ClaPD (Clarithromycin/[Biaxin ], Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma Tomer Mark 1, Angelique Boyer 1, Adriana Rossi 1, Manan Shah 1, 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 1 Department of Medicine, Division of Hematology and Oncology; and 2 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
DISCLOSURE STATEMENT SPEAKER: 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 Listing TM: 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.
Thalidomide Pomalidomide 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 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) Leleu X, et al. 3 IFM 2009-02 (Double refractory) Vij R, et al. 4 MM-002 Lacy MQ, et. al. 5 (Double refractory) 4 34 28/28 (2 mg) 32 5 43 21/28 (4 mg) 35 5 41 28/28 (4 mg) 34 5 113 21/28 (4 mg) 30 5 108 21/28 (4 mg) (no dex) 6 35 28/28 (2 mg) 25 6 35 28/28 (4 mg) 29 9 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. 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 exposure 2 4 acts as a weak immunomodulatory agent 5,6 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. 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. 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.
Study Design A single-center, phase 2 study of Clarithromycin (Biaxin ) combined with Pomalidomide + Low Dose Dexamethasone in RRMM Day 1 2 8 9 15 16 21 22 28 Dex 40mg PO Dex 40mg PO Dex 40mg PO Dex 40mg PO Pomalidomide 4 mg PO Clarithromycin 500mg PO BID p.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.
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 Age > 18 years Relapsed or progressive MM after at least 3 prior therapeutic treatments/regimens for MM Exclusion criteria Nonsecretory 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 β 2 -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 Durie-Salmon stage, N = 100 n (%) 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 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) 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). 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) Bortezomib Refractory (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.
Results 1.00 PFS Median PFS: 8.67 months No progression (%) 0.75 0.50 0.25 0 0 200 400 600 800 Time (days) Number at risk 100 41 16 8 0
Results PFS by cytogenetic risk 1.00 No progression (%) 0.75 0.50 0.25 Standard risk High risk 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 0 0 200 400 600 800 Time (days) Number of patients at risk Standard risk 41 19 7 5 0 High risk 55 21 8 2 0
Results PFS by lenalidomide history PFS by bortezomib history 1.00 1.00 No progression (%) 0.75 0.50 0.25 Len relapsed Len refractory No progression (%) 0.75 0.50 0.25 Bort relapsed Bort refractory 0 Time (days) Number of patients at risk Relapsed 15 5 2 1 0 Refractory 85 36 14 7 0 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 0 0 200 400 600 800 Time (days) Number of patients at risk Relapsed 16 10 3 2 0 Refractory 84 31 13 6 0 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.
Results 1.00 PFS by Lenalidomide AND Bortezomib history No progression (%) 0.75 0.50 0.25 Not double-refractory Double-refractory 0 0 200 400 600 800 Time (days) Number of patients at risk Relapsed 26 14 5 3 0 D-Refractory 74 27 11 5 0 There was no difference seen in PFS in double-refractory patients. HR 1.35, 95% CI (0.75,2.43), P = 0.307 Bort, bortezomib; Len, lenalidomide.
Results OS Survival (%) 1.00 0.75 0.50 0.25 Median survival has not been reached. After median follow-up time for survival of 9.6 months, 72% of patients are alive 0 0 200 400 600 800 Time (days) Number of patients at risk 99 62 36 20 0
Results OS by cytogenetic risk OS by double-refractory state 1.00 1.00 0.75 0.75 Survival (%) 0.50 0.25 Standard risk High risk Survival (%) 0.50 0.25 Not double-refractory Double-refractory 0 0 200 400 600 800 Time (days) Number of patients at risk Relapsed 41 26 16 10 0 Refractory 54 33 18 9 0 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 0 0 200 400 600 800 Time (days) Number of patients at risk Relapsed 26 18 13 6 0 Refractory 74 44 23 14 0 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 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 *Occurring in 10% of patients.
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 doublerefractory 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: MSKCC NYU University of Hackensack Mayo Clinic Norwalk Hospital UCLA Mount Sinai Nikoletta Lendvai Amitabha Mazumder David Siegel Angela Dispenzieri Richard Frank Robert Vescio Sundar Jagannath This study is supported by Celgene Corporation.