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
CALGB 100104 Schema
Registration
Restaging
Randomization
Days 90100
Placebo
SD 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 and thalidomide and
lenalidomide therapy during induction
Objectives
· Primary Objective:
Determine the efficacy of lenalidomide in prolonging time
to progression (TTP) in myeloma patients following ASCT
Powered to determine a prolongation of TTP from 24
months to 33.6 months (9.6 months)
· Secondary Objectives:
CR rate postASCT
PFS and OS
Feasibility of longterm lenalidomide administration
Accrual
· Target Accrual: Register 538 with a goal of 462 randomized based
on 10% drop out rate
· First enrollment in April of 2005
CALGB: n=376; ECOG : n=133; BMT CTN: n=59
· Closed in July of 2009: 568 registered pts 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
CALGB DSMB Reports
· CALGB DSMB Report (the 2nd analysis) analyzed outcomes up to
September of 2009 for 418 pts: 210 on lenalidomide and 208 on
placebo and approximately 28% of required events observed
(progression or death due to any cause)
· 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 3rd 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 approximately 33% of required events
observed
· The Pvalues in this analysis have not been adjusted for
sequential setting (unadjusted Pvalues)
Patient Characteristics
Lenalidomide
Placebo
Number
231
229
Median Age (Range)
58 (2970)
57 (3970)
Male gender
48%
52%
2M >2.5 mg/L
28%
27%
Median Follow-up has increased from 12.5 to 17.5 months with this analysis
Induction Regimens: Preliminary Results
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
74 % of patients received either lenalidomide or thalidomide prior to enrollment
Adverse Events during maintenance
for 405 of 460 randomized patients
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
for 405 of 460 randomized patients
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
Excluding PD, 12% (27 of 231) on lenalidomide and 1% on placebo (2 of 208)
came off therapy due to AEs and 20% (46 of 231) on lenalidomide and 7%
(14 of 208) on placebo came off therapy for other reasons
Results
· TTP was defined as disease progression or death due to
any cause
· TTP was calculated from day 0 of ASCT
· Of 231 lenalidomide patients, 46 have experienced an
event (progression or death)
· Of 229 placebo patients, 95 have experienced an event
(p < 0.0001)
· Estimated hazard ratio of 0.40, thus a 60% reduction in
the risk of disease progression with lenalidomide
Median TTP: 42.3
Median TTP: 21.8mo
CALGB 100104,
ITT Analysis with a Median Followup from
follow up to 12/17/2009
transplant of 17.5 months (p < 0.0001)
13 deaths in lenalidomide arm and 24 deaths in the placebo arm
(p<0.052) There may have been a difference between the 2
arms which may no longer be present due to cross-over
CALGB 100104
ITT Analysis: OS based on follow-up forms
submitted on or before 12/17/2009
OS based on all followup forms to Nov 2010
on an ITT basis (p<0.078)
CALGB 100104
Results
· There was a benefit between lenalidomide over placebo in each
stratification
· 86 of ~ 110 eligible placebo patients started lenalidomide therapy
· As of November 2010, 122 lenalidomide patients and 86 placebo
patients remain on lenalidomide
· 25 new malignancies reported so far
4 before randomization
15 of 231 on lenalidomide arm
6 of 229 on the placebo arm
· Of the 25 new malignancies, there are 5 cases of AML/MDS
2 MDS cases did not receive lenalidomide
Of 3 MDS/AML lenalidomide pts, 1 received breast cancer therapy in the past
CALGB 100104, Dec 17 2009
CALGB 100104, Dec 17 2009
CALGB 100104, Dec 17 2009
Conclusions
· Maintenance therapy with lenalidomide when compared to
placebo will significantly prolong time to disease progression
· Currently, there is no difference in OS at a median followup of
1.5 years postASCT
· Lenalidomide prolonged TTP within patient stratification by high
and low 2M, and prior thalidomide or lenalidomide induction
therapy
· Lenalidomide maintenance produced some hematologic toxicity,
but this was not severe with dropouts due to all AEs at 12%
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
CALGB: C Linker, K Anderson, K Owzar, R Larson, R Schilsky, M
Bertagnolli, V Hars, 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
Ongoing Statistical Center Analyses
Evaluating other induction regimens (Bortezomib, other
agents)
Evaluating Detailed AEs
· relationship to lenalidomide or placebo dose
Response data
· prior to ASCT, at randomization, following maintenance
Ability to Continue Therapy
Dose modification
Other patient risk factors e.g. cytogenetics, LDH
Therapy after progression
Long term Followup