Lenalidomide in Combination With Dexamethasone Is More Effective Than Dexamethasone at First Relapse in Relapsed Multiple Myeloma
Edward Stadtmauer,1 Donna Weber,2 Meletios Dimopolous,3 Andrew Belch,4 Michel Attal,5 Miles Prince,6 Marta Olesnyckyj,7 Zhinuan Yu,7 Jerome Zeldis,7 Robert Knight7
1Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; 2MD Anderson Cancer Center, Houston, TX, USA; 3General Alexandras Hospital, Athens, Greece; 4Cross Cancer Institute, Edmonton, AB, Canada; 5Service d'Hématologie Clinique, Toulouse, France;
6Peter MacCallum Cancer Institute, Melbourne, Australia; 7Celgene Corporation, Summit, NJ, USA
Table 3. Grade 3/4 adverse events by number of prior regimens
Figure 2. Time to progression
Table 6. Summary of responses
ABSTRACT
AIMS
Minimal Response (MR)
½ 25%-49% decrease in serum M-protein
1 Prior Regimen
2+ Prior Regimens
1 Prior Therapy; Len/Dex
1 Prior Regimen
2+ Prior Regimens
100
Median = 15.5 months
Background: High-dose dexamethasone (Dex) remains a standard therapy for relapsed or refractory
½ Prospective subgroup analysis to determine the potential benefit of starting
½ 50%-89% decrease in Bence Jones protein
All
Len/Dex
Dex
P
All
Len/Dex
Dex
P
P < 0 .0001
Overall
Len/Dex
Dex
Overall
Len/Dex
Dex
1 Prior Therapy; Dex
Median = 4.7 months
multiple myeloma (MM). Lenalidomide is a novel, orally administered, immunomodulatory drug (IMiD®)
Len/Dex at first relapse
Stable Disease (SD)
80
>1 Prior Therapy; Len/Dex
No. of patients
241
120
121
451
226
225
No.of patients
241
120
121
451
226
225
that has single-agent activity against MM and additive effects when combined with Dex. At the interim
½ Analyze outcomes of patients receiving Len/Dex vs Dex after 1 vs >1 prior line
½ No more than a 25% change in M-protein over at least a 3-month period
Median = 10.2 months
P < 0 .0001
Hematologic toxicities
>1 Prior Therapy; Dex
CR, n (%)
22 (9)
19 (16)
3 (3)
34 (8)
30 (13)
4 (2)
analysis, lenalidomide/dexamethasone achieved a significant benefit over dexamethasone, providing a
of therapy
Progressive Disease (PD)
Median = 4.7 months
Anemia, n (%)
14
12 (10)
2 (1.7)
<0.01
40
23 (10.2) 17 (7.6)
ns
60
(%)
nCR, n (%)
20 (8)
17 (14)
3 (3)
18 (4)
16 (7)
2 (1)
longer median time to progression (TTP), higher response rates, and higher CR rates.
½ 25% increase in nadir M-protein (must be >0.5 g/dL increase in M-protein
Thrombocytopenia,
16
11 (9.2)
5 (4.1)
ns
46
30 (13.3) 16 (7.1)
<0.05
PR, n (%)
66 (27)
40 (33)
26 (22)
123 (27)
83 (37)
40 (18)
Aim: This prospective subgroup analysis of MM-009/010 was performed to determine the potential
METHODS
for PR or reappearance for CR relapse)
n (%)
Patients
40
SD, n (%)
97 (40)
32 (27)
65 (54)
204 (45)
75 (33)
129 (57)
benefit of starting lenalidomide/dexamethasone at first relapse by analyzing outcomes with lenalidomide/
½ New lytic bone lesion/plasmacytoma
Neutropenia, n (%)
45
41 (34.2)
4 (3.3)
<0.01
82
74 (32.7)
8 (3.6)
<0.01
PD, n (%)
20 (8)
4 (3)
16 (13)
37 (8)
3 (1)
34 (15)
dexamethasone versus dexamethasone among patients who had received only 1 versus >1 prior line of
Figure 1. Study design and objectives
½ Hypercalcemia due to MM
Infection, n (%)
23
17 (14.2)
6 (5.0)
<0.05
38
21 (9.3)
17 (7.6)
ns
20
Response not evaluable*
16 (7)
8 (7)
8 (7)
35 (8)
19 (8)
16 (7)
therapy.
½ Growth of soft tissue plasmacytoma
Nonhematologic toxicities
P value (Wilcoxon rank
DVT/PE, n (%)
16
13 (10.8)
3 (2.5)
<0.01
37
27 (12.0) 10 (4.4)
<0.01
0
sum test)
<0.001
<0.001
Methods: Patients who had received at least 1 prior treatment and were not refractory to dexa-
Multiple myeloma patients (1 prior therapies)
½ >25% BM plasma cells
0
6
12
18
24
30
Neuropathy, n (%)
2
0*
2 (1.7)
ns
10
7 (3.1)*
3 (1.3)
ns
Dichotomized response
methasone were randomized to either receive oral lenalidomide (25 mg daily for 3 weeks every 4 weeks)
Fatigue, n (%)
20
13 (10.8)
7 (5.8)
ns
49
24 (10.6) 25 (11.1)
ns
Time to progression (months)
CR, nCR or PR
108 (45)
76 (63)
32 (26)
175 (39)
129 (57)
46 (20)
plus Dex (40 mg on days 1-4, 9-12, 17-20 every 4 weeks for 4 months, then 40 mg on days 1-4 every
Statistical Methods
GI (nausea, vomiting,
5
3 (2.5)
2 (1.7)
ns
13
10 (4.4)
3 (1.3)
ns
Randomization/Stratification
MM-009 North America
SD, PD, or NE
133 (55)
44 (37)
89 (74)
276 (61)
97 (43)
179 (80)
cycle thereafter) or placebo plus Dex. The European Blood and Marrow Transplantation criteria were used
Response Rates
constipation)
B
P value (Continuity-corrected
2M (2.5 vs >2.5)
(354 pts)
Figure 3. Overall survival
to evaluate response. Randomization was stratified at entry by number of prior therapies (1 versus >1).
½ Based on highest assessment of response during treatment phase of the study
Prior transplant (0 vs 1)
MM-010 International
Pearson chi square test)
<0.001
<0.001
*Indicates a significant difference between the patients with 1 prior regimen vs 2+ regimens within
Results: Among the 248 patients who had received only 1 prior therapy, those receiving second-line
½ Wilcoxon rank sum test, Pearson chi square test
Number of prior anti-MM regimens (1 vs >1)
(351 pts)
Odds ratio (Len/Dex: Dex)
the Len/Dex group.
100
lenalidomide/dexamethasone had a significantly longer median TTP (71 vs 20 wks) and a higher response
Time to Progression, Overall Survival
[95% CI]
4.80 [2.78, 8.32]
5.18 [3.41, 7.86]
Note: The P-values are based on continuity-corrected chi square tests without controlling for
rate (complete response [CR] + partial response [PR]; 65% vs. 26%) versus those receiving second-
½ Based on the number of treated subjects
multiplicity, therefore can only be used as reference.
80
*Including subjects who did not have any response assessment data at the data cutoff point, or whose
line dexamethasone. Among the 456 patients who had received >1 prior line of therapy, the median
Len/Dex
Dex/Placebo
½ Median from Kaplan-Meier estimate; Mean is univariate mean without adjusting
only assessment was "Response not evaluable".
TTP (41 vs 20 wks) and response rate (58% vs 20%) were higher with lenalidomide/dexamethasone
for censoring; 95% confidence interval (CI) about the median
Len/Dex 25 mg d 121
Placebo d 128
Table 4. Time to progression
60
(%)
compared with dexamethasone. Comparing patients who received lenalidomide/dexamethasone as
Placebo d 2228
Dex 40 mg, d 14, 912, 1720
½ P value based on one-tailed log rank test of curve differences between the
1 Prior Therapy; Len/Dex
P = 0 .01
second-line versus as later salvage therapy, the median TTP appeared longer and the response rates
Dex 40 mg, d 14, 912, 1720
treatment groups
1 Prior Regimen
2+ Prior Regimens
Patients
40
1 Prior Therapy; Dex
CONCLUSIONS
higher in patients who received lenalidomide/dexamethasone earlier, although TTP and response rates
½ Hazard ratio based on a proportional hazards model comparing the hazard
Overall
Len/Dex
Dex
P
Overall
Len/Dex
Dex
P
>1 Prior Therapy; Len/Dex
were also significantly better with lenalidomide/dexamethasone than with dexamethasone in patients
x 4 cycles
functions associated with the treatment groups (Len/Dex: Placebo/Dex)
20
P = 0 . 0002
½ Len/Dex provided higher response rates, improved TTP and OS vs Dex alone
No. of patients
241
120
121
451
226
225
>1 Prior Therapy; Dex
who received lenalidomide/dexamethasone later. Differences in the groups included prior stem cell
and a manageable AE profile at first relapse and beyond.
Progressed, n (%) 151(63)
54 (45)
97 (80)
229 (66) 123 (54) 176 (78)
Same except Dex days 14
0
transplant (66% vs 54%), thalidomide (12.5% vs 53.2%), and bortezomib (0.4% vs 11.6%) in the second-
RESULTS
½
Censored, n (%)
90 (37)
66 (55)
24 (20)
152 (34) 103 (46)
49 (22)
TTP was superior when Len/Dex was used earlier at first relapse compared
0
6
12
18
24
30
line versus later salvage therapy groups. No difference was observed in grade 3-4 adverse events or
Overall time to
with use as later salvage therapy.
Continue until progressive disease (PD) or unacceptable toxicity
Overall survival (months)
Table 1. Patient characteristics at enrollment
survival with a median follow-up of 16.8 months.
progression,
6.5
15.5*
4.65
<0.001
5.6
10.2*
4.7
<0.001
½ These data support the use of Len/Dex for patients as 2nd line therapy for
Primary endpoint: Time to progression (TTP)
Conclusions: Lenalidomide/dexamethasone provided higher response rates and improved TTP compared
median [95%CI] [5.6, 8.9] [11.1, 27.1] [3.7, 5.8]
[5.5, 6.5] [8.3, 12.1] [3.9, 4.7]
relapsed MM.
1 Prior Regimen
2+ Prior Regimens
P
(months)
Figure 4. Response rates by number of prior therapies
with dexamethasone at first relapse and beyond. Response to lenalidomide/dexamethasone was superior
Secondary endpoints: Overall survival (OS),
Hazard ratio
2.856
2.660
to that to dexamethasone regardless of the type of prior therapy. TTP and response rates appeared more
response rate (RR), safety, 1st SRE, PS
No. of patients
241
451
Acknowledgments
80
[95%CI]
[2.037, 4.005]
[2.099, 3.371]
PR
favorable when lenalidomide/dexamethasone was administered earlier at first relapse compared with its
MM-009 Investigators: R Abonour, M Alsina, K Barton, A Belch, L Bertoli, I Borrello, A Brown, H Burris, M Castine, AA
Age (years), median
63
64
ns
70
nCR
Chanan-Khan, C Chen, L Chu, S Coutre, C de Castro, P Desjardins, T Dobbs, S Farag, H Fernandez, G Geils, T Gentile,
Male, %
65.6
55.9
<0.05
64%
use as later salvage therapy. These data support the use of lenalidomide/dexamethasone for patients as
*Indicates a significant difference between the patients with 1 prior regimen vs 2+ regimens within
CR
57%
K Graff, S Gregory, JE Hays, D Hurd, MA Hussein, S Jagannath, AJ Jakubowiak, D Kuter, A Kutlar, R Lambert-Falls, S
B M (mg/L), median
3.1
3.4
<0.01
60
the Len/Dex group.
second-line therapy.
2
Eligibility Criteria
Lonial, T Martin, M Modiano, J Moreb, AA Moreno, R Niesvizky, SV Rajkumar, P Richardson, GD Roodman, G Schiller,
Hemoglobin (g/dL), median
11.8
11.8
ns
50
33
S Seropian, C Shustik, D Siegel, M Silverman-DeMagalhaes, S Singhal, G Somlo, E Stadtmauer, R Stuart, N Tirumali,
Inclusion Criteria
(%)
Albumin <3.5 g/dL, %
27.5
34.2
ns
37
R Vij, JC Wade, M Wang, D Weber, D White, P Wiernik, J Zonder.
40
INTRODUCTION
½ Refractory or relapsing MM
Table 5. Overall survival
ECOG Score 01 (%)
90.0
89.8
ns
MM-010 Investigators: A Alegre, M Attal, M Baccarani, J Baro, D Ben-Yehuda, J Bird, J Blade, P Browne, J Catalano,
½
27%
1 previous anti-MM regimens
Patients
30
B Coiffer, M Delforge, M Dimopoulos, A Dmoszynska, M Drake, H Einsele, T Facon, R Fanin, R Fenk, J-P Fermand, A
1 Prior Regimen
2+ Prior Regimens
Background and Rationale
14
Ferrant, R Foa, M Gobbi, H Goldschmidt, H Gollasch, R Greil, J-L Harousseau, A Hellmann, F Hitz, C Hulin, D Joshua,
Exclusion Criteria
20
22
Overall
Len/Dex
Dex
P
Overall
Len/Dex
Dex
P
7
½
Table 2. Treatment history at enrollment
21%
P Kaplan, E Karamanesht, N Ketterer, L Konopka, V Kozlov, M Kropff, J-J Lahuerta, M Lazzarino, M Leahy, H Ludwig,
High-dose dexamethasone (Dex) remains a standard therapy for relapsed or
½ Resistance to >200 mg Dex (1 month)
10
16
T Lysaya, G Marit, Z Masliak, U-H Mellqvist, P Mitrou, E Morra, A Nagler, E Naparstek, M O'Dwyer, A Palumbo, G
13
18
refractory MM
½ Liver enzymes <3 × normal
1 Prior Regimen
2+ Prior Regimens
P
3
No. of patients
241
120
121
451
226
225
1
3
2
Pilipenko, M Prince, F Prosper, AD Rascu, JM Rowe, H Salem, J San Miguel, U Schneider, A Spencer, C Straka, M
0
½ Lenalidomide (Len) is a novel, oral immunomodulatory drug (IMiD) that has activity
Died, n (%)
67 (28)
28 (23)
39 (32)
147 (33)
64 (28)
83 (37)
Len/Dex
Dex
Len/Dex
Dex
Streetly, J Szer, C Taverna, K Taylor, N Tretyak, C Underhill, P Wood, K Yong.
½ Serum creatinine >2.5 mg/dL
against MM with additive effects when combined with Dex1-3
No. of patients
241
451
Censored, n (%)
174 (72)
92 (77)
82 (68)
304 (67) 162 (72) 142 (63)
1 Prior Therapy
> 1 Prior Therapy
References
No. prior lines of therapy, median (range)
1
3 (19)
<0.01
Response Criteria-EBMT criteria4
Overall survival
P < 0 .001
P < 0 .001
1. Weber D. IMiDs-Results of phase III studies in relapsed/refractory myeloma. Virtual meeting presentation. Available
Previous transplant, yes (%)
64.7
53.9
<0.01
time since
29.6
29.6
25.0
0.011
24.0
NR
18.2
<0.001
Interim Analyses of Phase III Studies of Len/Dex vs Dex
Complete Remission (CR)
at: www.asco.org/ac/1,1003,_12-002511-00_18-0034-00_19-005743,00.asp.
Years from diagnosis, median (range)
2.3 (0.312.8)
4.0 (0.426.6)
<0.001
randomization, [25.0, NR] [29.6, NR] [20.2, NR]
[21.3, NR] [27.8, NR] [16.6, 23.5]
½ MM-009 and MM-010 are 2 multicenter phase III trials of Len/Dex vs Dex alone
2. Dimopoulos MA, Spencer A, Attal M et al. Study of lenalidomide plus dexamethasone versus dexamethasone
½ No serum M-protein
median [95% CI]
alone in relapsed or refractory multiple myeloma (MM): Results of a phase 3 study (MM-010). Blood. 2005;106:6a
} By Immunofixation
for relapsed/refractory MM
½ No Bence Jones protein
½ For the Len/Dex group only, 71.7% of the patients who had 1 prior therapy had
(months)
[Abstract 6].
½ At the interim analysis, Len/Dex achieved a significant benefit vs Dex alone1,2
½ <5% marrow plasma cells
Treatment Cycles and Dose Modifications
dose reduction or discontinued study, compared with 85% of the patients with
3. Rajkumar SV, Hayman SR, Lacy MQ et al. Combination therapy with lenalidomide plus dexamethasone (REV/DEX)
Hazard ratio
1.889
1.891
Longer median TTP
for newly diagnosed myeloma. Blood. 2005;106:4050-4053.
Partial Remission (PR)
½ For Len/Dex group only, the median treatment phase duration for patients with
[95% CI]
[1.152, 3.098]
[1.352, 2.646]
2+ prior therapies (P<0.01).
4. Blade J, Samson D, Reece D et al. Criteria for evaluating disease response and progression in patients with multiple
Higher response rates; higher CR rates
½ 50% decrease in serum M-protein
1 prior therapy (N=120) was 52.1 weeks; for patients with 2+ prior therapies
½ Time to progression was superior when Len/Dex was used earlier at first relapse
myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the
NR = not reached.
Manageable adverse-events profile
½ 90% decrease in Bence Jones protein
(N=226), duration was 40.1 weeks, P=ns.
compared with use as later salvage therapy
EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998;102:1115-1123.