An Outcome Study on Survival and Disease Control in Patients with High-Risk Multiple Myeloma
for Relapse, Treated with High-Dose Melphalan Combined with Bortezomib for Autotransplant
followed by Post-Transplant Maintenance with Bortezomib and Lenalidomide
Choon Kee Lee, Jeff Kaiser, Han Myint, Mary Berg, Fred Kolhouse, William Robinson
The Myeloma and Amylodosis Program, The University of Colorado Cancer Center, Denver, CO
ABSTRACT
INTRODUCTION
STATISTICAL CONSIDERATIONS
RESPONSE TO THERAPY
SURVIVAL AND RELAPSE
Long-term survival and disease control following
Maintenance therapy following autotransplant for patients
Date of the first transplant was used for the landmark
Figure 1. Number of patients achieving response
autotransplant have been known to be poor in
with multiple myeloma has been shown to improve survival and
analysis of survival. Cumulative incidence curves were
Death:
N = 2
delay relapse. Use of conventional chemotherapy and additional
calculated for response and relapse. The response criteria
symptomatic MM patients who were in relapse prior to
(1 Myeloma; 1 Pulmonary embolism)
thalidomide for maintenance improved survival of patients, in
was based on the revised criteria of the International
transplant, had adverse cytogenetic abnormalities (CA) or
Relapse: N = 5
particular, with high-risk cytogenetic findings for relapse.
Myeloma Working Group in 2006.
high LDH (> 190 IU/mL) at diagnosis. In the study, we
ts
Event:
N = 6
Relapse defined as recurrence of monoclonal protein on
n
sought to improve the outcome of these patients by
We sought to investigate the benefit of bortezomib and
ie
immunofixation or an increase in bone marrow
combining bortezomib with standard high-dose melphalan
lenalidomide for post-transplant maintenance administered long-
Pat
term. We intended to advance survival of patients with high risk
plasmacytosis above 5% in case of CR and a 25%
of
for autotransplant and implementing 3-year post-
Figure 3. Overall Survival
factors for relapse by implementing a 3-year course of post-
increase from minimal tumor mass in case of PR.
ber
transplant maintenance with bortezomib, lenalidomide
transplant maintenance with a regimen of bortezomib,
Survival analyses were calculated by the product limit
Num
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1
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and dexamethasone. Between September 2006 and
lenalidomide and dexamethasone (VLD) and lenalidomide and
estimate of Kaplan-Meier method, and the logrank analysis
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March 2009, 34 patients (median age 62, range 38 to 77
dexamethasone (LD).We are reporting a preliminary data of the
was used for comparison of two groups. Events include
l0.8
N = 32 alive (96%)
years) were accrued to the sequential regimens of 1)
a
survival and disease control.
both relapse and death of any cause.
ivrv
tandem autotransplant prepared by the MVD of
u
lS0.6
`melphalan 200 mg/m2 (D-1) + bortezomib 1.3 mg/m2 x 2
a
IC
1st AUTO
2nd AUTO
MAINTENANCE
Response
on
(D-4, D-1) + dexamethasone 20 mg x 4 (D-4 through D-
PATIENTS & METHODS
RESULTS
ti
416
16
18
sCR
or0.4
1)'; 2) the VLD of `bortezomib 1.3 mg/m2/day x 4 (D1, 4, 8,
5
3
5
6
CR
op
Pr
11) + lenalidomide 10 mg/day x 14 (D1 through 14) +
34 patients accrued between September 2006 and
Table 1. Patient Characteristics
610
9
10
VGPR
dexamethasone 20 mg/day x 4 (D1, 4, 8, 11)' q 3 months
March 2009
10
3
4
0
PR
0.2
Characteristics
N = 34
82
0
0
SD
for 2 years; 3) the LD of `monthly lenalidomide 10 mg/day
Inclusion criteria
Median Age
62 yrs (38 77)
1
0
0
0
PD
x 14 + dexamethasone 20 mg q Monday in between of the
0
1.Symptomatic active multiple myeloma requiring therapy with
Sex
22 M; 12 F
0
1
2
3
VLD for the first 2 years, followed by a monthly course for
measurable paraprotein or marrow plasmacytosis of > 30%
IgG
16
Follow-Up in Years
the 3rd year. Of the 34 patients, 11 (32%) had unfavorable
2.No prior autotransplant
IgA
10
CA, 15 (44%) high LDH and 10 (29%) prior relapse. 16
3.No prior therapy of combination of `bortezomib + lenalidomide'
Light chain
6
patients (47%) had immunoglobulin (Ig) G, 10 (29%) Ig A,
4.Age up to 78 years old
Nonsecretory
2
Figure 2. Cumulative Incidence of > CR
Figure 4. Cumulative Incidence of Relapse
6 (18%) light chain only and 2 (6%) nonsecretory MM. 14
5.SWOG performance score 0-3
LDH
< Norm al
19 (56%)
patients (41%) received tandem transplant and 20 (59%)
1
1
6.Adequate organ function
> Norm al
15 (44%)
single transplant due to insurance reasons.
a. DLCO > 45%
Cytogenetics
Norm al
23 (68%)
32 patients (94%) were able to maintain the treatment
e 0.8
N = 24 (71%)
0.8
e
b. Left ventricular ejection fraction > 45%
Abnorm al
11 (32%)
nc
c
until the last follow-up on August 15, 2009 or until relapse
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ne
|
ide
c. Serum creatinine < 3.0 mg/dL
c
|
id
or death. 19 patients achieved either a stringent complete
Album in
> 3.5 gm /dL 16 (47%)
n
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c
I 0.6
|
0.6
e
||
In
remission (s-CR) (n = 16) or CR (n = 3), with an 1-year
TREATMENT SCHEME
< 3.5 gm /dL 18 (53%)
iv
e
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v
lat
ti
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a
cumulative incidence (CI) of 46%. 2 additional patients
u
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1.Stem cell mobilization & collection
2M
> 3.5 mg/dL 16 (47%)
|
0.4
0.4
mul
achieved CR following the 2nd transplant. During the
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Cum
u
Mobilization by chemotherapy + G-CSF x 5 days
< 3.5 mg/dL 18 (53%)
|
C
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maintenance, 3 additional patients achieved s-CR (N = 1)
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Collection of > 12 million CD34+ cells/kg
Prior therapy
Yes
24 (71%)
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0.2
0.2
N = 5 (15%)
or CR (n = 2), resulting in 71% of the 18-mo CI of
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No
10 (29%)
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response > CR. By the landmark analysis at the time of
2.Tandem autologous transplant, each within 3 months
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transplant, the estimated 3-year Kaplan-Meier survival, CI
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0
0
Myeloablative regimen
Prior Relapse
Yes
10 (29%)
0
1
2
3
0
1
2
3
of relapse and event free survival (EFS) are 96% with 2
No
24 (71%)
Melphalan 200 mg/m2 on D-1 for patients < 70 years old
Follow-Up in Years
Follow-Up in Years
deaths (1 of MM, 1 of pulmonary embolism), 15% with 5
140 mg/m2 on D-1 for patients > 70 years old
Prior Bortezom ib
Yes
12 (35%)
relapses and 70% with 6 events, respectively. Presence
Bortezomib 1.3 mg/m2 on D-4 & D-1
No
22 (65%)
of CA impacted adversely the EFS: 61% of patients
Dexamethasone 20 mg daily D-4 through D-1
Prior Thalidomide
Yes
9 (26% )
Figure 5. Event-Free Survival
without CA vs. 39% of those with CA (Logrank p = 0.06).
No
25 (74%)
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1
However, a history of prior relapse or high LDH was not
Infusion of stem cells of > 4 million CD34+ cells/kg D 0
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associated with inferior EFS: 42% with prior relapse vs.
Prior Lenalidom ide Yes
7 (21% )
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l
76% without prior relapse (p = 0.27); 45% with high LDH
3.Maintenance therapy starting 2 months post-
No
27 (79%)
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a 0.8
iv
N = 28 (70%)
transplant
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vs. 51% with normal LDH (p = 0.86).
rv
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u
a. VLD every 3 months x 2 years
COMPLETION OF THERAPY
lS
SUMMARY
Although the current findings are limited by a small
a 0.6
Bortezomib 1.3 mg/m2/d, on D+1, +4, +8, +11
on
number of patients and a short duration of follow-up, the
1.Induction chemotherapy
tior
Additional bortezomib to the
data suggests that additional bortezomib to the standard
Lenalidomide 10 mg QD D+1 D+14
a. Newly diagnosed (N = 10):VLD+Doxorubicin x 3 cycles
op 0.4
Pr
standard high-dose melphalan and
high-dose melphalan and implementation of long-term
Dexamethasone 20 mg QD on D+1, +4, +8, +11
b. Previously treated (N = 24): DTPACE x 2 cycles
maintenance post-transplant with bortezomib and
b. LD Q month in between of VLDs for the first 2 years,
a 3-year maintenance post-
2.Stem cell collection
0.2
lenalidomide may overcome the adverse factors in high-
then monthly for 1 year
Median CD34+ cells: 14.25 million/kg (5.86 75.71)
transplant with bortezomib and
risk MM patients for relapse. Further study is necessary to
Lenalidomide 10 mg QD on D+1 D+14
0
confirm the findings.
3.First autologous transplant:
N = 34 (100%)
lenalidomide may overcome the
Dexamethasone 20 mg Q Monday
0
1
2
3
4.Second autologous transplant: N = 14 (41%)
Follow-Up in Years
adverse factors in high-risk MM
5.Post-transplant maintenance: N = 32 (94%)
patients for relapse.