Comparison of lenalidomide Plus Dexamethasone Therapy Used at First Relapse
vs later Salvage Therapy in Relapsed or Refractory Multiple Myeloma Patients
Edward A. Stadtmauer1, Donna M. Weber2, Ruben Niesvizky3, Andrew Belch4, H. Miles Prince5, Jesús F. San Miguel6, Thierry Facon7, Zhinuan Yu8, Robert D. Knight8, Meletios A. Dimopoulos9
1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 2M. D. Anderson Cancer Center, Houston, TX, USA; 3Weill Cornell Medical College, New York, NY, USA; 4Cross Cancer Institute, Edmonton, AB, Canada; 5Peter MacCallum Cancer Institute and University of Melbourne, Melbourne, Australia; 6Hospital Universitario de Salamanca, Salamanca, Spain; 7Hôpital Claude Huriez, Lille, France;
8Celgene Corporation, Summit, NJ, USA; 9University of Athens School of Medicine, Athens, Greece
A B S T R A C T
O B J E C T I V E S
Response and quality of response (Table 2, Figure 1)
· There was a trend toward a higher ORR in patients who had received 1 prior
Figure 3. Median PFS with lenalidomide plus
· The median duration of treatment was significantly longer for patients who had
therapy compared to 2 prior therapies (Figure 1).
Table 3. Dose reductions and discontinuations.
dexamethasone in patients receiving 1 prior therapy
Introduction: The benefit of initiating lenalidomide plus dexamethasone at first
· To evaluate the benefit of initiating lenalidomide plus dexamethasone after
received 1 prior therapy compared with those who had received 2 therapies.
· More patients with 1 prior therapy achieved a complete response (CR) or
or 2 prior therapies.
1 prior therapy
2 prior therapies
P
relapse was evaluated in this subset analysis from phase 3 studies in patients
only 1 prior therapy versus as salvage therapy in patients with relapsed or
· Significantly better quality of response was achieved when lenalidomide plus
very good partial response (VGPR) compared with those who had 2 prior
n = 133
n = 220
value
with relapsed or refractory multiple myeloma (MM).
refractory MM.
dexamethasone was used at first relapse (Figure 1).
therapies (39.8% vs 27.7%) (Figure 1).
100
1 prior therapy
median 14.1 months
· To provide insight regarding the overall sequence of therapy for patients
2 prior therapies
Median duration
Methods:
Patients from the randomized, multicenter clinical trials
with MM.
Treatment outcomes
median 9.5 months
75
of treatment,
MM-009 and MM-010 who had received at least 1 prior treatment and were
· The median TTP was longer in patients receiving 1 prior therapy compared with
Table 1. Baseline patient characteristics.
(%)
months (range)
12.5 (0.3­24.1)
9.2 (0.03­24.8) < 0.001
not resistant to dexamethasone were treated with lenalidomide (25 mg daily for
M E T H O D S
those receiving 2 prior therapies (Figure 2).
Patients who had
50
21 days of every 28-day cycle) plus dexamethasone (40 mg on days 1­4, 9­12,
1 prior
2 prior
P
· A multivariate analysis showed that a lower number of prior therapies and
a dose reduction, %
33.1
38.0
0.36
and 17­20 every 28 days for 4 months, then 40 mg on days 1­4 every cycle
Study
therapy
therapies
value
baseline -microglobulin level
Patients
2
2.5 mg/L were predictive of longer TTP.
Patients who discontinued
thereafter until disease progression or intolerance), or dexamethasone (same
· Preplanned subanalysis of 2 large randomized, double-blind, pivotal phase 3,
n = 133
n = 220
· Prior therapy with bortezomib or thalidomide was not predictive of TTP.
25
HR 0.71
due to AE, %
14.3
14.5
0.54
dose and schedule) plus placebo. Baseline characteristics such as age, sex,
multicenter trials.2­4
· PFS was longer in patients receiving 1 prior therapy compared with those
95% CI 0.2­0.99
P = 0.047
ECOG score, and baseline -microglobulin levels between the 2 patient
Median age, years
62.1
63.1
0.34
receiving
2
2 prior therapies (Figure 3).
0
groups were similar; however, median time from diagnosis and prior
Dosing
Male sex, n (%)
82 (61.7)
128 (58.2)
0.58
0
10
20
30
Table 4. Grade 3 or 4 hematological AEs with
therapy were statistically different.
· Lenalidomide 25 mg on days 1­21 of each 28-day cycle.
-Microglobulin level
lenalidomide plus dexamethasone.
2
PFS (months)
· Dexamethasone 40 mg on days 1­4, 9­12, and 17­20 of each 28-day cycle for
> 2.5 mg/L, n (%)
86 (64.7)
164 (74.6)
0.054
Figure 1. Response rates.
Results: Multivariate analysis showed that more prior therapies is associated
4 cycles, followed by days 1­4 only of each 28-day cycle.
ECOG score 0­1, n (%)
119 (89.5)
188 (85.5)
0.77
1 prior therapy
2 prior therapies
with shorter time to progression (TTP). Patients who received 1 prior therapy
· Treatment until disease progression or intolerance.
Median time from diagnosis,
n = 133
n = 220
100
P = 0.06
Figure 4. Median OS with lenalidomide plus
demonstrated a significant improvement in outcomes such as TTP, progression-
years (range)
2.2 (0.4­9.7) 4.1 (0.5­15.7) < 0.001
n (%)
n (%)
90
ORR
dexamethasone in patients receiving 1 prior therapy
free survival (PFS), overall response rate (ORR), complete response/very good
Patients
Prior ASCT, n (%)
89 (66.9)
117 (53.2)
0.014
80
CR
or 2 prior therapies.
P = 0.028
partial response rate (CR/VGPR), median duration of treatment, and overall survival
· Received at least 1 prior antimyeloma regimen.
Prior treatment with
Anemia
13 (9.8)
25 (11.4)
70
66.9
VGPR
(%)
(OS) after first relapse compared with those who received 2 prior therapies.
· Not resistant to dexamethasone.
thalidomide, n (%)
13 (9.8)
114 (51.8)
< 0.001
100
1 prior therapy
Thrombocytopenia
12 (9.0)
34 (15.5)
60
56.8
median 42.0 months
Toxicity, rate of dose reduction, or treatment discontinuation in the cohort with
· Stratified according to number of prior therapies (1 vs 2).
Prior treatment with
rate
Neutropenia
55 (41.4)
70 (31.8)
50
2 prior therapies
1 prior therapy did not increase, despite longer treatment.
bortezomib, n (%)
2 (1.5)
25 (11.4)
< 0.001
median 35.8 months
Infection
24 (18.0)
29 (13.2)
40
75
End points
ECOG, Eastern Cooperative Oncology Group.
Febrile neutropenia
2 (1.5)
6 (2.7)
Response
30
(%)
Conclusions: When used at first relapse compared with salvage therapy,
· The main end points were overall response rate (ORR), time to progression
20.3
19.5
20
15.9
11.8
50
lenalidomide plus dexamethasone treatment resulted in significantly prolonged
(TTP), progression-free survival (PFS), and overall survival (OS).
10
Patients
C O N C l U S I O N S
TTP, PFS, and OS, and an improved quality of response. Lenalidomide plus
· Response was assessed using international uniform response criteria5 and
0
Table 2. Response.
P = 0.041
dexamethasone should be considered at an early stage of therapy for patients
European Group for Blood and Marrow Transplantation criteria.6
1 prior
2 prior
25
· Lenalidomide plus dexamethasone is effective and well tolerated in patients
with MM.
· Adverse events were graded according to the National Cancer Institute
therapy
therapies
1 prior
2 prior
P
with MM.
Common Toxicity Criteria (NCI-CTC) version 2.0.
therapy
therapies
value
0
· Use of lenalidomide plus dexamethasone at first relapse resulted in
B A C K G R O U N D
0
20
40
60
80
n = 133
n = 220
unprecedented long TTP, PFS, and OS, and improved the quality of response,
Statistical methods
Figure 2. Median TTP with lenalidomide plus
OS (months)
compared with use as salvage therapy.
· Patients with multiple myeloma (MM) often relapse despite treatment with
· The Cox proportional-hazards model was used in an exploratory analysis
ORR, n (%)
89 (66.9)
125 (56.8)
0.060
dexamethasone in patients receiving 1 prior
· The greatest benefit of lenalidomide plus dexamethasone is observed with
chemotherapy or autologous stem cell transplantation (ASCT).1
to identify covariates predictive of TTP. After controlling for other baseline
CR, n (%)
27 (20.3)
26 (11.8)
0.028
therapy or 2 prior therapies.
earlier use, so this combination should be considered at an early stage
· The ideal second-line treatment regimen in patients with relapsed MM has
variables, the multivariate analysis showed that the number of prior therapies
VGPR, n (%)
26 (19.5)
35 (15.9)
· At extended follow-up, median OS was significantly longer in patients
of therapy.
100
1 prior therapy
not been standardized.
was a significant predictor of TTP (hazard ratio [HR] 1.18, 95% confidence
CR + VGPR, n (%)
53 (39.8)
61 (27.7)
0.025
median 17.1 months
who had received 1 prior therapy than in those who received 2 prior
PR, n (%)
36 (27.1)
64 (29.1)
· Lenalidomide (Revlimid®; Celgene Corporation, Summit, NJ, USA) is an oral
interval [CI] 1.06­1.32; P = 0.0032).
2 prior therapies
therapies (Figure 4).
Stable disease, n (%)
30 (22.6)
77 (35.0)
median 10.6 months
75
References
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· Univariate models then compared outcomes in patients with 1 prior therapy
Progressive disease, n (%)
6 (4.5)
2 (0.9)
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exerts a direct cytotoxic effect on myeloma cells and modifies the tumor
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Safety
2. Weber DM, et al. N Engl J Med. 2007;357:2133-42.
Response not evaluable, n (%) 8 (6.0)
16 (7.3)
microenvironment.
3. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-32.
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· Patients who had a dose reduction, with or without interruption of lenalidomide
4. Stadtmauer E, et al. Eur J Haematol. 2009;82:426-32.
· Lenalidomide has demonstrated significant efficacy and tolerability in 2 large
R E S U lT S
of treatment,
treatment, were similar among those who had 1 or 2 prior therapies (Table 3).
Patients
5. Durie BG, et al. Leukemia. 2006;20:1467-73.
randomized, double-blind, pivotal phase 3 registration trials for the treatment
months (range)
12.5 (0.3­24.1) 9.2 (0.03­24.8) < 0.001
· There was no significant difference in discontinuation rates due to adverse
6. Bladé J, et al. Br J Haematol. 1998;102:1115-23.
25
of relapsed or refractory MM.
Baseline patient characteristics (Table 1)
Median duration of
HR 0.68
events (AEs) between patients treated with 1 or 2 prior therapies (Table 3).
Disclosures
· A total of 353 patients received lenalidomide plus dexamethasone.
response, months (range) NR (11.4­NR) 13.0 (8.4­NR)
95% CI 0.48­0.97
· The most common grade 3 or 4 AE was neutropenia in patients with both 1 prior
E.A.S. has received consulting and lecture fees from Celgene Corporation. D.M.W. has received
P = 0.026
· There were significant differences in prior ASCT, prior treatment with
Patients who relapsed, %
34.5
44.4
0.16
0
grant support and lecture fees from Celgene Corporation. R.N. has received grant support
therapy and 2 prior therapies (Table 4).
0
10
20
30
and consulting and lecture fees from Celgene Corporation. H.M.P. has received grant support
thalidomide or bortezomib, and median time from diagnosis between those with
· The incidences of febrile neutropenia and anemia were similar in patients with
and consulting fees from Celgene Corporation. J.F.S.M. and T.F. have participated in Celgene
NR, not reached; PR, partial response.
1 prior therapy compared with those with 2 prior therapies.
TTP (months)
1 prior therapy or 2 prior therapies (Table 4).
Corporation Advisory Boards. Z.Y. and R.D.K. are employees of Celgene Corporation. M.A.D.
has received honoraria from Celgene Corporation.
Stadtmauer EA, Weber DM, Niesvizky R, Belch A, Prince HM, San Miguel JF, Facon T, Yu Z, Knight RD, Dimopoulos MA. Comparison of Lenalidomide Plus Dexamethasone Therapy Used at First Relapse vs Later Salvage Therapy in Relapsed or Refractory Multiple Myeloma Patients. Poster presented at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), Orlando, FL, USA, May 29 ­ June 2, 2009 J Clin Oncol. 2009;27 (15 Suppl): [abstract 8594].

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