Poster: 1497
Depsipeptide in the Treatment of Relapsed and Refractory Multiple Myeloma (MM): A Prospective Evaluation of
the Cell Cycle.
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Zoe Goldberg, MD ; Scott Ely, MD ; Selina Chen-Kiang, PhD ; Martha Chesi, PhD ; Peter L. Bergsagel, MD ; Karen Pekle, RN, ANPC ; Larry Lyons, MPH ; Udi
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Gelbshtein ; Roger Pearse, MD, PhD ; John Harpel, MD, PhD ; Hearn J Cho, MD, PhD ; Morton Coleman, MD and Ruben Niesvizky, MD . Hematology/Medical
Oncology(1) and Department of Pathology(2), Weill Medical College of Cornell University, New York, NY, United States.
Background
Results
Results Cont.
Dysregulation of the cell cycle and apoptosis are two critical events in the pathophysiology of
Depsipeptide induces apoptosis in several MM cell lines:
Depsipeptide is safe in a limited cohort of MM patients
MM:
1.All lines were susceptible, however differential sensitivities were noted (Fig. 1)
1.Grade 2 fatigue and anorexia were the most common toxicities
·
High tumor burden despite low rate of tumor cell proliferation
2.Three cell lines containing 11q13 translocation (Cyclin D1 overexpression) were the most
2.Mild thrombocytopenia (mean of 67 K/ul) did not require transfusions
·
G1 arrest is common in myeloma plasma cells
sensitive with IC50s at least 2 fold lower than other lines (Fig. 2)
3.1 patient had stable disease after 3 cycles of treatment, 1 patient had progression of disease
st
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Cyclin D1 is often overexpressed without a defined genetic substrate
after 3 cycles of treatment, and 2 patients progressed after the 1 cycle (Fig. 4)
Several studies have shown that aberrant histone acetylation may play a role in a variety of
tumors by altering expression of survival and apoptotic factors.
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Depsipeptide (FR901228, FK288):
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Histone-deacetylase inhibitor isolated from chromobacteium violaceum
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Induces cell differentiation and apoptosis in several cell lines including MM
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Increases expression of P21 and hypophosphorylation of RB
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Decreases expression of Cyclin D1, bcl-2, and other apoptotic proteins
Objectives
Cell Cycle changes are induced by depsipeptide: (Fig 3A, Fig 3B)
To evaluate cell cycle regulation and genomic patterns in myeloma patients when exposed to
1.In 2/4 patients, a significant increase of the PCPI was seen, whereas a marked reduction in the
depsipeptide and correlate the findings with clinical outcomes.
PCPI in a patient with Cylclin D3 overexpression (27% to 16%) was also noted.
2.One patient had an increase of Cyclin D1 post treatment.
Conclusion
Patients and Methods
Pt.#
TreatmentStatus PCPI(%) BCL-2(%) CD31(%) Fgfr-3(%) Cleaved
cyD1 +
cyD3 +
Cas3 (%)
PCs (%)
PCs (%)
In vitro studies were performed in 12 human MM cell lines with defined cytogenetic abnormalities. 1
Baseline
0.20
100
100
NA
<1
60
0
The IC50 for depsipeptide was determined by evaluation of apoptosis by standard methods.
24 hr S/P
0.00
100
100
NA
<1
60
0
Four stage III patients with relapsed MM (Table 1) have been treated with 1 to 3 cycles of
depsipeptide at a dose of 13mg/m2, as a 4-hour infusion on days 1, 8, and 15, repeated every 28
4 wks S/P
10.16
100
100
NA
<1
70
0
days. In vivo immunohistochemistry (IHC) correlates were done before treatment and at 24
2
Baseline
27.00
100
100
NA
<1
0
100
hours and 4 weeks after treatment with depsipeptide as part of our phase II protocol.
24 hr S/P
19.40
100
90
NA
<1
0
100
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Table1. Baseline Patient Characteristics
4 wks S/P
16.40
100
100
NA
<1
0
100
Patient
Age
Gender
M-spike
KPS(%)
Albumin(gm/dl) LDH(U/L)
Prior
3
Baseline
18.20
100
100
NA
<1
0
0
Therapies
24 hr S/P
9.06
100
100
NA
<1
0
0
1
55
M
IgG
90
3.3
179
3
4 wks S/P
33.71
100
100
NA
<1
0
0
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Depsipeptide given on this schedule is safe and can stabilize tumor-mass in patients with
2
55
F
free light
90
4.6
266
3
4
Baseline
11.0
100
100
NA
<1
100
0
progressive relapsed and refractory disease.
3
67
F
IgG
80
3.6
315
3
24 hr S/P
qns
qns
qns
qns
qns
qns
qns
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Evidence of cell cycle modulation seen during treatment with depsipeptide.
4
72
F
IgG
80
3.2
212
3
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No evidence for changes in apoptosis.
4 wks S/P
qns
qns
qns
qns
qns
qns
qns
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Patients with 11q13 translocation should be a target for treatment with depsipeptide.
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Supported by NCI grant (SAIC1N01-CO-12400-02) and SCOR for Myeloma grant from the Leukemia and Lymphoma Society of America.
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