Pomalidomide With or Without Low-dose Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma: Outcomes in Patients Refractory to Lenalidomide and Bortezomib Ravi Vij 1, Paul G. Richardson 2, Sundar Jagannath 3, David S. Siegel 4, Rachid C. Baz 5, Gail Larkins 6, Min Chen 6, Mohamed H. Zaki 6, Mohamad A. Hussein 6, Kenneth C. Anderson 2 1 Washington University School of Medicine, Saint Louis, MO; 2 Dana-Farber Cancer Institute, Boston, MA; 3 Mount Sinai Medical Center, New York, NY; 4 John Theurer Cancer Center, Hackensack, NJ; 5 H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 6 Celgene Corporation, Summit, NJ; USA 1
Disclosures Consultancy, Research Funding and Speakers Bureau: Celgene Corporation, Millennium, Onyx, Cephalon 2
Background There is currently no approved treatment for patients () failing LEN and BORT treatment RRMM patients to BORT and immunomodulatory drugs have an overall survival of 9 months, but only 3 months if they receive no therapy following relapse, 1 thus reflecting the poor outcome among these patients Effective new treatments are urgently needed to improve outcomes for these patients BORT, bortezomib; LEN, lenalidomide; LoDEX, low-dose dexamethasone; POM, pomalidomide; RRMM, relapsed or multiple myeloma. 1. Kumar SK, et al. Leukemia. 2012;26:149-57 3
Background Pomalidomide (POM) is an oral immunomodulatory drug with significant antimyeloma activity in vitro 1,2 When combined with low-dose dexamethasone, POM has clinical activity in RRMM patients previously treated with lenalidomide and/or bortezomib 3 6 This pre-planned subset analysis of MM-002 phase 2 trial data evaluates outcomes with POM + LoDEX in patients with disease to LEN and/or BORT 7,8 O N O N H O POM NH 2 O 1. Hideshima T, et al. Blood. 2000;96:2943-50; 2.Mitsiades N, et al. Blood. 2002;99:4525-30; 3. Lacy MQ, et al. J Clin Oncol. 2009;27:5008-14; 4. Lacy MQ, et al. Leukemia. 2010;24:1934-9; 5. Lacy MQ, et al. Blood. 2011;118:2970-5; 6. Richardson PG, et al. Blood. 2011;118:abstract 634; 7. Richardson PG, et al. Blood. 2011;118:abstract 634; 8. 4
MM-002: Phase 2 Study Design Primary endpoint: PFS Secondary endpoints: ORR, 1,2 safety, DOR, OS Stratification factors: Age ( 75 vs >75 yrs), prior THAL, and 2 vs >2 prior treatments Randomization POM (4 mg days 1 21 of 28-day cycles) POM (4 mg days 1 21 of 28-day cycles) + LoDEX* (40 mg/week) Progressive disease Option to add LoDEX* (40 mg/week) Discontinue and follow up for survival Progressive disease Progressive disease and subsequent treatment Aspirin (80 100 mg) or equivalent was mandated for all patients * Patients aged > 75 years had a starting DEX dose of 20 mg/week. DOR, duration of response; G-CSF, granulocyte colony-stimulating factor; LoDEX, low-dose dexamethasone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; POM, pomalidomide; RBC, red blood cell; yrs, years. 1. Bladé J, et al. Br J Haematol. 1998;102:1115-23; 2. Richardson PG, et al. N Engl J Med. 2003;348:2609-17. 5
MM-002: Phase 2 Key Eligibility Criteria Aged 18 years Relapsed and multiple myeloma: measurable levels of M paraprotein in serum or urine 2 prior therapies prior therapy must have included 2 cycles of lenalidomide and 2 cycles of bortezomib (separately or in combination) documented progression during or within 60 days of last treatment ( disease) 6
MM-002: Phase 2 Patient Disposition ITT Population* Baseline characteristics were well balanced between the study arms Median number of prior therapy was 5 (range 2 13) Randomization (N = 221) POM (n = 108) POM + LoDEX (n = 113) PD Added LoDEX (n = 61) Continued treatment (n = 22) Discontinued (n = 86) - PD (n = 47) - PD unconfirmed (n = 6) - Adverse events (n = 13) - Death (n = 9) - Consent withdrawal (n = 7) - Other (n = 4) Continued treatment (n = 23) Discontinued (n = 90) - PD (n = 58) - PD unconfirmed (n = 7) - Adverse events (n = 8) - Death (n = 8) - Consent withdrawal (n = 5) - Other (n = 4) * As of April 1, 2011; LoDEX, low-dose dexamethasone; PD, progressive disease; POM, pomalidomide. 7
MM-002: Best Response by IRAC Review Using EBMT Criteria, ITT Population Median number of cycles received was 5 (range 1-17) Disease control ( SD) was observed in 76% of overall patients POM (n = 108) POM + LoDEX (n = 113) ORR ( PR) (%) 9 30 Median DOR*, months NR 7.4 MR 25 45 CR 0 1 PR 9 29 MR 16 15 SD 46 35 PD 16 6 Median time to ORR*, months 2.0 1.9 Discrepancies in totals are due to rounding. *For patients who achieved PR. CR, complete response; DOR, duration of response; LoDEX, low-dose dexamethasone; IIT, intent-to-treat; IRAC, Independent Response Adjudication Committee; MR, minor response; ORR, overall response rate; PD, progressive disease; POM, pomalidomide; PR, partial response; NR, not reached; SD, stable disease. 8
MM-002: Progression-Free Survival in ITT Population* Median PFS was longer with POM + LoDEX Proportion of patients 1.0 0.8 0.6 0.4 0.2 POM + LoDEX (n=113) POM (n=108) HR = 0.73 P = 0.037 Median PFS 3.8 months 2.5 months 0 0 2 4 6 8 10 12 14 16 Progression-free survival (months) (Median follow-up: POM, 2.0 months; POM + LoDEX, 3.6 months) * Not censored; HR, hazard ratio; LoDEX, low-dose dexamethasone; PFS, progression-free survival; POM, pomalidomide. 9
MM-002: Overall Survival in ITT Population Median OS was comparable Proportion of patients 1.0 0.8 0.6 0.4 0.2 POM + LoDEX (n=113) POM (n=108) HR = 0.85 P = 0.449 Median OS 14.4 months 13.6 months 0 0 2 4 6 8 10 12 14 16 Overall survival (months) (Median follow-up: POM, 9.2 months; POM + LoDEX, 9.6 months) HR, hazard ratio; LoDEX, low-dose dexamethasone; OS, overall survival; POM, pomalidomide. 10
MM-002: Baseline Characteristics of Refractory Patients, POM + LoDEX Arm LEN BORT LEN-BORT LEN-BORT + prior transplant Patient Characteristics (n = 87) (n = 82) (n = 69) (n = 47) Median age, years (range) 65 (46 88) 64 (34 88) 66 (46 88) 62 (47 76) Male (%) 60 54 58 51 Baseline MM stage (%) II 94 93 94 94 Baseline performance status (%) 0 1 89 87 87 91 2 3 11 13 13 9 BORT, bortezomib; DEX, dexamethasone; LEN, lenalidomide; LoDEX, low-dose dexamethasone; MM, multiple myeloma; POM, pomalidomide; SCT, stem cell transplant; THAL, thalidomide. 11
MM-002: Analysis of Refractory Patients, POM + LoDEX Arm Prior Therapies LEN (n = 87) BORT (n = 82) LEN-BORT (n = 69) LEN-BORT + prior transplant (n = 47) Median no. prior therapies (range) 5 (2 12) 5 (2 13) 5 (2 11) 5 (2 11) - Prior LEN (%) 100 100 100 100 - Prior BORT (%) 100 100 100 100 - Prior Steroids (%) 100 100 100 100 - Prior HDM + SCT (%) 89 87 86 100 - Prior THAL (%) 68 68 67 68 - Prior Cyclophosphamide (%) 48 54 48 53 - Prior Doxorubicin (%) 37 35 33 38 - Prior Vincristine (%) 30 29 26 34 - Prior Melphalan (%) 15 17 18 0 - Prior Carfilzomib (%) 18 16 16 19 - Prior Cisplatin (%) 14 12 12 17 - Prior Vorinostat (%) 13 13 12 13 Patients could have received more than one prior therapy. BORT, bortezomib; HDM, high-dose melphalan: LEN, lenalidomide; LoDEX, low-dose dexamethasone; POM, pomalidomide; SCT, stem cell transplant; THAL, thalidomide. 12
MM-002: Best Response by IRAC Review Using EBMT Criteria, POM + LoDEX Arm Response LEN (n = 87) BORT (n = 82) LEN-BORT (n = 69) LEN-BORT + prior transplant (n = 47) ORR ( PR) (%) 25 29 28 34 MR (%) 41 46 46 53 CR (%) 0 0 0 0 PR (%) 25 29 28 34 MR (%) 16 17 19 19 SD (%) 40 33 35 28 PD (%) 7 7 7 6 Time to PR (mo) 1.9 1.9 1.8 1.6 Median duration of PR (mo) 7.0 5.8 6.2 5.7 Median duration of MR only (mo) 3.4 3.2 3.0 5.7 Patients could be classified under more than one category. Discrepancies in totals due to rounding. BORT, bortezomib; CR, complete response; DOR, duration of response; LEN, lenalidomide; LoDEX, low-dose dexamethasone; MR, minor response; ORR, overall response rate; PD, progressive disease; POM, pomalidomide; PR, partial response; SD, stable disease. 13
MM-002: Overall Survival Refractory to LEN Refractory to BORT Median OS Median OS 1.0 POM + LoDEX (n=87) POM (n=85) 14.4 mo 12.9 mo 1.0 POM + LoDEX (n=82) POM (n=75) 13.4 mo 12.9 mo Proportion of patients 0.8 0.6 0.4 0.2 HR = 0.72 P = 0.16 Proportion of patients 0.8 0.6 0.4 0.2 HR = 0.89 P = 0.64 0 0 2 4 6 8 10 12 14 16 0 0 2 4 6 8 10 12 14 16 Overall survival (months) Overall survival (months) BORT, bortezomib; HR, hazard ratio; LEN, lenalidomide; LoDEX, low-dose dexamethasone; OS, overall survival; POM, pomalidomide. 14
MM-002: Overall Survival Proportion of patients 1.0 0.8 0.6 0.4 0.2 Refractory to LEN and BORT POM + LoDEX (n=69) POM (n=64) HR = 0.80 P = 0.41 Median OS 13.5 mo 10.8 mo Proportion of patients 1.0 0.8 0.6 0.4 0.2 Refractory to LEN and BORT with prior transplant POM + LoDEX (n=47) POM (n=49) Median OS NR mo 10.6 mo HR = 0.63 P = 0.14 0 0 2 4 6 8 10 12 14 16 0 0 2 4 6 8 10 12 14 16 Overall survival (months) Overall survival (months) BORT, bortezomib; HR, hazard ratio; LEN, lenalidomide; LoDEX, low-dose dexamethasone; NR, not reached; OS, overall survival; POM, pomalidomide. 15
MM-002: Overall Grade 3 4 AEs Adverse Event 10% of pts (%) POM (n = 107) POM + LoDEX (n = 112) Hematologic Neutropenia 47 38 Thrombocytopenia 22 19 Anemia 22 21 Leukopenia 6 10 Non-hematologic Pneumonia 14 19 Fatigue 10 10 Back pain 12 9 Dyspnea 7 13 This analysis is based on the safety population; AE, adverse event. 16
MM-002: Grade 3 4 Hematologic AEs, POM + LoDEX Arm Adverse Event 10% of pts (%) Neutropenia LEN (n = 86) BORT (n = 81) LEN-BORT (n = 68) LEN-BORT + prior transplant (n = 46) 42 43 47 50 Thrombocytopenia 21 20 22 28 Anemia 20 20 19 22 Leukopenia 11 11 12 15 This analysis is based on the safety population; AE, adverse event; BORT, bortezomib; LEN, lenalidomide; LoDEX, low-dose dexamethasone; POM, pomalidomide. 17
MM-002: Grade 3 4 Non-Hematologic AEs, POM + LoDEX Arm No grade 3 4 peripheral neuropathy Incidence of deep-vein thrombosis was between 2 3% Adverse Event 10% of pts (%) LEN (n = 86) BORT (n = 81) LEN-BORT (n = 68) LEN-BORT + prior transplant (n = 46) Pneumonia 17 20 21 20 Back pain 12 10 12 17 Dyspnea 11 15 12 11 This analysis is based on the safety population BORT, bortezomib; LEN, lenalidomide; LoDEX, low-dose dexamethasone; POM, pomalidomide. 18
MM-002: Conclusions POM (4 mg/day, for 21 days of each 28-day cycle) in combination with LoDEX (40 mg/week) has shown a 30% ORR based on the IMWG criteria in a population of patients who are heavily pre-treated Response rates were similar regardless of prior refractoriness to LEN, BORT, or both suggesting lack of cross-resistance between POM and LEN The main adverse events associated with POM with or without LoDex were hematologic POM + DEX is being investigated in Phase 3 trials: POM + LoDEX vs. high-dose DEX in RRMM currently enrolling in Europe POM+BORT+DEX vs. BORT+DEX in RRMM planned in USA BORT, bortezomib; LEN, lenalidomide; LoDEX, low-dose dexamethasone; MM, multiple myeloma; POM, pomalidomide; RRMM relapsed/ MM. 19
Acknowledgments Our Patients and Families Phase 2 Investigators Including: Paul Richardson, Craig Hofmeister, Sundar Jagannath, Christine Chen, Sagar Lonial, Andrzej Jakubowiak, Nizar Bahlis, Kevin Song, Andrew Belch, Noopur Raje, Joseph Mikhael, Martha Lacy, Suzanne Lentzsch, Jeffrey Matous, Chaim Shustik The Cancer Center - Hackensack University Medical Center H. Lee Moffitt Cancer and Research Institute Massachusetts General Hospital Mayo Clinic Arizona Mayo Clinic Minnesota Roswell Park Cancer Institute The Ohio State University - James Cancer Hospital University of Michigan Comprehensive Cancer Center Washington University - Siteman Cancer Center Institutions With Study Sites St. Vincent's Comprehensive Cancer Center University of Pittsburgh Cancer Institute Emory University Princess Margaret Hospital - UHN Cross Cancer Center University of Calgary - Tom Baker Cancer Center Vancouver General Hospital, Diamond Health Care Centre Royal Victoria Hospital - McGill University Multiple Myeloma Research Consortium Clinical Research Staff Celgene Corporation 20