CALGB 100104
A Phase III Randomized, DoubleBlind Study of
Maintenance Therapy With Lenalidomide (CC 5013) or
Placebo Following Autologous Stem Cell
Transplantation for Multiple Myeloma
Philip McCarthy, Roswell Park Cancer Institute, representing CALGB, ECOG and BMT CTN
Disclosures
· Consulting
Celgene
Onyx
1
CALGB 100104 Schema
Registration
Restaging
Randomization
Days 90100
Placebo
DS Stage 13, <70 years
>2 cycles of induction
Mel 200
CR
Attained SD or better
PR
1 yr from start of therapy
ASCT
SD
Lenalidomide*
>2 x 106 CD34 cells/kg
10 mg/d with
(515 mg)
* provided by Celgene
Corp, Summit, NJ
Patient stratification based on diagnostic 2M level and prior thalidomide and
lenalidomide use during Induction
A Priori Trial Objectives
· Primary Objective:
Determine the efficacy of lenalidomide in prolonging time
to progression (TTP) in multiple myeloma patients
following single ASCT
Powered to determine a prolongation of TTP from 24
months to 33.6 months (9.6 months)
· Secondary Objectives:
CR rate postASCT
Overall Survival (OS)
Feasibility of longterm lenalidomide administration
2
Accrual
· First enrollment in April of 2005
CALGB: n=376; ECOG: n=133; BMT CTN: n=59
· Closed in July of 2009: 568 registered patients from 47 Centers
· Drop out rate before randomization is 19%
PD/NR (16%)
AEs (5%)
Died during Rx (2%)
Refusal (26%)
Other disease (1%)
Other Rx (4%)
Other reasons (33%)
Unknown (14%)
· Patients continued on therapy until progression
Induction Regimens
Regimen
N
%
Thalidomidebased (No Bortez or Len)
152
27
Lenalidomidebased (No Bortez or Thal)
122
22
Bortezomibbased (No Len or Thal)
109
20
Bortezomib+Thalidomidebased (No Len)
68
12
Bortezomib+Dex+Lenalidomide (No Thal)
52
9
Dexamethasonebased (No Bortez, Len or Thal)
23
4
Thalidomide and Lenalidomide treatment
17
3
Bortezomib, Lenalidomide and Thalidomide treatment
3
1
Other
2
1
Missing
6
1
Total
554
100
43% of patients received a thalidomidecontaining, 35% a lenalidomidecontaining
and 42 % a bortezomibcontaining regimen prior to enrollment
3
Adverse Events during Maintenance
Max Adv Events
3 Severe
4 Life Threat
5Lethal
Total
n
%
n
%
n
%
n
Hematologic
P<0.0001
Lenalidomide
64
31
29
14
0
0
208
Placebo
14
7
8
4
0
0
197
Non Hematologic
P=0.0350
Lenalidomide
61
29
7
3
3
1
208
Placebo
37
19
8
4
3
2
197
Grade 35 Adverse Events during Maintenance
Lenalidomide n=208
Placebo n=197
PValue
N
%
N
%
Thrombocytopenia
26
13
7
4
=0.0009
Neutropenia
89
43
17
9
<0.0001
Anemia
9
4
2
1
=0.0629
Fatigue
11
5
7
4
=0.4736
Rash
9
4
3
2
=0.1418
Diarrhea
9
4
5
3
=0.4182
Febrile neutropenia
12
6
3
2
=0.0329
All other Infections
33
16
11 5
=0.0012
There were no Gr 5 AEs due to neutropenia in both arms and 11% Gr 4 neutropenia
AEs for lenalidomide and 2 % for placebo.
Excluding PD, 12% on Lenalidomide and 1% on placebo came off therapy due to
AEs and 20% on Lenalidomide 7% on placebo came off therapy for other reasons
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Second Cancers
· 29 new second cancers reported from 568 registered patients
not including 5 non melanoma skin cancers
· Hematologic Malignancies
3 occurred before randomization
· MDS (3)
2 protocol violations
8 of 231 on lenalidomide arm
· ALL (1), HL (1), AML (5), MDS (1)
0 of 229 on placebo arm
· Solid Tumors
4 occurred before randomization
· Breast (1), Prostate (1), Melanoma (1), Unknown Primary (1)
10 of 231 on lenalidomide arm
· GI (2), Breast (2), Gyn (2), CNS (1), Prostate (1), Thyroid (1), Melanoma (1)
4 of 229 on placebo arm
· Carcinoid (1), Sarcoma (1), Melanoma (2)
Second Cancers
· Second Cancer Screening the past 2 months
· 345 patient screening forms have been submitted so far
· No new hematologic malignancies, 5 solid tumors
· Hematologic Malignancies
· Median onset: 28 months post randomization (Range 12 to 46 months)
· Anthracycline Regimens: 6 of 11 patients
· Cytogenetics: No correlation with second cancer but < 30% with
adequate data and pending central review
· Solid Tumors
· Lenalidomide arm median onset: 14 months post randomization (range
3 to 52 months)
· Placebo arm times to onset: 6, 24, 37 months post randomization with
one pending dates
· No correlation with a specific cancer type
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CALGB Data Safety and Monitoring Board
(DSMB) Report
· CALGB DSMB as per protocol analyzed outcomes up to
September of 2009 for 418 pts: 210 on lenalidomide and 208 on
placebo and with 28% of required events observed (progression
or death before progression)
· The DSMB released the study results on 12/17/09
· The study was unblinded allowing patients to cross over to
openlabel lenalidomide with MD support
· This report is the 6th Intent to Treat (ITT) analysis for TTP and
includes events up to 12/17/09 for 460 pts: 231 on lenalidomide
and 229 on placebo with 33 % of required events observed as
well as events up to 04/17/2011
· The Pvalues in these analyses have not been adjusted for
sequential setting (unadjusted Pvalues)
TTP Results
· TTP was defined as time to disease progression or
death due to any cause
· TTP was calculated from day 0 of ASCT
· As of 12/17/2009, of 231 lenalidomide patients,
47 experienced an event (progression or death)
· Of 229 placebo patients, 97 experienced an event
(p < 0.0001)
· Estimated hazard ratio of 0.38 (95% CI = 0.27 to
0.55), thus a 62% reduction in the risk of disease
progression in the lenalidomide arm
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Median TTP: 39.6 mo
Median TTP: 21.9 mo
CALGB 100104,
ITT Analysis with a Median Followup from
follow up to study unblinding
transplant of 18 months P < 0.0001
TTP Results
· 86 of ~ 110 eligible placebo patients crossed over and
started lenalidomide therapy after 12/17/2009
· As of February 2011, 122 lenalidomide arm patients
and 86 placebo arm patients continue on lenalidomide
· As of 04/17/2011, of the original 231 lenalidomide
patients, 69 have experienced an event (progression or
death)
· Of 229 placebo patients, 116 have experienced an
event (p < 0.0001)
· Currently, the estimated hazard ratio is 0.44 (95% CI =
0.32 to 0.60), thus a 56% reduction in the risk of
disease progression in the lenalidomide arm
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Median TTP: 48 mo
Median TTP: 30.9 mo
CALGB 100104,
ITT Analysis with a Median Followup from
follow up to 04/17/2011
transplant of 28 months. P < 0.0001
Overall Survival Results
· OS was a secondary endpoint of this study
· OS was calculated from day 0 of ASCT
· As of 12/17/2009, when the study was un
blinded, of 231 lenalidomide patients, there
were 13 deaths and of 229 placebo patients,
there were 24 deaths (p = 0.05)
· The HR is 0.51 (95% CI = 0.26 to 1.014)
· As of 04/17/2011, there were 23 deaths in the
lenalidomide arm and 39 deaths in the placebo
arm (p = 0.018)
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13 deaths in the lenalidomide arm
and 24 deaths in the placebo arm
CALGB 100104,
Median Followup of 18 months
follow up to study unblinding
P = 0.05
23 deaths in the lenalidomide arm and 39 deaths
in the placebo arm
CALGB 100104,
Median followup of 28 months
follow up to 04/17/2011
P = 0.018
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Event Free Survival
· This is an unplanned and preliminary analysis pending final
second cancer data collection
· EFS was defined as time to first event: disease progression
or second cancer or death due to any cause
· Nonmelanoma skin cancer patients were included in the
analysis but their cancers did not count as events
· EFS was calculated from day 0 of ASCT
· As of 04/17/2011, of 231 lenalidomide patients, 78 have
experienced an event (progression, second cancer or death)
· Of 229 placebo patients, 116 have experienced an event (p
< 0.0001)
· Estimated hazard ratio of 0.51 (95% CI = 0.38 to 0.68), thus
a 49% reduction in events in the lenalidomide arm
Median EFS: 43.4 mo
Median EFS: 30.9 mo
CALGB 100104,
Median followup of 28 months
follow up to 04/17/2011
P < 0.0001
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Median EFS: Stratified by 2M level
CALGB 100104,
Placebo Nl 2M, 33 mo; Placebo elevated 2M, 24 mo;
follow up to 04/17/2011
Len Nl 2M, 48 mo; Len elevated 2M, 43 mo
Median EFS: Stratified by prior Thalidomide use
CALGB 100104,
Placebo No Prior Thal, 25 mo; Placebo Prior Thal, 34 mo;
follow up to 04/17/2011
Len No Prior Thal, 43 mo; Len Prior Thal, 39 mo
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CALGB 100104,
Median EFS: Stratified by Prior Lenalidomide Use
Placebo No Prior Len, 33 mo; Placebo Prior Len, 32 mo;
follow up to 04/17/2011
Len No Prior Len, 39 mo; Len Prior Len, Not reached
Median TTP: Stratified by Prior Lenalidomide Use
CALGB 100104,
Placebo No Prior Len, 33 mo; Placebo Prior Len, 28 mo;
follow up to 04/17/2011
Len No Prior Len, 46 mo; Len Prior Len, Not reached
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Conclusions
· Maintenance (continued) therapy with lenalidomide post
single ASCT when compared to placebo significantly
prolongs time to disease progression
· There is an Overall Survival improvement in the
lenalidomide arm at the most recent analysis with a
median followup of 28 months postASCT
· Second cancers may be increased in the lenalidomide arm
but without significant effect on EFS or OS at this time
· Research efforts continue to identify risk factors for the
development of second cancers
Conclusions
· Lenalidomide prolonged TTP and EFS even after
stratification by diagnostic 2M level and prior thalidomide
or lenalidomide induction therapy
· TTP and EFS were superior in patients receiving
lenalidomide as part of induction and postASCT
maintenance or continued therapy
· After primary therapy, maintenance or continued therapy
studies with lenalidomide and other agents, alone or in
combination may determine optimal strategies for long
term multiple myeloma disease control
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Participating Centers
· CALGB: Dana Farber Cancer Inst, Illinois Onc Res Assoc, Memorial Sloan
Kettering Cancer Ctr, Mt Sinai School of Med, North Shore Univ Hosp, Roswell
Park Cancer Inst, State Univ NY, Upstate Med Univ, Ohio State Univ Med Ctr,
Univ California San Diego, Univ California San Francisco, Univ Chicago, Univ
Illinois Chicago, Univ Minnesota, Univ Nebraska, Univ North Carolina Chapel
Hill, BMT Group Georgia, Virginia Commonwealth Univ, Univ of Vermont,
Wake Forest Univ School Medicine, Walter Reed Army Med Ctr, Washington
Univ School Medicine, Weill Med College Cornell Univ, Western Pennyslvania
Hosp
· ECOG: Cancer Inst of New Jersey, Case Western Metro Health Med Ctr,
Columbia Presbyterian, St Lukes Hsp, Univ of Florida Gainesville, Fox Chase
Cancer Ctr, Geisinger Med Ctr, Indiana Univ Medical Ctr, Jewish Hospital,
Marshfield Clinic, Med College Georgia, Univ Miami, Univ Pennsylvania, Univ
Pittsburgh, Scottsdale, Univ Hospital Cleveland, Vanderbilt Univ, Med College
of Wisconscin, Univ of Wisconsin
· BMTCTN: City of Hope, LDS Hosp, MD Anderson, Oregon Health Sciences
Univ, Univ of Mississippi Med Ctr
CALGB 100104 Cooperative Effort
Patients, Caregivers and the Clinical Teams
CALGB: C Linker, K Anderson, K Owzar, R Larson, R Schilsky, M
Bertagnolli, V Hars, C Jiang, M Kelly, M Seiler, L Bressler, J Postiglione,
S Sutherland, C Hofmeister, H Hassoun, D Hurd, P Richardson, D
Weisdorf, R Vij, T Gentile, K van Besien, T Shea, A Bashey, L Isola, S
Devine
ECOG: E Stadtmauer, J Wingard, N Callandar
BMTCTN: S Giralt, M Horowitz, M Pasquini, J Ferrara, J Antin, R
Maziarz, A Krishnan, G Somlo, S Carter, N Poland, A Foley, C Gurgol
This study was supported in part by grants from the NCI to
CALGB (M Bertagnolli, MD, Chair), to the CALGB Statistical Center (S
George, PhD), to ECOG and NHLBI/NCI funding to BMTCTN. The
content of this presentation is solely the responsibility of the authors
and does not necessarily represent the official views of the NCI
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