,15,22
d1,2,4,5(cyc5-8)
q35d x 5 cycles
T:100mg/d, po d1-21
VcMP
V: 1.3 mg/m2 IV, d1,4,8,11
RANDOMIZA
M: 9 mg/m2, po d1-4 q.o.cycle
P: 60 mg/m2, po d1-4 q.o.cycle
*Prophylactic ASA or full-dose
anticoagulants forVcTD
Niesvizky et al, ASH 2009: abstract 129
Elderly Untreated MM: UPFRONT Phase 3b Trial:
Community-based Trial of 3 Bortezomib-based Regimens
Efficacy
VcD*
VcTD*
VcMP*
(n=99)
n=93)
(n=99)
Age (med.yrs)
73.5
73
72
Stage II/III Patients
55/29
33/31
43/31
No. of Treatments (med cycles
9 (1-13)
6 (1-13)
7 (1-13)
received )
% pts. Receiving Vc maintenance
56
33
43
I
I+M
I
I+M
I
I+M
Response Rate
>PR (%)
68
71
78
79
71
73
CR/nCR (%)
24
31
36
38
31
34
>VGPR (%)
36
39
44
47
40
44
PR
32
32
34
32
31
29
*Interim analysis after 70 pts/arm enrolled
Niesvizky et al, IMW 2011: abstract P-228
4
Elderly Untreated MM: UPFRONT Phase 3b Trial:
Progression-Free Survival
Med. PFS 14.9
Med. PFS 17.2
Med. PFS 14.7
Niesvizky et al, IMW 2011: abstract P-228
Med. Follow-up 18.8 mos.
Elderly Untreated MM: UPFRONT Phase 3b Trial:
Community-based Trial of 3 Bortezomib-based Regimens
Toxicity
TOXICITY
VcD
VcTD
VcMP
At least 1 > Gr 3 Adverse Event
77
90
81
At Least 1 SAE
62
72
54
All Gr peripheral neuropathy
52
65
48
> Gr 3 Peripheral Neuropathy (%)
15
26
20
> Gr3 PN during maintenance (%)
56
2
All gr PN resulting in d/c all study drugs
7 + 4
18
18
I + M
Any Gr Thromboembolic events (%)
9 + 2
5
3
Niesvizky et al, IMW 2011: abstract P-228
5
SWOG S0777: Lenalidomide-Dexamethasone (LLD) Vs
Bortezomib-Lenalidomide-Dexamethasone (BLLD)
Induction q 28d x 6 cycles
LLD
L: 25 mg/d po/d d1-21
PFS
D: 40 mg po/d d1,8,15,22
ASA 325 mg po daily
Overall Survival
*qmo. pamidronate/zoledronic
(n=375/484)
acid If bone disease
Maintenance
Response IMWG
w/ LLD
Bank specimens for
TION
Until
future translational
Induction q 21d x 8 cycles
Disease
research
Progression
BLLD
SNP/GEP for
V: 1.3 mg/m2 IV d1,4,8,11
prognosis, biology,
L: 25 mg/d po d1-14
risk factors,
response for each
D: 20 mg po d1,2,4,5,8,9,11,12
regimen
RANDOMIZA
ASA 325 mg po daily
70 GEP validation
*qmo. pamidronate/zoledronic
acid if bone disease
Stratified by ISS Stage (I Vs II Vs III) and Intent to transplant
Durie et al, SWOG, S0777
Conclusions in Non-transplant Patients
· What are the best IMiD + bortezomib-based regimens?
· Can we identify optimal regimens for subgroups?
· Are 3-drug regimens better than novel agent 2 drug
regimens?
6
Conclusions in Non-transplant Patients
ECOG Age > 65 : Landmark Survival Probability
Regimen
1 YR
2 YR
3 YR
No AuSCT
ALL
.94
.81
.69
LD
.92
.77
.70
Ld
.95
.86
.67
AuSCT
ALL
.95
.91
.83
LD
.92
.92
.92
Ld
1.00
.90
.75
Siegel et al, ASH 2010: abstract 38
Revisit myeloablative therapy with
autologous stem cell transplant for age
> 65 yrs old?
Acknowledgements
UPFRONT
SWOG
Investigators
Investigators
Nurses
ECOG
Nurses
235sites
Investigators
394sites
RubenNiesvizky
Nurses
BrianDurie
310sites
KeithStewart
MDACC
Investigators
Nurses
7