Guido Tricot, MD, PhD
University of Arkansas for Medical Sciences
Thalidomide
Thalidomide once daily oral dose at bedtime.
Thalidomide dose escalated in each patient:
Week
Dose
Level
1 - 2
200 mg po qHS
1
3 - 4
400 mg po qHS
2
5 - 6
600 mg po qHS
3
7 +
800 mg po qHS
4
Thalidomide
Major Eligibility Criteria
-Previously treated, active multiple myeloma
-Measurable disease:
-presence of serum M­protein or urinary M­protein
or bone marrow plasmacytosis 20%
-Adequate liver function (direct bilirubin 2 mg/dL)
-Women of childbearing age and fertile men must use a
medically acceptable means of birth control while on study
and for 6 months thereafter
-Total white cell count > 2000/mm3
-Age 18 years
Thalidomide
Factor
%
Age >=60
26%
B2M >=4
33%
CRP>=4mg/L
16%
LDH >=190
24%
Albumin<3.5 g/dL
20%
Creatinine>=2.0 mg/dL
14%
Prior therapy >=60mo
23%
IgA Isotype
25%
Abnormal cytogenetics
64%
CA13/Hypo
44%
Prior Transplant
76%
Thalidomide
100%
12-Month
Events / N
Estimate
80%
Overall
56 / 169
32%
60%
40%
20%
0%
0
24
48
72
96
Months from Enrollment
Thalidomide
Time-To-Event Outcomes
100%
Median
Month
80%
Overall Survival
21
Event-Free Survival
6
60%
40%
20%
0% 0
24
48
72
96
Months from Start of Protocol Therapy
Thalidomide
Multivariate Analysis
%
HR (95% CI) P-value
Abnormal cytogenetics
66% 1.70 (1.15,2.53)
0.01
B2M >=4 mg/L
34% 1.50 (1.04,2.16)
0.03
CRP>=4mg/L
16% 1.62 (1.01,2.59)
0.05
HR- Hazard Ratio, 95% CI- 95% Confidence Interval,
P-value from Wald Chi-Square Test in Cox Regression
Thalidomide
Event-Free Survival
By Cytogenetic Abnormalities
100%
12-Month
N
Estimate
80%
CA
107
26%
No CA
60
53%
60%
Logrank P-value < .0001
40%
20%
0% 0
24
48
72
96
Months from Start of Protocol Therapy
VTD
Treatment Plan
Open-label, single center phase I dose escalation study for patients with
advanced and refractory multiple myeloma
· Velcade 1.0 mg/m2 IV push or 1.3 mg/m2 twice weekly x 2 wks
followed by 10 day rest (on days 1, 4, 8, and 11) for a total of 8 cycles
· Daily oral Thalidomide added at Cycle 2 in all patients
· Dose escalations:
Bortezomib 1.0 mg/m2 with
Bortezomib 1.3 mg/m2 with
thalidomide
thalidomide
Cohort 1: 50 mg
N = 12
Cohort 5: 50 mg
N = 11
Cohort 2: 100 mg
N = 10
Cohort 6: 100 mg
N = 10
Cohort 3: 150 mg
N = 10
Cohort 7: 150 mg
N = 12
Cohort 4: 200 mg
N = 14
Cohort 8: 200 mg
N = 6
· Dexamethasone permitted if suboptimal response after 3 cycles
· Patients in PR-CR after 8 cycles received maintenance therapy (V-T
every three months)
VTD
Major Eligibility Criteria
-Relapsed or resistant multiple myeloma after > 1 line of prior therapy
-Measurable disease:
Serum M­protein 1.0 mg/dL
Urinary M­protein 200 mg/24 hrs
Bone marrow plasmacytosis 30%
-SWOG performance status 2
-Absolute neutrophil count > 750/mm3
-Platelet count 25,000/mm3
-Age 18 years
VTD
Patient Characteristics
Vel 1.0
Vel 1.3
P-value
LDH>=190 UI/L
44%
38%
0.6
Albumin<3.5 g/dL
24%
8%
0.04
B2M>=4 mg/L
59%
37%
0.04
CRP>=4 mg/L
64%
59%
0.7
Prior Thalidomide
80%
67%
0.2
Cytogenetics
84%
68%
0.1
abnormalities
Prior Transplant
96%
87%
0.2*
VTD
Time to 50% or
Best Response through Treatment Cycle*
Better Response, by Velcade Dose
100
100%
90
80
ts
70
80%
P = .97
60
atien
50
Pf 40
60%
o% 30
3-Month
20
40%
Events / N Estimate
10
0
Vel 1.0
25 / 45
53%
123
45
678
20%
Vel 1.3
25 / 39
49%
Treatment Cycle
0%
100%
99%
90%
0
2
4
6
8
10
12
% M-Protein Reduction
75%
50%
25%
Months from Cycle 1
*N=84 Patients Receiving Minimum of 1 Cycle of
Treatment as of 3/30/2005
VTD
Event-Free Survival
By Velcade Dose
100%
12-Month
N
Estimate
V 1.3 mg/m2
39
51%
80%
V 1 mg/m2
45
26%
Logrank P-value = .004
60%
40%
20%
0%
0
12
24
36
Months from Start of Protocol Therapy
VTD
Event-Free Survival
By Thalidomide Dose
100%
12-Month
Deaths / N
Estimate
80%
Thal =>150
42
48%
Thal <=100
42
30%
60%
Logrank P-value = .83
40%
20%
0%
0
12
24
36
Months from Start of Protocol Therapy
VTD
Multivariate analysis
(%)
HR (95% CI)
P-value
Prior Thalidomide
73%
2.12 (1.06,4.23)
0.03
Cytogenetics abnormalities
77%
2.12 (1.03,4.35)
0.04
HR- Hazard Ratio, 95% CI- 95% Confidence Interval, P-
value from Wald Chi-Square Test in Cox Regression
VTD
Event-Free Survival by Cytogenetics
100%
12-Month
N
Estimate
No CA
20
55%
80%
Any CA
63
33%
Logrank P-value = .04
60%
40%
20%
0%
0
12
24
36
Months from Start of Protocol Therapy
VTD
Grade 3 and 4 Toxicities* Total%
Thrombocytopenia
52
Neutropenia
49
Anemia
37
Fatigue
32
Sensory neuropathy
11
Anorexia
8
Nausea
7
Renal failure
7
Hemmorrhage
6
Pneumonitis
6
Dizziness
4
Fever, NOS
2
010 20 30 40 50 60 70 80 90 100
% of Patients
Maximum Toxicity Grade
34
*N=84 Patients Receiving Minimum of 1 Cycle of Treatment, as of 03/30/2005
Lenalidomide
Treatment schedule
Arm 1:
Arm 2:
Continuous Dosing
Syncopated Dosing
25 mg x 20 days
50 mg qod x 20 days
8 days Bridge therapy
8 days Bridge therapy
5 mg QD
10 mg QOD
Repeat day 29
Repeat day 29
Starting Cycle 3:day 57, add Dexamethasone 40 mg Days 1-4 every 28 days
Continue until disease progression or unacceptable side effects
Lenalidomide
Eligibility criteria
Multiple Myeloma Patients with relapse or resistant disease
after > 1 line of prior therapy or after autologous transplantation.
Measurable Disease:
· Serum M-protein level > 1.0 gm/dl (10.0 g/L).
· Urinary M-protein excretion > 200 mg/24-hrs.
· Bone marrow plasmacytosis > 30%.
Adequate renal and liver function (creatinine < 2.5, LFTs < 2 x
upper limit of normal.)
Platelet count 80,000/mm3, and an ANC of at least 1,000/µl
and a hemoglobin level (infused or with EPO) of at least 9 g/dL.
Lenalidomide
Patient Characteristics
Continuous
Syncopated
Dosing
Dosing
P-value
LDH>=190 UI/L
41%
49%
0.5
Albumin<3.5 g/dL
16%
8%
0.3
B2M>=4 mg/L
42%
42%
1.0
CRP>=4 mg/L
73%
67%
0.6
Creatinine>=2.0 mg/dL
11%
6%
0.4*
Prior Thalidomide or Velcade
89%
94%
0.4*
Cytogenetics abnormalities
60%
58%
0.8
Prior transplant
82%
86%
0.6
At least 60 months of prior th
44%
35%
0.4
Lenalidomide
Continuous Dosing*
Syncopated Dosing*
100
100
90
90
80
80
70
70
60
60
50
50
fPatients
fPatients
o 40
o 40
%
%
30
30
20
20
10
10
0
0
12345678
12345678
Cycle
Cycle
Best Response
>=99%
75%
Best Response
>=99%
50%
25%
75%
90%
No Response
None Recorded Yet
25%
50%
None Recorded Yet
No Response
*Restricted to Patients Receiving Cycle 1 (N=44)
*Restricted to Patients Receiving Cycle 1 (N=37)
Lenalidomide
Most Common Toxicities
%
Neutropenia
45
Thrombocytopenia
39
Anemia (HGB)
15
Fatigue
7
Sensory neuropathy
2
0123
456789
10
# of Patients
Maximum Toxicity Grade
34
Lenalidomide
Difference in Toxicities Between
the Two Arms
P-value
Febrile neutropenia
0.006
Hypernatremia
0.004
Tremor
0.007
Lenalidomide
Time-To-Event Outcomes
100%
Median
N
Month
Overall Survival
81
21
80%
Event-Free Survival
81
8
60%
40%
20%
0%
0
12
24
36
Months from Start of Protocol Therapy
Lenalidomide
Event-Free Survival
100%
12-Month
N
Estimate
Continuous
44
46%
80%
Syncopated
36
34%
Logrank P-value = .02
60%
40%
20%
0%
0
12
24
36
Months from Start of Protocol Therapy
Lenalidomide
Event-Free Survival
By Cytogenetic Abnormalities
100%
12-Month
Events / N
Estimate
CA
48
37%
80%
No CA
32
42%
Logrank P-value = .59
60%
40%
20%
0%
0
12
24
36
Months from Start of Protocol Therapy
Lenalidomide
Univariate Analysis for EFS
%
HR (95% CI)
P-value
LDH>=190 UI/L
44%
0.71 (0.40,1.26)
0.2
Albumin<3.5 g/dL
13%
1.54 (0.72,3.28)
0.3
B2M>=4 mg/L
42%
0.88 (0.50,1.54)
0.7
CRP>=4 mg/L
70%
1.15 (0.62,2.12)
0.7
Creatinine>=2.0 mg/dL
9%
0.72 (0.26,2.00)
0.5
Prior Thalidomide or Velcade
91%
3.05 (0.74,12.56)
0.1
Cytogenetics abnormalities
60%
1.17 (0.67,2.04)
0.6
Prior transplant
84%
1.76 (0.75,4.15)
0.2
At least 60 months of prior therapy
41%
0.51 (0.28,0.93)
0.03
Conclusions
·Approximately 15% of refractory/relapsed
patients on thalidomide have > 5 year disease
control.
·The same prognostic factors are relevant for
high dose therapy and novel drugs. Revlimid
may be the exception.
·Novel drugs are probably most effective in
combination with high dose chemotherapy.