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ClaPD (Clarithromycin/[Biaxin ®], Pomalidomide, Dexamethasone) Therapy
in Relapsed or Refractory Multiple Myeloma
Tomer Mark 1, Angelique Boyer 1, Adriana Rossi 1, Manan Shah1, Roger Pearse 1, Faiza Zafar 1, Karen Pekle 1, Linda
Tegnestam 1, Erlinda Sacris 1, June Greenberg 1, Stephanie Speaker 1, David Jayabalan 1, Scott A. Ely 2, Morton Coleman 1, Selina Chen-Kiang 2, Ruben Niesvizky 1
1Department of Medicine, Division of Hematology and Oncology; and 2Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
DISCLOSURE STATEMENTSPEAKER: Tomer Mark MD, MSc
Tomer Mark MD, MSc has disclosed the following financial or other interest that
might be construed as resulting in an actual, potential, or perceived conflict.
Disclosure ListingTM: Research Funding: Celgene Corp; Onyx Corp;
Speakers Bureau: Celgene Corp; Millenium Inc.; Onyx Corp.; Sanofi-Aventis Corp;
Membership on an entity's advisory committees: Celgene Corp;
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.Onyx Corp:
Corporation – speakers bureau, research funding
The remaining authors have no conflict of interests to declare.
There is no FDA indication for pomalidomide at this time.
PomalidomideThalidomide
• Pomalidomide is a distinct immunomodulatory agent– direct antimyeloma activity
– activity in lenalidomide-refractory multiple myeloma
– significant antiproliferative activity in vitro.1,2
– activity in relapsed MM across a dose range of 2–5 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.
Response to Pomalidomide / Dexamethasone In Previously Treated MM
§ Responses assessed by the investigator.Dex, dexamethasone; PR, partial response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; Pom, pomalidomide; VGPR, very good PR.
Study # of prior Regimens
N Pom schedule (dose)
ORR, %
Lacy MQ, et al. 1 2 60 28/28 (2 mg) 63
Lacy MQ, et al. 2
(Len-refractory)4 34 28/28 (2 mg) 32
Leleu X, et al. 3
IFM 2009-02(Double refractory)
5 43 21/28 (4 mg) 35
5 41 28/28 (4 mg) 34
Vij R, et al. 4
MM-002
5 113 21/28 (4 mg) 30§
5 10821/28 (4 mg)
(no dex)9§
Lacy MQ, et. al. 5
(Double refractory)6 35 28/28 (2 mg) 25
6 35 28/28 (4 mg) 29
1. Lacy MQ, et al. J Clin Oncol. 2009;27:5008-14. 2. Lacy MQ, et al. Leukemia. 2010;24:1934-9.
3. Leleu X, et al. Blood. 2011; 118(21):812.4. Vij R, et al. J Clin Oncol. 2012:[abstract 8016].
5. Lacy MQ, et al. Blood. 2011;118:2970-5.
Rationale for Clarithromycin
• Treatment in newly diagnosed, symptomatic multiple myeloma (MM) with BiRD (clarithromycin [Biaxin®], lenalidomide [Revlimid®], dexamethasone) in a phase 2 trial yielded:
– N = 72, 90.3% ≥ partial response (PR), 38.9% complete response (CR)1
• Clarithromycin:
– slows hepatic clearance of dexamethasone leading to greater corticosteroid exposure2–4
– acts as a weak immunomodulatory agent5,6
• A case-control study showed superior clinical outcomes for BiRD versus lenalidomide plus low-dose dexamethasone.7
5. Takizawa H, et al. Biochem Biophys Res Commun. 1995;210:781-6.6. Matsuoka N, et al. Clin Exp Immunol. 1996;104:501-8.
7. Gay F, et al. Am J Hematol. 2010;85:664-9.
1. Niesvizky R, et al. Blood. 2008;111:1101-9. 2. Garey KW et al. Chest. 2000;118:1826-7. 3. Fost DA, et al. J Allergy Immunol. 1999;103:1031-5.4. Spahn JD, et al. Ann Allergy Asthma Immunol. 2001;87:501-5.
Study Design
A single-center, phase 2 study of Clarithromycin (Biaxin®) combined with Pomalidomide + Low Dose Dexamethasone in RRMM
p.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.
1 2 8 9 15 16 21 22 281 2 8 9 15 16 21 22 28Day
Dex40mg PO
Dex40mg PO
Dex40mg PO
Dex40mg PO
Dex40mg PO
Dex40mg PO
Dex40mg PO
Dex40mg PO
Pomalidomide 4 mg POPomalidomide 4 mg PO
Clarithromycin 500mg PO BIDClarithromycin 500mg PO BID
Study Objectives
Primary objective:
– to determine the overall response rate (ORR) of ClaPD in patients with relapsed or refractory MM who have received prior lenalidomide
Secondary objectives:
– progression-free survival (PFS)
– safety
Key Patient Eligibility Criteria
Inclusion criteria Exclusion criteriaAge > 18 years Nonsecretory MM
Relapsed or progressive MM after at least 3 prior therapeutic treatments/regimens for MM
History of thromboembolic event within the past 6 months prior to enrollment
Must have been previously treated with lenalidomide
Unable to take prophylactic anticoagulation or antiplatelet therapy
Adequate bone marrow, liver, and renal function
Patient Baseline Characteristics
Median (range) N = 100
Age, years 63 (42–87)
Sex 46 male, 54 female
β2-Microglobulin, mg/L 3.4 (1.2–12.4)
Albumin, g/dL 3.5 (0.7–4.5)
Lactate dehydrogenase, U/L 171 (110–1353)
Hemoglobin, g/dL 10.4 (6.4–14.6)
Creatinine, mg/dL 0.9 (0.44–2.5)
Calcium, mg/dL 9.1 (7.8–12.3)Number of prior therapies 5 (3–15)
Baseline MM Stage and Cytogenetic Abnormalities
n (%)
Durie-Salmon stage, N = 100
Ia 42
IIa 43
IIb 3
IIIa 11
IIIb 1
International Staging System stage, N = 84
I 32 (38)
II 29 (35)
III 23 (27)
Cytogenetics*, N = 96
Standard risk 41 (43)
High risk 55 (57)
*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.
Prior Therapy History (N = 100)
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 MM.ASCT, autologous stem cell transplantation.
Results
98 patients completed at least 1 cycle of ClaPD.
– median number of cycles received was 6 (range 1–25)
– median study follow-up was 9.6 months (range 1.0–25.6)
In responding patients, median time to PR was 1 cycle (range 1–7).
Median time to best response was 2 cycles (range 1-14).
Best Response (IMWG Criteria)
n (%) Overall(N = 98)
ORR (≥ PR) 56 (57)
CBR (≥ MR) 65 (66)
sCR 6 (6)
VGPR 17 (17)
PR 33 (34)
MR 9 (9)
SD 23 (23)
PD 10 (10)
IMWG, International Myeloma Working Group; CBR, clinical benefit rate; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.
Treatment History With Len/Bort Did Not Influence Response to ClaPD
Best Response (IMWG Criteria)n (%) Overall
(N = 98)Lenalidomide
refractory(N = 83)
BortezomibRefractory
(N = 82)
Lenalidomide and bortezomib refractory
(N = 72)
ORR (≥ PR) 56 (57) 47 (63) 46 (56) 39 (54)
CBR (≥ MR) 65 (66) 56 (67) 54 (65) (65)
sCR 6 (6) 6 (7) 5 (6) 5 (7)
VGPR 17 (17) 13 (16) 13 (16) 9 (13)
PR 33 (34) 28 (34) 28 (34) 25 (35)
MR 9 (9) 8 (10) 8 (10) 8 (11)
SD 23 (23) 18 (22) 19 (23) 16 (22)
PD 10 (10) 8 (12) 9 (11) 9 (13)
IMWG, International Myeloma Working Group; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.
Median PFS: 8.67 months
ResultsPFS
No
prog
ress
ion
(%)
1.00
0.75
0.50
0.25
0
0 200 400 600 800Time (days)
Number at risk 100 41 16 8 0
Results
At latest analysis, adverse cytogenetics did not appear to influence the risk of progression:
HR = 1.23, 95% CI (0.73,2.07), P = 0.448
PFS by cytogenetic risk
0 200 400 600 800
Time (days)
1.00
No
prog
ress
ion
(%)
0.75
0.50
0.25
0
Number of patients at risk Standard risk 41 19 7 5 0High risk 55 21 8 2 0
Standard riskHigh risk
Results
At latest analysis, a history of lenalidomide resistance did not statistically influence the risk of progression: HR 1.00, 95% CI =(0.49-2.03), P = 0.995
Similarly, bortezomib resistance did not statistically influence the risk of progression: HR 1.09, 95%CI = (0.56,2.09), P = 0.806
Bort, bortezomib; Len, lenalidomide.
PFS by lenalidomide history
Time (days)Number of patients at risk Relapsed 15 5 2 1 0Refractory 85 36 14 7 0
1.00
No
prog
ress
ion
(%)
0.75
0.50
0.25
0
Len relapsedLen refractory
PFS by bortezomib history
0 200 400 600 800
Time (days)
1.00
No
prog
ress
ion
(%)
0.75
0.50
0.25
0
Number of patients at risk Relapsed 16 10 3 2 0Refractory 84 31 13 6 0
Bort relapsedBort refractory
Results
There was no difference seen in PFS in double-refra ctory patients. HR 1.35, 95% CI (0.75,2.43), P = 0.307
Bort, bortezomib; Len, lenalidomide.
0 200 400 600 800Time (days)
Number of patients at risk Relapsed 26 14 5 3 0D-Refractory 74 27 11 5 0
1.00
No
prog
ress
ion
(%) 0.75
0.50
0.25
0
Not double-refractoryDouble-refractory
PFS by Lenalidomide AND Bortezomib history
Median survival has not been reached.
After median follow-up time for survival of 9.6 months, 72% of patients are alive
Results
OS
0 200 400 600 800
Time (days)
Number of patients at risk 99 62 36 20 0
1.00
Sur
viva
l (%
)
0.75
0.50
0.25
0
Results
OS by cytogenetic risk OS by double-refractory state
0 200 400 600 800
Time (days)Number of patients at risk Relapsed 41 26 16 10 0Refractory 54 33 18 9 0
1.00
Sur
viva
l (%
)
0.75
0.50
0.25
00 200 400 600 800
Time (days)
1.00
Sur
viva
l (%
)
0.75
0.50
0.25
0
Number of patients at risk Relapsed 26 18 13 6 0Refractory 74 44 23 14 0
Not double-refractoryDouble-refractory
Standard riskHigh risk
Adverse cytogenetics did not appear to influence risk of death as of last study follow-up.HR 1.05, 95%CI (0.49,2.26), P = 0.888
A history of being double-refractory, however, approached a significant effect on survival time. HR 2.67, 95%CI (0.93,7.69), P = 0.068
Grade 3/4 Adverse Events*Adverse event, (%) Grade 3 Grade 4
Anemia 21 4
Thrombocytopenia 17 16
Neutropenia 33 14
Lymphopenia 31 6
Hyperglycemia 7 3
Febrile neutropenia 2 1
Pulmonary embolism 1
DVT 4
*Occurring in ≥ 10% of patients.
Three patients withdrew from study due to adverse events: – 1 grade 3 fatigue – 1 grade 4 muscular weakness– 1 grade 4 neutropenic sepsis
There was no treatment-related mortality
Conclusions
• ClaPD has proven to be a highly effective regimen for a large cohort of heavily treated relapsed or refractory MM patients.
• The addition of clarithromycin to pomalidomide + low dose dexamethasone appears to enhance expected efficacy.
• 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 > 8 months in the majority of patients.
Conclusions (2)
• High-risk cytogenetics did adversely impact PFS or OS in patients treated with ClaPD.
• A history of being refractory to prior lenalidomide, bortezomib, or double-refractory to both agents did not adversely influence PFS in patients treated with ClaPD; however, there is a trend towards shorter survival in double-refractory patients.
• Incidence of venous thrombosis while on low-dose aspirin prophylaxis was 5%
• Discontinuation rate due to adverse events was low at 3%.
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:
• This study is supported by Celgene Corporation.
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
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