ClaPD (Clarithromycin/[Biaxin®],
Pomalidomide, Dexamethasone) Therapy
in Relapsed or Refractory Multiple
Myeloma
Tomer M. Mark1, Melissa Rodriguez1, Manan Shah1,
Ryann Quinn1, Jessica Campbell1, Ramsey Abdullah1,
Roger Pearse1, Faiza Zafar1, Karen Pekle1, Patrice
Mignott1, David Jayabalan1, Scott A. Ely2, Morton
Coleman1, Selina Chen-Kiang2, Ruben Niesvizky1
1Department of Medicine, Division of Hematology and Oncology; and 2Department of Pathology
and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
Disclosures
T.M.: Celgene Corporation speakers bureau, research funding, and
advisory board; Millennium Pharmaceuticals Inc. speakers bureau;
Genzyme Corporation speakers bureau.
M.C.: Celgene Corporation speakers bureau, advisory board; Millennium
Pharmaceuticals Inc. speakers bureau and advisory board.
R.N.: Celgene Corporation speakers bureau, research funding, and
advisory board; Millennium Pharmaceuticals Inc. speakers bureau,
research funding, and advisory board.
The remaining authors have no conflict of interests to declare.
Pomalidomide is not yet approved for the treatment of patients with
multiple myeloma.
1
Pomalidomide
(CC-4047)
Thalidomide
· Pomalidomide is a distinct immunomodulatory agent that has
demonstrated direct antimyeloma effects, including effects in
lenalidomide-refractory multiple myeloma (MM) patients, with significant
antiproliferative activity in vitro.1,2
· Pomalidomide has promising activity in relapsed MM across a dose
range of 25 mg dosed continuously.3
1. Hideshima T, et al. Blood. 2000;96:2943-50.
2. Mitsiades N, et al. Blood. 2002;99:4525-30.
3. Schey SA, et al. J Clin Oncol. 2004;22:3269-76.
Pomalidomide + Dexamethasone in
Relapsed or Refractory MM
Study
Regimen
N
Pom schedule
ORR,
PR,
VGPR,
Median PFS/
(no. of prior regimens)
(dose)
%
%
%
Duration of response/
OS, months
Lacy MQ, et al.1 (2)
Pom/Dex
60
28/28 (2 mg)
63
30
33
11.6/ 21.3/94% at 6 months,
76% at 2 years
Lacy MQ, et al.2 (4)*
Pom/Dex
34
28/28 (2 mg)
32
23
9
4.8/ 9.1/13.9
Leleu X, et al. 3 (4)
Pom/Dex
43
21/28 (4 mg)
42
26.5
16
7/--/88% alive at 6 months
IFM 2009-02
Pom/Dex
41
28/28 (4 mg)
39
27
12
9.7/--/85% alive at 6 months
Lacy MQ, et. al.4 (6)
Pom/Dex
35
28/28 (2 mg)
25
11
14
6.5/--/78% alive at 6 months
Pom/Dex
35
28/28 (4 mg)
29
17
12
3.2/--/67% alive at 6 months
Richardson P, et al.5 (5)
Pom/Dex
113
21/28 (4 mg)
34§
--
--
4.6/--/14.4
MM-002
Pom
108
21/28 (4 mg)
13§
--
--
2.6/--/13.6
*Lenalidomide refractory subjects.
Lenalidomide and bortezomib refractory subjects.
1. Lacy MQ, et al. J Clin Oncol. 2009;27:5008-14.
§Responses assessed by the investigator.
2. Lacy MQ, et al. Leukemia. 2010;24:1934-9.
Dex, dexamethasone; PR, partial response; ORR, overall response rate;
3. Leleu X, et al. IMW 2011;P-148.
OS, overall survival; PFS, progression-free survival; Pom, pomalidomide;
4. Lacy MQ, et al. Blood. 2011;118:2970-5.
VGPR, very good PR.
5. Richardson P, et al. Blood. 2011;118:[abstract 634].
2
Rationale for Clarithromycin
· Treatment in newly diagnosed, symptomatic MM with BiRD
(clarithromycin [Biaxin®], lenalidomide [Revlimid®], dexamethasone) in a
phase 2 trial yielded impressive response rates:
N = 72, 90.3% partial response (PR), 38.9% complete response1
· Clarithromycin is postulated to have antimyeloma activity by:
slowing hepatic clearance of dexamethasone leading to greater
corticosteroid exposure24
acting as a weak immunomodulatory agent5,6
· A case-control study showed superior clinical outcomes for BiRD versus
lenalidomide plus low-dose dexamethasone.7
1. Niesvizky R, et al. Blood. 2008;111:1101-9.
2. Garey KW et al. Chest. 2000;118:1826-7.
5. Takizawa H, et al. Biochem Biophys Res Commun. 1995;210:781-6.
3. Fost DA, et al. J Allergy Immunol. 1999;103:1031-5.
6. Matsuoka N, et al. Clin Exp Immunol. 1996;104:501-8.
4. Spahn JD, et al. Ann Allergy Asthma Immunol. 2001;87:501-5.
7. Gay F, et al. Am J Hematol. 2010;85:664-9.
Study Design
A single-center, phase 2 study of clarithromycin (Biaxin®) combined with
Pomalidomide+Dexamethasone in RRMM
Day
1
2
8
9
15
16
21
22
28
Dex
Dex
Dex
Dex
40mg p.o.
40mg p.o.
40mg p.o.
40mg p.o.
Pomalidomide 4 mg p.o.
Clarithromycin 500mg PO b.i.d.
p.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.
3
Study Objectives
· Primary objective:
to determine the overall response rate of ClaPD in patients with
relapsed or refractory MM who have received prior lenalidomide
· Secondary objectives:
progression-free survival (PFS)
safety
Patient Eligibility
Inclusion criteria
Exclusion criteria
Age > 18 years
Nonsecretory MM
Relapsed or progressive MM after at least 3 prior
Prior history of other malignancies (except for
therapeutic treatments/regimens for MM
basal cell or squamous cell carcinoma of the skin
or carcinoma in situ of the cervix or breast)
unless disease free for 5 years
Must have been previously treated with
Unable to take prophylactic anticoagulation or
lenalidomide
antiplatelet therapy
Measurable disease as defined by:
Active heart disease
0.5 g/dL serum M-protein
0.1 g/dL serum free light chains
0.2 g/24 hours urinary M-protein excretion
measurable plasmacytoma(s)
Karnofsky performance status 70% (> 60% if
Active HIV, hepatitis B virus, hepatitis C virus
due to bony involvement of myeloma)
Life expectancy 3 months
Known hypersensitivity to thalidomide or
lenalidomide
Adequate organ reserve, as measured by:
History of thromboembolic event within the past
absolute neutrophil count 750 cells/mm3
6 months prior to enrollment
platelet count 50,000/mm3 (50 × 109/L)
SGOT/AST 2.0 × ULN
SGPT/ALT < 3.0 × ULN
serum creatinine 2.5 × ULN
serum total bilirubin 1.5 × ULN
ALT, alanine transaminase; AST, aspartate transaminase; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvate transaminase;
ULN, upper limit of normal.
4
Patient Baseline Characteristics
Median (range)
N = 46
Age, years
65 (4187)
Sex
21 male, 25 female
2-Microglobulin, mg/L
3.4 (1.212.4)
Albumin, g/dL
3.6 (1.84.5)
Lactate dehydrogenase, U/L
171 (131447)
Hemoglobin, g/dL
10.4 (7.513.5)
Creatinine, mg/dL
0.9 (0.442.5)
Calcium, mg/dL
9.15 (7.911.5)
Number of prior therapies
5 (315)
Baseline MM Stage and
Cytogenetic Abnormalities
n (%)
Durie-Salmon stage, N = 46
Ia
25 (54)
IIa
16 (35)
IIb
3 (7)
IIIa
2 (4)
International Staging System stage, N = 33
I
14 (42)
II
11 (33)
III
8 (24)
Cytogenetics*, N = 44
Standard risk
20 (45)
High risk
24 (55)
*Standard risk, n (%), defined by the presence of one or more of the following: t(11;14): 4(16); hyperdiploidy, 12(46); FISH del 13q14, 12(46);
no abnormality: 5(19).
High risk, n (%), defined by the presence of one or more of the following: del 17p: 5(19); karyotype del 13q: 3(12); amp 1q/ del 1p: 5(19);
t(14;20): 1 (6); t(14;16): 1(6); t(4;14): 1(6); or other complex cytogenetic abnormalities.
5
Prior Therapy History (N = 46)
100%*
91%*
Refractory to treatment
Relapsed after treatment§
*33 patients (71%) were refractory to both lenalidomide and bortezomib.
Refractory: disease that is nonresponsive while on therapy, or progresses within 60 days of last therapy.
§Relapsed: previously treated myeloma that progresses and requires initiation of salvage therapy but does not meet the definition of refractory myeloma.
ASCT, autologous stem cell transplantation.
Results
· 46 patients completed at least 1 cycle of ClaPD.
median number of cycles received was 6 (range 210)
median study follow-up was 9.4 months (range 3.214.4)
· In responding patients, median time to PR was 1.5 cycles (range 17)
Best Response (IMWG Criteria)
n (%)
Overall
Lenalidomide
Lenalidomide and
(N = 46)
refractory
bortezomib refractory
(N = 38)
(N = 33)
ORR ( PR)
27 (60)
24 (63)
20 (61)
sCR
3 (7)
3 (8)
3 (9)
VGPR
9 (20)
7 (18)
5 (15)
PR
15 (33)
14 (37)
12 (36)
MR
3 (7)
2 (5)
2 (6)
SD
7 (15)
4 (11)
3 (9)
PD
9 (20)
8 (21)
8 (24)
IMWG, International Myeloma Working Group; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.
6
Results
PFS
PFS by Cytogenetic Risk
100
100
75
(%)
75
(%)
n
n
50
50
progressio
progressio
Standard risk
25
No
25
No
High risk
0
0
0
100
200
300
0
100
200
300
Time (days)
Time (days)
No. of patients at risk:
No. of patients at risk:
46
33
17
0
Standard risk 20
16
8
0
High risk
24
15
8
0
Median PFS: 8.13 months
As of last study audit, adverse cytogenetics did
not appear to influence the risk of progression
(log-rank P = 0.40)
Results
PFS by Len history
PFS by Len/Bort history
100
100
75
(%)
75
(%)
50
50
progression
progression
No
25
25
No
Relapsed
Relapsed
Refractory
Double-refractory
0
0
0
100
200
300
0
100
200
300
Time (days)
Time (days)
No. of patients at risk:
No. of patients at risk:
Relapsed
8
4
2
0
Relapsed
13
9
6
0
Refractory
38
29
15
0
Double-
33
24
11
0
refractory
As of last study audit, a history of being
As of last study audit, a history of being
refractory to lenalidomide did not
refractory to both bortezomib and
statistically influence the risk of
lenalidomide did not statistically influence the
progression (log-rank P = 0.14)
risk of progression (log-rank P = 0.97)
Bort, bortezomib; Len, lenalidomide.
7
Results
OS
OS by Cytogenetic Risk
1.00
1.00
0.75
0.75
(%)
(%)
al 0.50
al
iv
0.50
iv
Surv
Surv
Standard risk
0.25
0.25
High risk
0
0
0
100
200
300
400
0
100
200
300
400
Time (days)
Time (days)
No. of patients at risk:
No. of patients at risk:
46
45
37
20
4
Standard risk
20
20
17
9
2
High risk
24
23
18
11
2
Median survival has not been reached.
As of last study audit, adverse
After median follow-up time for survival of
cytogenetics did not appear to influence
9.4 months, 39 patients (85%) are alive
risk of death (log-rank P = 0.48)
Grade 3/4 Adverse Events
Adverse event, n (%)
Grade 3*
Grade 4
Anemia
6 (13)
2 (4)
Thrombocytopenia
6 (13)
8 (17)
Neutropenia
15 (32)
6 (13)
Febrile neutropenia
5 (11)
1 (2)
Lymphopenia
11 (24)
5 (11)
Hypoglycemia
5 (11)
4 (9)
· Two patients withdrew from study, both due adverse events:
1 due to grade 3 fatigue
1 due to grade 4 muscular weakness
*Occurring in 10% of patients.
8
Conclusions
· ClaPD is a highly effective regimen for heavily treated relapsed or
refractory MM patients.
· ClaPD demonstrates clinical activity in patients with advanced MM who
have received multiple prior therapies, including many who are refractory
to both lenalidomide and bortezomib.
· PFS in patients treated with ClaPD is sustained for > 6 months in the
majority of patients.
· High-risk cytogenetics did not impact PFS or OS in patients treated with
ClaPD.
· A history of being refractory to prior lenalidomide or double-refractory to
lenalidomide and bortezomib did not influence PFS in patients treated
with ClaPD.
· Discontinuation due to adverse events was low (2 patients).
Acknowledgments
· Thanks to all of the participating patients and their families, as well as
the network of investigators, research nurses, study coordinators, and
operations staff.
· Thanks to referring physicians:
MSKCC
Nikoletta Lendvai
NYU
Amitabha Mazumder
University of Hackensack
David Siegel
Mayo Clinic
Angela Dispenzieri
Norwalk Hospital
Richard Frank
UCLA
Robert Vescio
Mount Sinai
Sundar Jagannath
· This study is funded by Celgene Corporation.
9