Transcript Myelodysplastic Syndromes: Emerging Treatment Options

Myelodysplastic Syndromes:
Emerging Treatment Options
Carlos M. de Castro, MD
Duke University Medical Center
Durham, North Carolina
Myelodysplastic Syndromes





Not 1 disease, but several lumped together as a
“syndrome”
Heterogeneous biology and clinical course
Clonal disorder of the bone marrow
Impaired maturation of hematopoietic cells and
increased apoptosis leading to peripheral blood
cytopenia(s)
Predominantly a disease of the elderly
Myelodysplastic Syndromes (cont’d)

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
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
Clinical presentation generally related to symptoms of
bone marrow failure
Splenomegaly uncommon (<10%); usually seen in
chronic myelomonocytic leukemia (CMML)
Increasing numbers of patients diagnosed following
incidental lab
No accepted standard of care
Eventual lethal outcome
Symptoms of Cytopenias



Anemia
– Fatigue
– Exacerbation of heart failure, angina
– Shortness of breath on exertion
Thrombocytopenia
– Bleeding or bruising
Neutropenia
– Infections, fevers, chills
Diagnosis

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
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Dependent on careful examination of the blood and
bone marrow for dysplastic findings
Cytogenetic analysis
– Chromosomal abnormalities in 40%–70% of
patients with primary myelodysplastic
syndromes1,2
Flow cytometry
Immunohistochemical staining
Other methods (MRI, etc) considered experimental
1. Bernasconi C. Hematol Oncol. 1993;11:20. 2. Greenberg P, et al. Blood. 1997;89:2079.
Cytogenetic Abnormalities:
Primary MDS


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Most common single abnormalities
– Del (5q): ~5% to 12% 1,2
– Monosomy 7/del (7q): ~6%1
– Del (11): ~4%1
– Trisomy 8: ~2% to 6%1,2
Complex karyotypes: ~18% 1
Survival (single defects):
– Best: del (5)(q13-q33)1
– Worst: monosomy 7/del (7q)1
1. Bernasconi C. Hematol Oncol. 1993;11:20. 2. Greenberg P, et al. Blood. 1997;89:2079.
Prognosis
International Prognostic Scoring System (IPSS)
Score
Prognostic variable
0
0.5
1.0
1.5
2.0
Bone marrow blasts
<5%
5%–10%
–
11%–20%
21%–30%
Karyotype*
Good
Intermediate
Poor
–
–
Cytopenias
0/1
2/3
–
–
–
*Good = normal, -Y (alone), del(5q) (alone), del(20q) (alone); Intermediate = other karyotypic
abnormalities; Poor = complex (3 abnormalities) or chromosome 7 abnormalities
Risk: Low = 0; Int 1 = 0.5-1.0; Int 2 = 1.5-2.0; High = >2.5
Reprinted with permission from Greenberg P, et al. Blood. 1997;89:2079.
Survival and AML Evolution by IPSS
Classification
Survival
Low
Int-1
Int-2
High
100
90
80
AML Evolution
267 pts
314 pts
179 pts
56 pts
100
90
80
235 pts
295 pts
171 pts
58 pts
70
Percent
Percent
70
60
50
40
60
50
40
30
30
20
20
10
10
0
Low
Int-1
Int-2
High
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Years
Years
(From diagnosis in untreated pts)
(From diagnosis in untreated pts)
AML = acute myeloid leukemia; IPSS = International Prognostic Scoring System.
Reprinted with permission from Greenberg P, et al. Blood. 1997;89:2079.
Treatment Strategies

Low-risk disease/poor performance status:
conservative management appears appropriate

High-risk disease: more aggressive therapies
are currently being explored

Any risk: a period of cautious observation is
always warranted
Past Treatments
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Supportive care
Prednisone, androgens
Differentiating agents—retinoids, vitamin D
Chemotherapy–cytarabine
Bone marrow transplantation
Supportive Care
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Packed red blood cell (PRBC) transfusions for
symptomatic anemia
Platelet transfusions for bleeding
Antibiotics for bacterial infections
Aminocaproic acid
Iron chelation for iron overload
Cytokines
Chemotherapy
Author
Pts (N)
Regimen
CR (%)
Toxic Deaths (%)
Preisler1
15
HiDAC
13
40+
Mertlesmann2
45
AT ± D
51
NR
Armitage3
20
DNR/A
15
25
Tricot4
15
HiDAC;DNR/A
53
33+
De Witte5
14
D or Ad/A
64
20
Fenaux6
20
R/A;HiDAC
50
30
Aul7
16
DAT
56
13
CR = complete response; HiDAC = high-dose cytarabine; A = cytarabine; DNR = daunorubicin;
T = 6-thioguanine; D = daunomycin; R = rubidazone; Ad = doxorubicin
1. Preisler HD, et al. Am J Hematol. 1986.23:131. 2. Mertlesmann R, et al. Blood.1980;56:773.
3. Armitage JO, et al. Cancer Treat Rep. 1981;65:601. 4. Tricot G, Boogaerts MA. Br J Haematol.
1986;63:477. 5. De Witte, et al. Bone Marrow Transplant. 1989;4(suppl 3):33. 6. Fenaux P, et al.
Blut. 1988;57:297. 7. Aul C, et al. Cancer. 1989;64:1812.
Reprinted from Semin Oncol, Vol 19, Cheson BD, Chemotherapy and bone marrow transplantation
for myelodysplastic syndromes, p.85, Copyright 1992, with permission from Elsevier.
Allogeneic Stem Cell Transplant


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40%–60% cure rate with allogeneic transplantation1-4
– Traditionally, a high morbidity and mortality (30%–50%) that increases
with age 3
– In some recent studies, treatment-related mortality has been 23% to
28% overall and 7% in younger patients (<50 yrs)5,6
Appropriate candidates include 1,3
– Younger patients
– Low-grade myelodysplastic syndromes (MDS) (eg, IPSS Int-1)
– Favorable cytogenetics
– Good performance status
– Appropriately matched donor
Estimated that <5% of MDS patients are candidates for allogeneic transplant7
1. Hellström-Lindberg E. Int J Hematol. 1999;70:141. 2. Deeg HJ, et al. Blood. 2000;95:1188.
3. List AF. Oncologist. 2002;7(suppl 1):39. 4. Gordon MS. Semin Hematol. 1999;36:21.
5. Solomon SR, et al. Biol Blood Marrow Transplant. 2005;11:619. 6. Deeg HJ, et al. Blood.
2002;100:1201. 7. Silverman LR, et al. J Clin Oncol. 2002;20:2429-2440.
Maximizing Survival with Allogeneic SCT

Optimal timing
– IPSS low-risk/Int-1 patients: Delayed (but
prior to the development of AML)
– IPSS Int-2/high risk patients: At the time of
diagnosis
Cutler CS. Blood. 2004;104:579.
New (Current) Therapies
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Growth factors and cytokines
Differentiating agents
Antiapoptotic therapies — programmed cell death,
amifostine, thalidomide and analogs, arsenic trioxide
Immunosuppressive agents — lymphocyte immune
globulin, cyclosporine A
Demethylating agents — azacitidine, decitabine
Bone marrow transplant
Cytokine Treatments

Erythropoietin: approximately 25% response rate1,2

G-CSF, GM-CSF: 80%–90% neutrophil response3-7
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IL-3: 60% neutrophil response; 20% platelet response8

Erythropoietin + G-CSF: 36%–48% erythroid
response9-11
1. Rose EH, et al. Br J Haematol. 1995;89:831. 2. Stein RS, et al. Blood. 1991;78:1658. 3. Negrin RS, et al. Ann Intern
Med. 1989;110:976. 4. Negrin RS, et al. Blood. 1990;76:36. 5. Ganser A, et al. Blood. 1989;73:31. 6. Yoshida Y, et al.
Leuk Lymphoma. 1995;18:457. 7. Vadhan-Raj S, et al. N Engl J Med. 1987;317:1545. 8. Legare RD, Gilliland DG. Curr
Opin Hematol. 1995;2:283. 9. Hellstrom-Lindberg E, et al. Br J Haematol. 1997;99:344. 10. Hellstrom-Lindberg E, et al.
Blood. 1998:92:68. 11. Negrin RS, et al. Blood. 1996;87:4076.
Immunosuppression
Antithymocyte (ATG)
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61 patients received ATG at 40 mg/kg/day for
4 days; evaluated for a median of 30 months (range 1
to 88 months)
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21 patients (34%) became transfusion-independent
within 8 months of treatment

Maintained in 81% of responding patients for a median
of 36 months (range 3 to 72 months)
Molldrem JJ, et al. Ann Intern Med. 2002;137:156.
Emerging Therapies

Methylation inhibitors
– Azacitidine
– Decitabine

Lenalidomide
CALGB Trial: Azacitidine vs Supportive
Care1
 N=191; median age = 68 y; male = 69%; all FAB subtypes; transfusion dependent =71%*
Treatment**
Response
Time to Leukemia
or Death
Transformation to
AML as 1st event
Azacitidine
(n = 99)
CR = 7%
PR = 16%
Improved = 37%
(Overall = 60%)
21 months
15%
Supportive care
(n = 92)
CR = 0%
PR = 0%
Improved = 5%
(Overall = 5%)
13 months
38%

Quality of life significantly improved with treatment: fatigue (P = .001), dyspnea
(P = .0014), physical functioning (P = .002), positive affect (P = .0077), and psychological
distress (P = .015).
* Transfusion-dependent patients in azacitidine arm only2
**16-week course of treatment with azacitidine 75 mg/m 2/d SC for 7 d in 28-d cycles x 4 or supportive care
1. Silverman LR, et al. J Clin Oncol. 2002;20:2429. 2. Kaminskas E. Oncologist. 2005;10:176.
Azacitidine for MDS
Probability of Survival
1.0
Induction azacitidine
Crossed before 6 months
Did not cross before 6 months
0.8
0.6
0.4
0.2
0.0
0
5
10
15
20
25
30
35
Months from 6-Month Landmark
Silverman LR, et al. J Clin Oncol. 2002;20:2429. Reprinted with permission.
40
45 50
Response* to Decitabine (ITT)
IWG Response Rate,
Onset & Duration
Decitabine
(n = 81)
Supportive Care
(n = 81)
Overall response rate (CR+PR)
15 (17%)**
0 (0%)
Complete response (CR)
8 (9%)
0 (0%)
Partial response (PR)
7 (8%)
0 (0%)
89 days (55–153)
N/A
Onset & duration of response
Median time to (CR+PR) response
Median duration of (CR+PR)
response
266 days (131–346)
Best response observed after 2 cycles (median number of cycles = 3)
*IWG MDS criteria, Blood. 2000;96:3671.
**P-value <.001 from 2-sided Fisher’s Exact Test
Reprinted from Semin Hematol, Vol 42, Saba HI, Wijermans PW, Decitabine in Myelodysplastic
Syndromes, S23.2004, Abstract 67, Copyright 2005, with permission from Elsevier.
Time to AML or Death
(All Patients)
Percent Alive Without AML
100
Analyzed Population = All Patients
Decitabine
Supportive Care
75
50
25
0
0
100
200
300
400
500
600
Survival (Days) Without AML
2-sided Wilcoxon test for homogeneity of survival distributions P = .042
2-sided Log-rank test for homogeneity of survival distributions P = .198
AML = acute myeloid leukemia.
Reprinted from Semin Hematol, Vol 42, Saba HI, Wijermans PW, Decitabine in Myelodysplastic
Syndromes, S23.2004, Abstract 67, Copyright 2005, with permission from Elsevier.
700
Time to AML or Death
High-Risk Patients (n = 44)
Analyzed Population = High Risk IPSS Patients
Percent Alive Without AML
100
Decitabine
Supportive Care
75
50
25
0
0
100
200
300
400
500
600
700
Survival (Days) Without AML
2-sided Wilcoxon test for homogeneity of survival distributions, P < .001
2-sided Log-rank test for homogeneity of survival distributions, P = .004
AML = acute myeloid leukemia.
Saba H, et al. 46th ASH Annual Meeting; December 4-7, 2004. Abstract 67. Reprinted with permission.
Copyright © 2005 Elsevier, Inc. Semin Hematol. 2005;42(suppl 2):S23.
Lenalidomide (CC-5013) Pharmacologic
Evolution
O
O
N
O
H
N
Thalidomide
H
N
N
O
O
O
NH2
Lenalidomide

4-amino-glutamyl analog1
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Up to1000 times more potent2

Safety profile: non-neurotoxic, non-teratogenic, nonsedating1
1. Bartlett JB, et al. Nat Rev Cancer. 2004;4:314. 2. Stirling D. Semin Oncol. 2001;28:602.
O
Treatment-Associated Adverse Events
(>10% of Patients)
Adverse Event
Lenalidomide (# of patients)
25 mg/d
(n = 13)
10 mg/d
(n = 13)
10 mg/d Q
21 d
(n = 17)
All patients,
any grade
(N = 43)
Grade 1–2/Grade 3–4
Neutropenia
0/10
0/8
0/10
28 (65%)
Thrombocytopenia
2/7
4/7
3/9
32 (74%)
Pruritis
5/0
4/0
3/0
12 (28%)
Diarrhea
0/0
2/1
6/0
9 (21%)
Urticaria
0/0
4/0
2/0
6 (14%)
Adapted from List A, et al. N Engl J Med. 2005;352:549.
Hematologic Responses to Lenalidomide
Treatment
Lenalidomide Dose
IWG Erythroid Response, n (%)
Major
Minor
Total
25 mg/day (n = 13)
6
0
6 (46)
10 mg/day (n = 13)
6
1
7 (54)
10 mg/day for 21 days
(n = 17)
9
2
11 (65)
21 (49)
3 (7)
24 (56)
Total (N = 43)
Transfusion dependent = 32
No transfusions needed = 11
Transfusion independent = 20/32 (63%)
Increase in Hgb >2 g/dL = 1/11 (9%)
2/12 patients with neutropenia had increase in ANC of >500/µL
1/10 patients with thrombocytopenia had platelet increase of >30,000/µL
IWG = International Working Group.
Reprinted with permission from List A, et al. N Engl J Med. 2005;352:549.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Lenalidomide Response Parameters


Median time to response
– Increased from 9 weeks in 25-mg cohort to
11.5 weeks in 10 mg/21 d cohort
Median duration of major response
– Not yet reached (median follow-up of 81
weeks; range 42–110 weeks)
– >48 weeks; range 13+ – 101+ weeks
List A, et al. N Engl J Med. 2005;352:549.
Correlation Between Karyotype and
Erythroid Response to Lenalidomide
Erythroid Response
N (%)
Karyotype (n)
P-value*
.007
Del (5q31.1) (n = 12)
10 (83)
Normal (n = 23)
13 (57)
Other (n = 8)
1 (12)
*Fisher’s exact test
Adapted from List A, et al. N Engl J Med. 2005;352:549.
Lenalidomide Trial — Conclusions



Lenalidomide has hematologic activity in patients with lowrisk MDS who have no response to erythropoietin or are
unlikely to benefit from conventional therapy
– 24/43 (56%) achieved IWG-defined erythroid response
– 20 had sustained transfusion independence; 1 had
>2 g/dL increase in Hgb
– Response correlated significantly with karyotype
Neutropenia and thrombocytopenia were the most common
adverse events; no correlation with response.
Cytogenetic remission occurred in 55% with abnormal
karyotype, and in 83% with del (5)(q31.1)
List A, et al. N Engl J Med. 2005;352:549.
Choosing the Right Therapy



Very dependent on patient, performance status,
clinical characteristics, tolerance of side effects,
and goals of therapy
When appropriate, referral for clinical trials is
preferred
Possibly dependent on chromosomal
abnormality
Summary



MDS is a biologically and clinically diverse
group of diseases that remain difficult to
understand and treat
Treatment options are improving and there is
both excitement and reason for hope
Referral of appropriate patients for clinical trials
is greatly appreciated
New Paradigms in the Treatment of
Multiple Myeloma
Jeffrey A. Zonder, MD
Assistant Professor of Medicine
Karmanos Cancer Institute
Wayne State University School of Medicine
Detroit, Michigan
Multiple Myeloma (MM)



Prevalence
– 50,000 Americans have MM1
1
 15,000 people diagnosed with MM each year
 >11,000 MM patients in the United States expected to
die in 20051
– Median age at diagnosis: 70 years1
– Median survival from diagnosis: 3–5 years
Population subgroups
– Incidence 2  higher in African Americans 1,2
Remains essentially incurable
1. SEER Cancer Statistics Review, 2004. http: seer.cancer.gov/statfacts. Accessed on
November 7, 2005. 2. American Cancer Society. Facts and Figures. 2004.
Criteria for Diagnosis of MM
All 3 Criteria Required:

Monoclonal plasma cells in the bone marrow 10% and/or
presence of a biopsy-proven plasmacytoma

Monoclonal protein present in the serum and/or urine

Myeloma-related organ dysfunction (≥1)
(C) Calcium elevation in the blood (serum calcium
>10.5 mg/L or upper limit of normal)
(R) Renal insufficiency (serum creatinine >2 mg/dL)
(A) Anemia (hemoglobin <10 g/dL or 2g <normal)
(B) Lytic bone lesions or osteoporosis
Other organ dysfunction if proven to be myeloma related
Durie BGM, et al. Hematol J. 2003;4:379.
International Staging System for MM
Stage 1
2M <3.5 and
ALB ≥3.5
Stage 2
ALB <3.5 and
2M <3.5
or
2M 3.5–<5.5*
* Irrespective of ALB level
Stage 3
2M ≥5.5
2M = serum 2 microglobulin in mg/dL
ALB = serum albumin in g/dL
Adapted from Greipp P, et al. J Clin Oncol. 2005;23:3412. Reprinted with permission
from the American Society of Clinical Oncology.
Durie-Salmon Staging System



Stage I
– Hgb >10, IgG <5, IgA <3, normal calcium, urine
monoclonal protein <4 g/d, no lytic lesions
Stage II
– Not stage I or stage III
– Stage I vs II differentiated on basis of Cr < or >2
Stage III
– Hgb <8.5, IgG >7, IgA >5, calcium >12, urine
monoclonal protein >12 g/d, advanced lytic lesions
Durie BGM, Salmon SE. Cancer. 1975;36:842.
MM Chromosomal Translocations



Cyclins D1 (11q13), D3 (6p21), and possibly D2
(12p13): 20%-25% of tumors
4p16: MMSET and FGFR3: ~15% of tumors
c-MAF (16q23) and MAFB (20q11): ~10% of tumors
MMSET = Multiple Myeloma SET domain; FGFR = fibroblast growth factor receptor;
c-MAF = oncogene promoting MM proliferation; MAFB = gene loci
Kuehl WM, Bergsagel PL. Nat Rev Cancer. 2002;2:175-187.
Melphalan and Prednisone (MP)







Oral regimen, repeating 4–6 wk cycles
Relatively nontoxic (myelosuppression)
40% response rate
Maximum response may take months
Median time to progression ~ 2 years
Median survival ~ 3 years
Not recommended prior to autologous stem cell
transplant (ASCT)
Alexanian R, Dimopoulos M. N Engl J Med. 1994;330:484-489.
Vincristine, Doxorubicin,
Dexamethasone (VAD)





Intravenous therapy, 28–35 d cycles
May require central venous catheter
50%–65% response rates (VAD, DVd, etc)
– < 5% CR/nCR
Faster response rate: 0.9 mos.
Preferred prior to ASCT
DVd = doxorubicin/vincristine/reduced-dose dexamethasone; CR = complete response;
nCR = near complete remission; ASCT = autologous stem-cell transplantation.
doxorubicin = Adriamycin
1. Barlogie B, et al. N Engl J Med. 1984;310:1353.
2. NCCN Practice Guidelines. v.1, 2004.
Combination Chemotherapy vs MP
Myeloma Trialists' Collaborative Group
Meta-Analysis
6333 patients in 27 trials
Estimated percentage still alive
100
0
1
2
3
Years
4
5
6+
90
80
70
60
50
40
30
24.4%
19.4%
20
23.0%
– Allocated cct (% ± SD)
10
18.0%
– Allocated MP (% ± SD)
0
MP = melphalan and prednisone; cct = combination chemotherapy.
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16:3832.
Reprinted with permission from the American Society of Clinical Oncology.
1.4% SD 1.4
(log-rank
2P > .1; NS)
ASCT vs Conventional Chemotherapy
(N = 200)
R
a
n
d
o
m
i
z
e
VMCP/BVAP x 18
(IFN-)
(n = 74)
VMCP/BVAP x 4-6
MEL 140 + TBI 8Gy
(IFN-)
P
r
o
g
r
e
s
s
i
o
n
ASCT = autologous stem cell transplantation; VMCP = vincristine/melphalan/cyclophosphamide/prednisone;
BVAP = vincristine/carmustine/doxorubicin/prednisone; MEL = melphalan; TBI = total body irradiation;
IFN- = interferon alfa.
Attal M, et al. N Engl J Med. 1996;335:91-97.
ASCT vs Conventional Chemotherapy
Overall Survival (%)
Results
100
Transplant
75
50
P = .03
Conventional
25
15
30
45
60
Standard Dose
5-y EFS: 10%
5-y OS: 12%
vgPR/CR: 14%
High Dose
5-y EFS: 28%
5-y OS: 52%
vgPR/CR: 38%
Treatment (mo)
ASCT = autologous stem cell transplant; EFS = event-free survival; OS = overall survival;
vgPR/CR = very good partial response/complete response.
Attal M, et al. N Engl J Med. 1996;335:91-97.
Copyright ©2005 Massachusetts Medical Society. All rights reserved.
Intergroup Randomized Trial
Chemotherapy vs Autologous Transplant
(n = 556)
(n = 42)
P
R
r
a
o
(n = 260)
n
g
(N = 810)
d
r
CTX
MEL 140 + TBI
VAD x
o
(n = 84) e
4.5
12Gy +/-IFN-
4
m
s
g/m2
(n = 254)
i
s
VBMCP (M2) x
z
i
2 +/-IFN-
e
o
n
VAD = vincristine/doxorubicin/dexamethasone; CTX = cyclophosphamide; MEL = melphalan;
X
Matched Sibling
Allotransplant
TBI = total body irradiation; VBMCP = vincristine/carmustine/melphalan/cyclophosphamide/prednisone;
doxorubicin = Adriamycin
Barlogie B, et al. ASH 2003. Abstract 135.
Comparable Survival with ASCT and
Conventional Therapy
ASCT
VBMCP*
CR
17%
15%
PR
93%
91%
PFS
25 mo
P = .05
P = .8
21 mo
53 mo
*VBMCP failures went on to receive ASCT
ASCT = autologous stem cell transplantation
VBMCP = vincristine/carmustine/melphalan/cyclophosphamide/prednisone
Barlogie B, et al. ASH 2003. Abstract 135.
OS
58 mo
Biology of Thalidomide
MM Cells
X
IL-6 
TNF 
IL-1 
VEGF 
bFGF 
X
X
IL-2
IFN
Marrow
Blood
Vessels
CD8+ Lymphs
NK Cells
Adapted from Anderson KC. Semin Hematol. 2001;38:286-294.
Marrow
Stromal
Cells
Thalidomide/Dexamethasone vs Dexamethasone
in Newly Diagnosed MM
Phase III Trial
Thalidomide, 200 mg/d orally
Dexamethasone, 40 mg/d
Days 1–4, 9–12, and 17–20*
(n = 103)
207 pts
CR/PR/SD§
Stop therapy at month 4 for
stem cell transplantation or
continue at physician’s
discretion
 4 cycles
Dexamethasone alone, 40 mg/d
Days 1–4, 9–12, and 17–20*
(n = 104)
Endpoint
PD
Stop therapy
Thal/Dex (n = 99)
Dex (n = 100)
Response rate
58%
42% †
Corrected response rate‡
69%
51%
Median time to response, mo
1.1
1.1
Disease progression within first 4 mo
3%
5%
*Administered as a monthly cycle; †P = .0164; ‡Serum M protein levels used if urine m protein unavailable;
§CR/PR/SD = complete response, partial response, stable disease.
Rajkumar SV, et al. 46th ASH; December 4-7, 2004. Abstract 205.
Thalidomide/Dexamethasone
(Thal-Dex) vs VAD
≥ PR
Cr
NCR
VGPR
PR
NR/P
Thal-Dex
(n = 100)
76
10
3
6
57
24
VAD
(n = 100)
52*
8
5
1
38
48*
*P <.001
Thal = thalidomide; dex = dexamethasone; VAD = vincristine, doxorubicin, dexamethasone;
≥PR = ≥partial response (incl. CR); CR = complete response, nCR = near CR; vgPR = very good PR; PR =
partial response; NR/P = no response/progression.
Adapted from Cavo M, et al. Blood. 2005;106(1):35-39. Copyright American Society of Hematology, used with
permission.
Melphalan, Prednisone, Thalidomide (MPT)
in Elderly Patients with MM: Phase III Trial
MPT arm
Melphalan, 4 mg/m2 (7 days per month)
Prednisone, 40 mg/m2 (7 days per month)
Thalidomide, 100 mg/d (continuously)
Newly diagnosed MM
patients; Median age 72
years
MP arm
N = 200
Melphalan, 4 mg/m2 (7 days per month)
(102 evaluable)
Prednisone, 40 mg/m2 (7 days per month)
6 courses
Response
MPT Arm, %
MP Arm, %
CR + nCR
31.4%
4.2%*
PR
50% - 99%  M-protein
48.2%
43.6%
EFS at 26 months
67.8%
32.4%
P < .001
*Reached statistical significance
CR = complete response; nCR = near complete response; PR = partial response; EFS = event-free survival.
Palumbo A ,et al. 46th ASH; December 4-7, 2004. Abstract 207.
MP vs MPT vs MEL100 in Newly Diagnosed MM
Patients Aged 65–75 Years
(N = 500)
3
MP Arm
Standard MP. 12 courses at 6-week
intervals
2
MPT Arm
MP as arm 1 + thalidomide at MTD but
400 mg/day, stopped at end of MP
2
MEL100 Arm
VAD x 2; cyclophosphamide 3 g/m2;
melphalan, 100 mg/m2, 2 courses
Facon T, et al. 46th ASH, December 4-7, 2004. Abstract 206.
Primary
Endpoint:
Overall survival
Thalidomide and Thrombosis
Regimen
% DVT
Regimen
% DVT
ECOG1
DEX
3
Thal-DEX
18
MD
THAL
4
Thal-DEX
15
MP
2
MPT
19
Anderson2
Italy3
DVT = deep vein thrombosis; DEX = dexamethasone; Thal = thalidomide;
VAD = vincristine/doxorubicin/dexamethasone; T-VAD = vincristine/doxorubicin/dexamethasone/thalidomide;
DVd = doxorubicine/vincristine/reduced-dose dexamethasone; MP = melphalan/prednisone;
MPT = melphalan/prednisone/thalidomide.
1. Rajkumar SV, et al. Presented at 46th ASH; December 4-7, 2004, San Diego, CA. Abstract 205.
2. Weber D, et al. J Clin Oncol. 2003;21:16. 3. Palumbo A, et al. Cancer. 2005;104:1428.
Thalidomide
Conclusions



Superior response rates with thalidomide combinations
compared with dexamethasone alone1, VAD 2, and MP 3 in
newly diagnosed MM
Thalidomide combinations associated with higher toxicities1-4
– Need for DVT prophylaxis with thalidomide/
dexamethasone
– Neuropathy generally occurs following chronic use, but can
also occur after short-term use.
Higher response rates of thalidomide combinations must be
weighed against increased toxicity for individual patients
1. Rajkumar SV, et al. 46th ASH; December 4-7, 2004. Abstract 205. 2. Cavo M, et al. Blood. 2005;106:2.
3. Palumbo A, et al. 46th ASH; December 4-7, 2005. Abstract 207. 4. Thalomid® PI. Celgene Corporation.
Summit, NJ.
Newer Agents and Regimens
Bortezomib
(PS-341)
Bortezomib
Velcade® PI. Millenium. Cambridge, MA.
Courtesy of Jeffrey A. Zonder, MD.
Bortezomib vs Dexamethasone in
Relapsed/Refractory Multiple Myeloma
1.0
P = .005
Proportion of Patients
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Bortezomib
Dexamethasone
0.2
0.1
Bortezomib
Dexamethasone
1-yr survival
All Pts
Pts 1 relapse*
80%
89%
66%
72%
* Patients treated as second-line, after first relapse
0.0
0
30
60
90
120
150
180
210
240
Time (days)
Richardson PG, et al. N Engl J Med. 2005;352:2487.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
270
300
330
360
First-Line Bortezomib for MM




Bortezomib: 1.3 mg/m2 d 1, 4, 8 and 11 q21 d  4 cycles
Dexamethasone: 40 mg/d d 1+2, 4+5, 8+9, 11+12
– If <PR (2 cycles) or <CR (4 cycles)
19 pts accrued; 12 evaluable pts completed 6 cycles
– 4 (33%) nCR
– 5 (42%) PR
– 1 (8%) MR
– 2 (17%) PD
Most common adverse events (grade 1–3) fatigue (67%),
diarrhea (58%), constipation (42%), nausea (42%), peripheral
neuropathy (33%), and vomiting (33%)
Jagannath S, et al. Blood. 2003;102:452a [abst 1650].
Jagannath S, et al. ASCO, June 5–8, 2004; New Orleans, LA [abst 6551].
Bortezomib/PS-341, Doxorubicin, and
Dexamethasone (PAD) Induction
Results


Response rate: 20/21 at least PR (95%)
– Complete response in 24%
Painful neuropathy: 48%
– Improved after discontinuing therapy
doxorubicin = Adriamycin
Oakervee HE, et al. Br J Haematol. 2005;129:755.
Lenalidomide + Dexamethasone vs
Dexamethasone: Phase III Trial

Patients with relapsed multiple myeloma randomized to
– Arm A



Lenalidomide: 25 mg/d d 1-21
Dexamethasone: 40 mg/d d 1-4, 9-12, 17-20, q 28 d
Placebo: d 22-28
– Arm B


Dexamethasone: 40 mg/d d 1-4, 9-12, 17-20 q 28
Placebo: d 1-28
Weber D. Presented at 41st ASCO, May 13-17, 2005. Orlando, FL.
Lenalidomide + Dexamethasone vs
Dexamethasone
TTP (weeks)
– North American
– International
ORR (%)
– North American
– International
CR
– North American
– International
DVT
– North American
– International
Results* DEX
Lenalidomide+DEX
20.7
20.6
60.1
53.4
22.8%
21.7%
61.2%
57.9%
4.1%
4.0%
26.5%
13.6%
3.5%
3.4%
13.5%
4.5%
N = 342 (North American trial) N = 351 (International trial)
*Interim Analysis: Data Available as of March 31, 2005.
TTP = time to tumor progression; ORR = objective response rate; CR = complete remission; DVT = deep vein thrombosis
Weber D. Presented at 41st ASCO, May 13-17, 2005. Orlando, FL.
Lenalidomide + Dexamethasone
Up Front for MM




34-patient phase II trial at Mayo Clinic
Lenalidomide 25 mg/d x 21 d q 28d
Dexamethasone 40 mg/d d 1–4, 9–12, 17–20
ORR: 91%
– 6% CR
– 32% vgPR/nCR
ORR = objective response rate; CR = complete response; vgPR/nCR = very
good partial response/near complete response
Rajkumar, V. Blood. 2005. Epub Aug 23rd.
Conclusions and Questions (I)


New combinations using thalidomide, lenalidomide, and/or
bortezomib induce deep responses previously only seen
with ASCT in patients with newly diagnosed multiple
myeloma.
Awaiting longer-term data
– Does nCR/CR with thalidomide/chemotherapy
combinations mean the same thing as nCR/CR with
ASCT?
– Is ASCT effective after relapse from these regimens?
Conclusions and Questions (II)



New thalidomide-containing combinations are
more toxic than traditional regimens
For now, thalidomide combinations other than
thalidomide-dexamethasone, and possibly MPT,
should be limited to clinical trials
Lenalidomide has a different side-effect profile
than thalidomide, and is in large-scale
randomized trials for newly diagnosed myeloma
through SWOG and ECOG
Managing MDS and MM Treatment-Related
Toxicities/Drug Interactions and Improving
Patient Compliance
Deborah A. Blamble, PharmD
Clinical Pharmacy Specialist, Leukemia
Division of Pharmacy
University of Texas
M.D. Anderson Cancer Center
Houston, Texas
Myelodysplastic Syndromes (MDS) Cytopenias





Occur due to bone marrow failure or replacement
Transfusion support is the primary therapy for anemia
and thrombocytopenia
Limitations of RBC and platelet transfusion support
Epoetin alfa ± G-CSF can reduce red cell transfusion
requirements in low-risk MDS
G-CSF/GM-CSF can be used for neutropenic fever
– Less evidence supports the treatment of
neutropenia alone
Multiple Myeloma (MM) Cytopenias



Mostly anemia, due to cytokine production, marrow
replacement, and renal failure
Transfusion support and use of erythroid-stimulating factors
during chemotherapy are the primary treatments
– Epoetin alfa/darbepoetin recommended for
Hgb < 10 g/dL
Hematopoietic growth factors may be used in select
patients undergoing chemotherapy
– Neutropenic fever is uncommon with most treatment
regimens
Rizzo JD, et al. J Clin Oncol. 2002;20:4083. Ozer H, et al. J Clin Oncol. 2000;18:3558.
Transfusion-Related Iron Overload


Iron overload can lead to cardiac, pancreatic, and
hepatic dysfunction
Iron chelating therapy is recommended when
–
–
–

Deferoxamine is the recommended agent
–

Long-term survival is expected
Serum ferritin > 1500 mcg/L or LFTs > 2 x ULN
Or, after approximately 25 units of PRBC (5g of iron)
IV or SQ continuous infusion
Deferasirox, an oral iron chelator, has recently been
approved for treatment-related iron overload
Porter, JB. Semin Hematol. 2005;42 (suppl 1):S14.
MM Bone and Renal Complications



Renal dysfunction may occur due to myeloma light
chain excretion or hypercalcemia
– Avoid administration of nephrotoxic agents
– Use bisphosphonates with caution in renal failure
Bisphosphonates are the preferred treatment for
hypercalcemia
– Ensure adequate hydration
Myeloma bone disease is managed with
bisphosphonates and pain control measures
– Monitor for spinal cord compression
MDS Drug Therapies



Epigenetic therapies
– Azacitidine (Vidaza®)
– Decitabine (Dacogen™)
Immunomodulating agents
– Lenalidomide (Revlimid®)
– Thalidomide (Thalomid®)
Arsenic trioxide (Trisenox™)
MM Drug Therapies



Arsenic trioxide (TrisenoxTM)
Bortezomib (Velcade®)
Immunomodulating agents
– Thalidomide (Thalomid®)
– Lenalidomide (Revlimid®)
Azacitidine



Approved dose of 75 mg/m2 SQ daily for 7 days every
4 weeks for at least 4 cycles
– If no benefit after 2 months and minimal toxicity,
increase to 100 mg/m2
Primary side effects are hematologic
– Other side effects include nausea, vomiting,
diarrhea, fever, and injection site reactions
Volume of reconstituted 100-mg vial is 4 mL,
necessitating several syringes for a single SQ dose
VidazaTM PI. Pharmion Corp, Boulder,CO. August 31, 2004.
Decitabine



Multiple intravenous schedules are under
investigation
The most common side effects are hematologic
Other toxicities include liver dysfunction,
nausea, vomiting, and diarrhea
Lenalidomide



Structural analog of thalidomide
– Designed to be more potent/less toxic
– Appears to be nonteratogenic
Optimal dose still being determined
Neutropenia and thrombocytopenia are the
most common side effects
– Pruritis, urticaria, rash, diarrhea, fatigue,
and thyroid dysfunction have been reported
Rajkumar SV, et al. Blood. 2005. Prepublished online August 23, 2005.
Arsenic Trioxide




Differentiating and pro-apoptosis activity
Several dosing regimens (IV infusion) published
Risk of QT interval prolongation
– Keep potassium and magnesium corrected
– Avoid concomitant drugs that prolong QT
– EKG monitoring
Other common side effects include cytopenias,
nausea, vomiting, diarrhea, fever, and fatigue
Bortezomib


Approved dosing in multiple myeloma
– 1.3 mg/m2 on Days 1, 4, 8, and 11 of every
21- day cycle
– Responses occur within 1–2 cycles
Side effects include GI toxicity, fatigue, cytopenias, and
neuropathy
– Neuropathy and thrombocytopenia more common
in patients with baseline abnormalities
Physicians Desk Reference. 59th ed. 2005, p 2207.
Thalidomide




Usual dose is ~100 mg to 200 mg (escalating to maximum of
400 mg) orally daily,1-5 although higher and lower doses have
been reported
Teratogenic
– Requires physician/patient education/registration
– STEPS guidelines
Common side effects include sedation, fatigue, constipation,
shortness of breath, fluid retention, peripheral neuropathy, and rash
Other serious side effects include venous thromboembolism
(MM and other disease states), bradycardia, and hypothyroidism
1. Raza A, et al. Blood. 2001;98:958. 2. Weber D, et al. J Clin Oncol. 2003;21:16. 3. Rajkumar SV, et al. 46th ASH,
December 4–7, 2004. Abstract 205. 4. Palumbo A, et al. 46th ASH, December 4–7, 2004. Abstract 207. 5. Facon T, et al.
46th ASH, December 4–7, 2004. Abstract 206.
Patient-Related Variables





Renal dysfunction
– Azacitidine, arsenic trioxide, lenalidomide,
decitabine
Liver dysfunction
– Azacitidine, decitabine, bortezomib
Cytopenias
– Avoid aspirin and NSAIDs if thrombocytopenic
– Treat neutropenic fever as an emergency
Peripheral neuropathy
– Thalidomide, bortezomib, arsenic trioxide
Coagulopathies
Improving Patient Compliance




Reassure patients
– New therapies may take several cycles to
determine efficacy
Encourage early reporting of side effects
– Side effects may be dose-related or irreversible
Recommend growth factors in suitable patients to
improve quality of life
Where possible, choose therapies with the most
convenient administration and dosing schedules
Summary



Several new agents are in development or are
now available to treat myelodysplastic
syndromes and multiple myeloma
Side-effect profiles and patient-related variables
should also be considered when choosing
therapies
Unlike traditional chemotherapy, time to
response may be delayed