Dexamethasone Dose Adjustments Seem to Result in Better Efficacy and Improved Tolerability in Patients With
Relapsed/Refractory Multiple Myeloma Who Are Treated With Lenalidomide/Dexamethasone (MM-009/010 Subanalysis)
Jesus F. San Miguel1, Meletios Dimopoulos2, Donna M. Weber3, Marta Olesnyckyj4, Zhinuan Yu4, Jerome B. Zeldis4, Robert D. Knight4, Vincent S. Rajkumar5
1Hospital Universitario de Salamanca, Salamanca, Spain; 2University of Athens School of Medicine, Athens, Greece; 3M.D. Anderson Cancer Center, Houston, TX, USA; 4Celgene Corporation, Summit, NJ, USA; 5Mayo Clinic Cancer Center, Rochester, MN, USA
BACKGROUND
· The following parameters of clinical outcome were recorded: overall response
· For patients with and without dose reductions, the median age was 62.0 and
Figure 1. Kaplan-Meier plots of TTP in patients treated with
Table 3. Most common grade 3 and 4 adverse events in patients by
(OR) rate, time to progression (TTP), OS, and AEs. Response rates and TTP were
63.5 years. In the two groups of patients, the median time from first pathological
lenalidomide plus dexamethasone.
dexamethasone dosing groups, post-dose reductions.
· Lenalidomide (Revlimid®; Celgene, NJ, USA) in combination with dexamethasone
based on data obtained before unblinding, which occurred in June 2005 for study
diagnosis was 3.2 and 2.9 years.
has shown efficacy in patients with relapsed or refractory multiple myeloma (MM) in
MM-009 and August 2005 for study MM-010.
Adverse event, n (%)
Dexamethasone
Dexamethasone
two recent trials, MM-009 and MM-010.1,2
Unchanged dose, median 10.3 months
Response
unchanged
reduced
Reduced dose, median NR
100
RESULTS
· In patients treated with lenalidomide plus dexamethasone, the OR rate was
(n = 224)
(n = 56)
· Rajkumar et al. have recently reported results from a pre-planned interim analysis
significantly higher among those who received a dexamethasone dose reduction
of a randomized phase III study comparing lenalidomide plus high (standard)-dose
Patient characteristics
compared with those who received the assigned dexamethasone dose (78.5% versus
80
Neutropenia
71 (31.7)
24 (42.9)
dexamethasone with lenalidomide plus low-dose dexamethasone in patients with
· Out of 280 patients, 224 patients were treated according to the planned
55.3%; P = 0.002) (Table 2).
newly diagnosed MM.3 The data-monitoring committee for this study recommended
)
schedule without dose reductions (dexamethasone 40 mg/day) and 56 patients
Infection
25 (11.2)
9 (16.1)
60
(%
releasing the survival data and offering all patients the low-dose option, because
required dose reductions.
· Similarly, patients who received a dexamethasone dose reduction had a higher
DVT/PE
26 (11.6)
4 (7.1)
ts
low-dose dexamethasone in combination with lenalidomide significantly improved
n
complete response rate compared with those who received the assigned
e
Thrombocytopenia
20 (8.9)
3 (5.4)
40
ti
overall survival (OS) compared with high-dose dexamethasone plus lenalidomide.
· Baseline characteristics were well balanced between the treatment groups (Table 1).
dexamethasone dose (23.2% versus 14.3%) (Table 2).
Pa
Anemia
18 (8.0)
3 (5.4)
20
Fatigue
12 (5.4)
1 (1.8)
· Of note in MM-009 and MM-010, dexamethasone dose reductions were permitted
TTP and OS
GI disorders
6 (2.7)
3 (5.4)
in relation to severity of adverse events (AEs).
· In patients who were treated with lenalidomide plus dexamethasone, the median TTP
Table 1. Baseline characteristics of patients treated with lenalidomide
0
Peripheral neuropathy
2 (0.9)
1 (1.8)
has not been reached in the dexamethasone dose-reduction group compared with
plus dexamethasone who received either dexamethasone at the
0
10
20
30
STUDY OBJECTIVE
10.3 months for the group treated with the assigned dose (P = 0.005) (Figure 1).
assigned dose or dexamethasone dose reductions.
TTP (months)
GI, gastrointestinal.
· In order to further examine the potential benefits of combining lenalidomide with
· Similarly, the median OS has not been reached in the dexamethasone
Dex, dexamethasone; NR, not reached.
Characteristic
Dexamethasone
Dexamethasone
low-dose
dexamethasone,
we
retrospectively
investigated
the
effect
of
dose-reduction group, while it was 33.5 months for the assigned-dose group
dexamethasone dose reductions on efficacy and tolerability of lenalidomide plus
unchanged
reduced
(P = 0.019) (Figure 2).
· The respective frequencies of the most common grade 3 and 4 AEs in patients
dexamethasone in patients with relapsed or refractory MM.
(n = 224)
(n = 56)
who received dexamethasone dose reductions, compared with those who did not,
Figure 2. Kaplan-Meier plots of OS in patients treated with
were: neutropenia (42.9% versus 31.7%); infection (16.1% versus 11.2%), deep
lenalidomide plus dexamethasone.
METHODS
Median age, years (range)
62.0 (33.086.0)
63.5 (40.081.0)
vein thrombosis (DVT) / pulmonary embolism (PE) (7.1% versus 11.6%);
Table 2. Clinical response in patients treated with lenalidomide plus
Male, n (%)
134 (59.8)
32 (57.1)
thrombocytopenia (5.4% versus 8.9%), and anemia (5.4% versus 8.0%) (Table 3).
dexamethasone who received either dexamethasone at the assigned
· This is a retrospective analysis of data from 704 patients with relapsed or
Unchanged dose, median 33.5 months
Median time since diagnosis, years (range)
3.2 (0.415.7)
2.9 (0.514.2)
dose or dexamethasone dose reductions.
Reduced dose, median NR
refractory MM, without prior resistance to dexamethasone, enrolled in the MM-009
100
Durie-Salmon stage, n (%)
CONCLUSIONS
and MM-010 trials.
I
7 (3.1)
5 (8.9)
Dexamethasone
Dexamethasone
P
80
· In this study, dexamethasone dose reductions improved the efficacy of
· In these studies, patients with MM previously treated with 1 prior antimyeloma
II
74 (33.0)
13 (23.2)
unchanged
reduced
lenalidomide plus dexamethasone in terms of response rates, TTP, and OS.
therapy were randomized to receive 25 mg/day oral lenalidomide on days 121 of
III
142 (63.4)
38 (67.9)
(n = 224)
(n = 56)
)
60
each 28-day cycle, or placebo.1,2
NA
1 (0.4)
0 (0.0)
(%
· Most dexamethasone dose reductions were due to AEs. However, by reducing the
ts
ECOG performance status, n (%)
n
dose, patients were able to maintain a safety profile similar to those who did not
Response, n (%)
e
40
ti
· Both groups received 40 mg/day oral dexamethasone on days 14, 912, and 1720
0
97 (43.3)
22 (39.3)
require dose reductions.
OR
124 (55.3)
44 (78.5)
0.002
Pa
of each 28-day cycle for 4 cycles. After 4 cycles, dexamethasone (40 mg/day) was
1
103 (46.0)
23 (41.1)
Complete response
32 (14.3)
13 (23.2)
20
administered on days 14.
· Overall, these results may have implications for the future use of different
2
21 (9.4)
7 (12.5)
Very good partial response
33 (14.7)
13 (23.2)
dexamethasone doses in the treatment of patients with relapsed or refractory MM.
· For this post hoc analysis, we pooled data from the MM-009 and MM-010
3
0 (0.0)
0 (0.0)
Partial response
59 (26.3)
18 (32.1)
0
0
10
20
30
40
50
studies for patients treated in the lenalidomide/dexamethasone group who had an
NA
3 (1.3)
4 (7.1)
Stable disease
75 (33.5)
10 (17.9)
OS (months)
unchanged lenalidomide dose, at least during the first 4 cycles (N = 280).
-Microglobulin level (mg/L), n (%)
Progressive disease
4 (1.8)
1 (1.8)
2
References
2.5
75 (33.5)
17 (30.4)
Response not evaluable
21 (9.4)
1 (1.8)
1. Weber D, et al. N Engl J Med. 2007;357:2133-42.
Dex, dexamethasone; NR, not reached.
· Patients with dexamethasone dose reductions were defined and classified as those in
2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-32.
> 2.5
149 (66.5)
39 (69.6)
whom:
3. Rajkumar SV, et al. J Clin Oncol. 2007;25 Suppl:[abstract LBA8025].
No. of prior antimyeloma therapies, n (%)
Efficacy, months*
a) either during the first 4 cycles, for at least 1 cycle, dose level was reduced
4. Bladé J, et al. Br J Haematol. 1998;102:1115-23.
Safety
1
79 (35.3)
24 (42.9)
Median TTP
10.3
NR
0.005
to 20 mg and the number of days on dexamethasone was reduced to 4,
· Among patients who were treated with lenalidomide plus dexamethasone, 89%
2
145 (64.7)
32 (57.1)
Median OS
33.5
NR
0.019
Conflicts of interest
b) or during the remaining cycles, for at least 1 cycle, dose level was reduced
received a dexamethasone dose reduction due to AEs.
MM, ZY, JBZ, and RDK are employees of Celgene Corporation. JBZ has stock options in Celgene Corporation. DMW has
to 20 mg.
received funding from Celgene Corporation. DMW, MD, and JSM are all on the Speakers Bureau for Celgene Corporation.
ECOG, Eastern Cooperative Oncology Group; NA, not available.
NR, not reached. *Most conservative median estimate obtained assuming all censored
· 14 of the 56 patients (25%) had their first dose reduction before cycle 5, 29 (52%)
· The European Group for Blood and Marrow Transplantation (EBMT) criteria were used
P > 0.05 for all characteristics.
patients died right after the censor date.
started between cycle 5 and 10, another 9 (16%) started between cycle 11 and 15,
Acknowledgments
to evaluate response.4
and the remaining 4 (7%) started between cycle 7 and 23.
The MM-009 and MM-010 studies were funded by Celgene Corporation.