The Impact of Withholding Immunomodulatory Drugs
for Stem Cell Mobilization on Disease Activity in Multiple Myeloma
Abstract 1884
Preeti Khetarpal, MD1, Amitabha Mazumder, MD1, Ajai Chari, MD1, Sundar Jagannath, MD1, David H. Vesole, MD, PhD2
1St. Vincent's Comprehensive Cancer Center, New York, NY; 2John Theurer Cancer Center, Hackensack, NJ
OBJECTIVES
RESULTS
had near progressive disease. In Group 3 (L), 54% (n=7) had stable disease, 8%
consequence of insufficient cycles of therapy, with the median being 4 prior to
(n=1) had progressive disease, and 38% (n=5) had near progressive disease. Ten
stem cell mobilization. Thus, the maximal benefit of these combination therapies
· To determine the frequency of disease progression during the washout
The median myeloma parameters, including serum M protein level, involved serum
patients in Group 3 (L) received cyclophosphamide to aid in stem cell mobilization.
may not have been reached, leading to unsustained responses. The frequency of
period from the end of induction therapy to the time of stem cell mobilization
immunoglobulin level, and involved serum free light chain level at baseline, end of
The median number of days from the end of induction to the time of transplant (i.e.
progression, however, did not appear to differ according to the induction regimen in
and transplant
induction, and time of transplant are shown in Table 1.
washout period) was 75 days in Group 1 (B), 80.5 days in Group 2 (T), and 72.7
our small sample size.
· To determine whether the choice of induction regimen influences the frequency
Table 1: Median myeloma parameters at initial diagnosis, end of induction therapy, time of transplant
days in Group 3 (L). It was incidentally noted that the patients across all treatment
This observation would support the Arkansas approach to continue
of disease progression during the treatment-free period
groups who had SD at the time of transplant had a slighter higher rate of achieving
immunomodulatory-based therapy throughout induction, stem cell mobilization, and
Induction
CR after ASCT than those who had PD or nPD.
Initial Diagnosis
End of Induction
Time of Transplant
transplant (8). In the setting of continued immunomodulatory agent therapy right up
Regimen
Table 3: Disease activity during washout period
to stem cell mobilization, the use of cyclophosphamide, combination chemotherapy
INTRODUCTION
(i.e. the Arkansas approach) or plerixifor may be required to improve stem cell yield
M (g/dL)
Ig (mg/dL) FLC(mg/L) M (g/dL)
Ig (mg/dL) FLC(mg/L) M(g/dL)
Ig (mg/dL) FLC(mg/L)
Median
Induction
pre-transplant.
Novel agents, such as lenalidomide, thalidomide, and bortezomib, are being
# Pts
#days
SD
PD
nPD
Bortezomib
2.56
4437
1935
0.32
590
153
0.30
728
321
Regimen
used with increased frequency in combination with dexamethasone as induction
washout
regimens for frontline treatment of multiple myeloma, especially in patients who
Thalidomide
2.9
4326
­
0.31
906
­
0.39
1155
­
Bortezomib (B)
12
75
6 (50%) 2 (17%)
4 (33%)
are eligible for high dose chemotherapy with autologous stem cell transplantation
Lenalidomide
2.42
3859
1215
0.89
1331
65.5
0.81
1696
129
CONCLUSIONS
(ASCT). One of the strategies prior to stem cell collection is to allow a "washout"
Thalidomide (T)
10
80.5
5 (50%) 2 (20%)
3 (30%)
Abbreviations: M=serum M protein level; Ig=involved serum immunoglobulin level; FLC=involved serum free light chain level.
· Even a short period without therapy may be associated with disease progression
period of at least 28 days from the end of induction therapy to the time of stem cell
Note: no FLC data in the thalidomide group (T) due to values unavailable across al three time points in majority of patients.
in a significant number of patients
mobilization and subsequent transplant. It has been generally observed that disease
Lenalidomide (L)
13
72.7
7 (54%)
1 (8%)
5 (38%)
progression is imminent in the majority of patients within a few months once an
· Continuing some form of therapy throughout induction may reduce the frequency
immunomodulatory agent is discontinued. We report our experience in disease
There were 33 patients who had an evaluable response to induction therapy, which
Total
35
75.7
18 (52%) 5 (14%) 12 (34%)
of disease progression during the washout period
progression during this "washout" period. Based on previous data of treatment-
are shown in Table 2. Although statistical analysis could not be performed on the
Abbreviations: SD=stable disease; PD=progressive disease; nPD=near progressive disease.
free intervals, we hypothesize that the patients who received bortezomib-containing
smal sample size, it was noted that a larger number of patients achieved VGPR or
regimens would have a lower incidence of disease progression from the end of
better in the bortezomib group (B) than in the thalidomide or lenalidomide groups
References
induction therapy to the time of transplant.
(T,L).
DISCUSSION
1 Harousseau JL, Attal M, Leleu X, et al. "Bortezomib plus dexamethasone as induction treatment prior to
autologous stem cel transplantation in patients with newly diagnosed multiple myeloma: results of an IFM
The use of novel agents as induction regimens for untreated multiple myeloma
phase I study." Haematologica. 2006; 91: 1498-1505.
Table 2: Response to induction therapy
patients eligible for ASCT is becoming increasingly common. When used in
2 Jagannath S, Durie BG, Wolf J, et al. "Bortezomib therapy alone and in combination with dexamethasone
METHODS
combination with dexamethasone, the overall response rates for untreated multiple
for peviously untreated symptomatic multiple myeloma." Br J Haematol. 2005; 129: 776-783.
Induction
3 Rajkumar SV, Rosinol L, Hussein M. "Multicenter, randomized, double-blind, placebo-control ed study
# Pts
CR
VGPR
PR
SD
We conducted a retrospective chart review of patients who received high dose
myeloma range from 66-88% with bortezomib (1,2), 63-74% with thalidomide
of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed
Regimen
chemotherapy with ASCT from January 2006 to July 2009. Inclusion criteria
(3,4), and 68-91% with lenalidomide (5,6). To our knowledge, however, there have
multiple myeloma." J Clin Oncol. 2008; 26: 2171-2177.
required a period of at least 28 days between the end of induction therapy to
been no prior studies examining the frequency of disease progression in the period
4 Abdelkefi A, Torjman L, Ben Romdhane N, et al. "First-line thalidomide-dexamethasone therapy in
Bortezomib (B)
11
1 (9)%
8 (73%) 2 (18%)
0 (0%)
preparation for autologous stem cel transplantation in young patients (<61 years) with symptomatic
transplant; treatment with a single novel agent and dexamethasone; and the
between the end of induction therapy to the time of transplant. In the VISTA trial
multiple myeloma." Bone Marrow Transplantation. 2005; 36: 193-198.
presence of secretory disease.
Thalidomide (T)
9
1 (11%)
3 (33%) 5 (56%)
0 (0%)
(7), comparing bortezomib plus melphalan-prednisone (VMP) versus melphalan-
5 Rajkumar SV, Jacobus S, Cal ander NS, et al. "Lenalidomide plus high-dose dexamethasone versus
prednisone (MP) in newly diagnosed multiple myeloma, the treatment-free interval
lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an
open-label randomised control ed trial." Lancet Oncol. 2009 Oct 21 [epub ahead of print].
Lenalidomide (L)
13
0 (0%)
2 (15%) 8 (62%)
3 (23%)
(TFI) was 16.6 months in the VMP arm compared to 8.4 months in the MP arm
Patients were divided into three groups: Group 1 included patients who received
6 Lacy MQ, Gertz MA, Dispenzieri A, et al. "Long-term results of response to therapy, time to progression,
(HR = 0.54, p<0.00001). Based on the statistically significant increase in TFI with
and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma." Mayo Clinic
bortezomib and dexamethasone (B; n=12); Group 2 included patients who received
Total
33
2 (6%) 13(39%) 15(46%)
3 (9%)
the addition of bortezomib, we hypothesized that during the treatment-free period
Proceedings. 2007; 82: 1179-1184.
thalidomide and dexamethasone (T; n=10); and Group 3 included patients who
Abbreviations: CR=complete response; VGPR=very good partial response; PR=partial response; SD=stable disease.
just prior to transplant, the patients treated with bortezomib-containing induction
7 San Miguel JF, Schlag R, Khuageva NK, et al. "Updated fol ow-up and results of subsequent therapy in
received lenalidomide and dexamethasone (L; n=13). Using EBMT/IBMTR criteria,
Note: 2 patients could not be evaluated for induction response due to unavailability of baseline data.
the phase I I VISTA trial: bortezomib plus melphalan-prednisone versus melphalan-prednisone in newly
regimens would have a lower frequency of disease progression compared to those
diagnosed multiple myeloma." Blood. 2008; 112: Abstract 650.
stable disease (SD) was defined as 25% increase and progressive disease (PD) as
treated with thalidomide- or lenalidomide-containing regimens.
8 Barlogie B, Pineda-Roman M, van Rhee F, et al. "Thalidomide arm of total therapy 2 improves complete
> 25% increase and a minimum of 0.5 g/dL increase in the serum M protein level.
remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood.
In addition, to examine more closely the kinetics of the disease, a third group of
The disease activity during the washout period was evaluated in 35 patients as
The average treatment-free period in our study was 75.7 days, which was similar
2008; 112: 3115-3121.
"near PD" (nPD) included those patients with > 25% increase but did not yet have a
shown in Table 3. In Group 1 (B), 50% (n=6) had stable disease, 17% (n=2) had
among the three groups. Interestingly, there was a subset of patients who showed
0.5 g/dL increase in the serum M protein level. For patients with unavailable serum
progressive disease, and 33% (n=4) had near progressive disease. In Group 2 (T),
evidence of progressive disease and near-progressive disease during this short
Conflict of Interest Disclosure: PK: no disclosures. AM: Speakers bureau: Millenium, Celgene. AC: Speakers bureau:
M protein levels, the involved immunoglobulin measurement was used.
50% (n=5) had stable disease, 20% (n=2) had progressive disease, and 30% (n=3)
washout period. The higher incidence of PD and nPD in all 3 groups may be a
Millenium. SJ: Advisory Board: Millenium, Merck. DHV: Advisory Board: Amgen, Celgene; Speakers bureau: Celgene,
Millennium, Centocor Ortho Biotech.

---