1
Retrospective Analysis of the Long-Term
Safety of Lenalidomide ± Dexamethasone in
Relapsed/Refractory Multiple Myeloma
Patients: Analysis of Pooled Data and
Incidence Rates of Second Primary Malignancy
Gareth Morgan1, Brian Durie2, Jesús San Miguel3, Robert Orlowski4,
Sagar Lonial5, Antonio Palumbo6, Ruben Niesvizky7, Bart Barlogie8,
Rachid Baz9, Sergio Giralt10, William Bensinger11, Nancy Brandenburg12,
Zhinuan Yu12, Mario Boccadoro13, Ken Anderson14, Paul Richardson14
1Bologna University School of Medicine, Bologna, Italy, 2Aptium Oncology, Inc., Cedars-Sinai Outpatient Cancer Center,
Los Angeles, United States, 3Hospital Universitario de Salamanca, Salamanca, Spain; 4University of Texas, MD Anderson
Cancer Center, Houston, United States; 5Emory University School of Medicine, Atlanta, United States; 6University of Turin,
AOU S. Giovanni Battista, Turin, Italy; 7Center of Excellence for Lymphoma and Myeloma, Weill Medical College of Cornell
University, New York, United States; 8 University of Arkansas for Medical Sciences, Little Rock, United States; 9Moffitt
Cancer Center, Tampa, United States; 10Memorial Sloan-Kettering Cancer Center, New York, United States; 11Seattle
Cancer Care Alliance, Seattle, United States; 12Celgene Corporation, Summit, United States; 13Divisione Universitaria di
Ematologia, Azienda Ospedaliera S. Giovanni Battista di Torino, Torino, Italy; 14Dana Farber Cancer Institute, Boston,
United States;
2
What are the questions in patients with
relapsed or refractory multiple myeloma?
· What is the background rate of malignancies in an
age-matched normal population?
· Is there an excess risk of second primary
malignancies in this patient group?
· If there is a signal, does it correlate with treatment
duration?
· What is the benefit-risk ratio for lenalidomide in this
indication?
1
3
Incidence Rates* of Invasive Cancer by Age
in the General Population (SEER, 2003-2007)
3
2.5
e
2
Rat
1.5
1
Incidence
0.5
0
5054
5559
6064
6569
7074
7579
8084
85+
Age
Overall incidence rate for persons >65 years = 2.1 per 100 patient years
*Per 100 Patient Years
4
MM-009 and MM-010
Two Randomized Phase III Trials of Len + Dex in RRMM
· North American MM-009 (48 centres in US and Canada; n = 353)1
· International MM-010 (50 centres in Europe, Australia and Israel; n = 351)2
Dex: 40 mg/day,
Lenalidomide: 25 mg/day,
days 1-4, 9-12, 17-20
days 1-21
for first 4 cycles;
MM-009, n = 177
40 mg/day, days 1-4 for
MM-010, n = 176
subsequent cycles
Continue until
disease progression or
unmanageable toxicity
Dex: 40 mg/day,
Placebo:
days 1-4, 9-12, 17-20
days 1-21
for first 4 cycles;
MM-009, n = 176
40 mg/day, days 1-4 for
MM-010, n = 175
subsequent cycles
· Primary endpoint: time to progression (by EBMT criteria)
· Secondary endpoints: overall survival, overall response rate, safety, first
skeletal-related event, performance status
Dex, dexamethasone; Len, lenalidomide; Pbo, placebo;
1. Weber DM, et al. N Engl J Med. 2007;357:2133-2142.
RRMM, relapsed/refractory multiple myeloma.
2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132.
2
5
Len + Dex in RRMM: Overall Survival Benefit
(Up to Unblinding)
Treatment
Median OS
P Value
Len + Dex
31 months
100
< 0.001
PBO + Dex
24 months
Hazard ratio (95% CI): 0.607 (0.459, 0.803)
75
)
Len + Dex
(%
50
Patients
25
Logrank
P < .001
PBO + Dex
Wilcoxan
P < .001
Pepe-Fleming
P = .003
0
0
25
50
75
100
Overall Survival (Months)
6
Len + Dex in RRMM: Overall Survival Benefit
(Including data after cross-over)
100
Treatment
Median OS
P Value
80
Len + Dex
38.0 months
.045
PBO + Dex
31.6 months
)
60
(%
Hazard ratio (95% CI): 0.822 (0.678-0.996)
40
Patients
Logrank
P =0.045
20
Wilcoxon
P =0.015
Pepe-Fleming
P =0.013
0
0
20
40
60
80
Overall Survival (months)
48% of Pbo + Dex patients crossed over to lenalidomide-based therapy
CI, confidence interval; Dex, dexamethasone; HR, hazard ratio;
Len, lenalidomide; PBO, placebo
1. Dimopoulos MA, et al. Leukemia. 2009;23:2147-2152.
3
7
Invasive SPM in RRMM: MM-009/010
Double-blind phase
Long-term follow-up only
SPM = 2
SPM = 0
PBO + Dex
IR: 0.91
817 PY
IR: 0
(95% CI 0.233.66)
(n = 350)
total
218 PY
599 PY
SPM = 8
SPM = 0
Len + Dex
IR: 1.71
886 PY
IR: 0
(n = 353)
(95% CI 0.863.43)
total
467 PY
419 PY
0
100
200
300
400
500
600
700
800
900
Person-Years
· Incidence of invasive SPM
­ Len + Dex: 6 solid tumours, 2 MDS (no AML/B-cell malignancy)
­ PBO + Dex: 2 solid tumours
a Includes MDS and breast carcinoma in situ, excludes non-melanoma skin cancers.
CI, confidence interval; Dex, dexamethasone; IR, incidence rate per 100 person-years (PY).
8
SPM in RRMM: MM-009/010
Time to invasive SPM (on study period)
50
Len + Dex
PBO + Dex
)
(%
Hazard ratio (95% CI): 1.445 (0.294 7.09)
25
P=0.649
Patients
0 0
10
20
30
40
50
60
Time (months)
No. at Risk
Len + Dex
353
176
108
66
48
19
0
PBO + Dex
350
66
28
17
15
2
0
4
9
SPM in RRMM: MM-009/010
Treatment and Outcome of Invasive SPM ­ Len + Dex
Invasive Malignancy
Demo-
Time Rx
Treatment
Outcome
graphics
to SPM
Recovered, death unrelated to
Fibrous histiocytoma
F, 67 yrs
19 months
Treated1
SPM
15 months later
Bronchioalveolar
carcinoma
F, 62 yrs
36 months
Treatment unknown
Alive as of 07 May 2008
Recovered; death unrelated to
Glioblastoma multiforme,
Resection,
grade 4
M, 73 yrs
13 months
SPM (pneumonia)
Radiotherapy
15 months later
Lung adenocarcinoma,
Palliative
Died (due to progressive lung
stage IV2
F, 57 yrs
45 months
chemotherapy
cancer) 21 months later
Prostate cancer
Alive at last follow-up 47 months
M, 73 yrs
1 month
Hormone therapy
later (as of 17 Oct 2005)
Transitional cell carcinoma
Resection,
M, 66 yrs
44 months
Relapse, alive as of Feb 2011
chemotherapy
Died (due to pneumonia,
MDS (RARS)
M, 60 yrs
21 months
Treatment unknown
myocardial infarction) 7 months
later
MDS (RA)3
No treatment except
Died (progression of myeloma) 18
M, 52 yrs
10 months
for Procrit for anemia
months later
Both MDS patients had a hypoplastic marrow at baseline.
1Details not provided
2Breast cancer in situ occurred in the same patient
3Complex karyotype: del(5); del(7); t(11;17), del 20
10
SPM in RRMM: MM-009/010
Treatment and Outcome of Invasive SPM ­ PBO + Dex
Invasive Malignancy
Demo-
Time Rx
Treatment
Outcome
graphics
to SPM
Recovered, no data
Fibrous histiocytoma
M, 51 yrs
25 months
Resection
available for survival
status
Recovered,
Death ( due to
Malignant melanoma
Excision with
M, 70 yrs
4 months
progression of
lymphadenectomy myeloma) 17 months
later
M: Male, F: Female
5
11
Long-Term Safety of Len in RRMM:
Analysis of Pooled Data
· 3,846 patients from 11 Celgene-sponsored
studies in RRMM
­ Mainly early phase studies or expanded access
programs
· Only MM-009/010 had control arms
­ Median age: 64 years (range 29-92);
14% were 75 years old
­ Treatment regimen:
· 263 (7%) patients received len monotherapy
· All other patients received lenalidomide +
dexamethasone
· Duration of lenalidomide-based therapy:
Median 5 months (range, 0.03-58 months)
12
Long-Term Safety of Len in RRMM:
Incidence Rates for Invasive SPM
(by Treatment Duration)
6.00
PY)
100
4.00
(per
Rate
2.00
Incidence
2.08
2.12
2.13
2.35
2.45
Incidence Rate
0.00
All Patients
12
18
24
36
(N=3,846)
(N=697)
(N=450)
(N=313)
(N=130)
Treatment Duration (Months)
6
13
Long-Term Safety of Len in RRMM:
Type of SPM (Based on 52 SPMs)
All pts
Treatment Duration
(N=3,846)
24 mon (N=313)
Haematologic SPM
MDS
5
3
AML
1
1
B-cell lymphoma
2 (1 EBV-ass. LPD)
0
Invasive Solid Tumours
Gastrointestinal
10
3
Prostate
6
2
Skin
5
3
Lung
5
3
Brain/Eye
6
1
Breast
3
2
Bladder
2
2
Oral cavity
2
0
Bone
1
0
Other/Unspecified
4
2
14
What are the questions in patients with
relapsed or refractory multiple myeloma?
· What is the background rate of malignancies in
an age-matched normal population?
­ App. two per one hundred patient years
· Is there an excess risk of second primary
malignancies in this patient group?
­ No, current evidence does not show a
statistically significant difference between
treatment arm or from normal population
7
15
What are the questions in patients with
relapsed or refractory multiple myeloma?
· If there is a signal, does it correlate with
treatment duration?
­ In patients with prolonged treatment no
significant difference was noted to shorter
treatment or background rates
· What is the benefit-risk ratio for lenalidomide in
this indication?
­ With the overwhelmingly positive overall
survival benefit and the low rate of SPMs
which do not differ from population estimates
the benefit-risk ratio should be considered
strongly positive
8