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