Table 4. Survival Outcomes and Best Response Rates for MM-002 and MM-003 Variable MM-002 MM-003 POM + LoDEX (n = 112) POM (n = 108) POM + LoDEX (n = 302) HiDEX (n = 153) Median PFS, mos (95% CI) 4.2 a (3.6–5.5) 2.7 (1.9–2.9) 4.0 b (3.6-4.7) 1.9 (1.9–2.2) Median OS, mos (95% CI) 16.5 c (12.4–18.5) 13.6 (9.6–18.1) 13.1 d (11.0–15.4) 8.1 (6.9–9.2) ORR (≥ PR), n (%) 37 (33) 19 (18) 97 (32) 17 (11) Median Tx duration e , mos (range) 5.0 (0.1–34.8) 4.7 (0.1–35.7) 4.2 (0.1–21.4) 1.8 (0.2–15.9) a P = 0.003 POM + LoDEX vs. POM. b P < 0.001 POM + LoDEX vs. HiDEX. c P = 0.709 POM + LoDEX vs. POM. d P < 0.001 POM + LoDEX vs. HiDEX. e Safety population. CI, confidence interval; HiDEX, high-dose dexamethasone; LoDEX, low-dose dexamethasone; mos, months; ORR, overall response rate; POM, pomalidomide; PR, partial response; Tx, treatment. Presented at the 55th Annual Meeting of the American Society of Hematology (ASH); New Orleans, LA, USA; December 7–10 2013. • Relapsed and refractory multiple myeloma (RRMM) patients (pts) following treatment (Tx) with bortezomib (BORT) or IMiDs ® immunomodulatory agents, have limited Tx options, and outcomes remain poor 1 • The immunomodulatory agent pomalidomide (POM) has demonstrated potent antimyeloma activity • Tx with POM is recommended in pts who have received at least 2 prior Tx, including lenalidomide (LEN) and BORT, and have demonstrated disease progression on or within 60 days of completion of their last Tx 2 • Randomized phase 2 and 3 trials (MM-002 and MM-003) have shown prominent efficacy results with combination POM plus low-dose dexamethasone (POM + LoDEX) Tx in RRMM pts who had received multiple prior Tx, including LEN and BORT 3–5 • To present a side-by-side analysis of the current efficacy and safety outcomes based on the MM-002 and MM-003 trials Study Design • The study designs for MM-002 and for MM-003 are shown in Figure 1 and Figure 2, respectively • Primary endpoint: Progression-free survival (PFS) • Secondary endpoints: Response rate, duration of response (DOR), OS, and safety Key Inclusion Criteria • Inclusion criteria were similar for the MM-002 and MM-003 trials • Age ≥ 18 years • In the POM + LoDEX groups, AEs were managed through dose reductions (29% and 27%) or interruptions (67% and 67%), supportive care with granulocyte-colony stimulating factor (46% and 43%), blood transfusions (45% and 49%), platelet transfusions (14% and 20%), and anti-infective agents (89% in both trials), in the MM-002 and MM-003 trials, respectively • The rate of discontinuations due to AEs in the POM + LoDEX groups was low (2–4%) – Rate of POM discontinuation due to infection was low (1% in MM-002 and 2% in MM-003) – One pt discontinued Tx due to neutropenia in both trials – No pts discontinued Tx due to febrile neutropenia • Although 60% and 50% of pts receiving POM + LoDEX in the MM-002 and MM-003 trials, respectively, had a history of PN at baseline, only 18% and 17% of PN was observed in the study – Four (1%) pts developed Gr ≥ 3 or greater neuropathy in the MM-003 trial – PN that occurred in study improved or resolved in half of the pts in the MM-002 trial (55%) • This side-by-side analysis of the MM-002 and MM-003 trials consistently showed that the combination regimen of POM + LoDEX extends PFS in RRMM pts – Median PFS was 4.2 and 4.0 months, respectively – PFS, OS, and ORR were not negatively impacted in pts who were refractory to LEN or BORT, even as last prior Tx – Occurrence of neutropenia did not seem to affect the incidence of infections • POM was generally well tolerated with dose modifications and supportive care, leading to few discontinuations due to AEs • POM + LoDEX could be a Tx option for pts with advanced RRMM who have exhausted LEN and BORT Tx 1. Kumar SK, et al. Leukemia. 2012;26:149-57. 2. Pomalyst ® (pomalidomide). Prescribing information, February 2013. http://www.accessdata.fda.gov/ drugsatfda_docs/label/2013/204026lbl.pdf 3. Richardson PG, et al. Blood. 2011;118:abstract 634. 4. Vij R, et al. J Clin Oncol. 2012;30 Suppl:abstract 8016. 5. San Miguel, et al. Lancet Oncol. 2013;14:1055-66. The authors would like to thank the patients who volunteered to participate in these studies, the staff members at the study sites who cared for them, and the representatives of the sponsors who were involved in data gathering and analyses. The authors acknowledge the financial support for this study from Celgene Corporation. The authors received editorial assistance and printing support from Excerpta Medica (Kathy Boon, PhD) sponsored by Celgene Corporation. D.S.S.: Celgene, Millennium, Onyx, Merck – advisory board, honoraria and speakers bureau P.G.R.: Celgene, Millennium, Johnson & Johnson – advisory board M.A.D.: Celgene, Ortho-Biotech – consultant/ advisor; Genesis Pharma – research funding C.C.: Roche – honoraria; Johnson & Johnson – consultancy, research funding; Lundbeck – consultancy; Celgene – consultancy, research funding; GlaxoSmithKline – research funding K.S.: Celgene, Janssen – consultancy, honoraria, and research funding R.V.: Celgene – consultancy, research funding, and speakers bureau; Millennium – speakers bureau; Onyx – consultancy and research funding N.B.: Johnson & Johnson – honoraria and research funding; Celgene – honoraria R.B.: Celgene, Millennium, Bristol-Myers Squibb, Novartis – research funding C.C.H.: Celgene – advisory board and honoraria K.C.W.: Celgene – consultant/advisor, honoraria S.J.: Celgene, Millennium, MSD, Onyx – honoraria and membership of an entity’s board of directors or advisory committees S.L.: Millennium, Celgene, Novartis, Bristol- Myers Squibb, Onyx, Merck – consultancy M.D.: Celgene, Janssen – consultant/advisor, research funding P.M.: Celgene, Millennium, Janssen – consultant/advisor, honoraria J.S.M.: Novartis, Roche, Pfizer, GSK, Astellas – consultant/advisor, honoraria L.K.: Celgene – consultant/advisor, honoraria, expert testimony, other remuneration; Janssen – honoraria, other remuneration H.G.: Celgene – consultant/advisor, honoraria, research funding A.B., M.L.: Celgene – research funding A.O.: Celgene – consultant/advisor A.A.: Celgene, Janssen - Membership on an entity’s Board of Directors or advisory committees, research funding P.C., L.S., M.H.Z., C.J.: Celgene – employment and equity ownership M.C.: Celgene, Janssen, Millennium, Onyx and Bristol-Myers Squibb – consultancy, honoraria, Membership on an entity’s Board of Directors or advisory committees K.C.A.: Celgene, Millennium, Bristol-Myers Squibb, Onyx – membership on board of directors or advisory committee; Acetylon, Oncopep – scientific founder POM (4 mg D1–21 of each 28-day cycle) Option to add LoDEX (40 mg/week) a Discontinue and follow up for survival and subsequent treatment Progressive disease Progressive disease Progressive disease POM (4 mg D1–21 of each 28-day cycle) + LoDEX (40 mg/week) a Randomization Figure 1. Study Design of MM-002 Open-Label, Phase 2 Study (n = 302) POM 4 mg/day D1–21 + LoDEX 40 mg (≤ 75 years) 20 mg (> 75 years) D1, 8, 15, 22 Follow-up for OS and SPM until 5 years post-enrollment Companion trial MM-003C POM 21/28 days PD a or intolerable AE Thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent was required for all pts receiving POM and those at high risk for thromboembolic events PD a (n = 153) HiDEX 40 mg (≤ 75 years) 20 mg (> 75 years) D1–4, 9–12, 17–20 Randomization 2:1 (N = 455) Figure 2. Study Design of MM-003 Open-Label, Phase 3 study Efficacy and Safety of Pomalidomide Plus Low-Dose Dexamethasone in Advanced Multiple Myeloma: Results of Randomized Phase 2 and 3 Trials (MM-002/MM-003) P3185 • Pts with RRMM: – Measurable levels of M-protein in serum or urine – ≥ 2 prior Tx (≥ 2 cycles of LEN and ≥ 2 cycles of BORT, separately or in combination) – Refractory disease with documented progression during or within 60 days of last Tx – Pts refractory to both LEN and BORT were allowed to enter the study Aspirin (81–100 mg) or equivalent was mandated for all patients. a Pts aged > 75 years had a starting DEX dose of 20 mg/week. D, days; LoDEX, low-dose dexamethasone; POM, pomalidomide; pts, patients. a Progression of disease was independently adjudicated in realtime. AE, adverse event; D, days; HiDEX, high-dose dexamethasone; LoDEX, low-dose dexamethasone; PD, progressive disease; POM, pomalidomide; pts, patients; SPM, second primary malignancy. Table 1. Key Exclusion Criteria MM-002 MM-003 POM + LoDEX (n = 112) POM + LoDEX (n = 302) Prior history of malignancies, other than MM Unless pt had been free of disease for ≥ 3 years Unless pt had been free of disease for ≥ 5 years Prior Tx – POM Tx, hypersensitivity to thalidomide, LEN, or DEX; or resistance to high-dose DEX Peripheral neuropathy grade ≥ 2 ≥ 2 Absolute neutrophil count (cells/mL) < 1,000 < 1,000 Platelet count (cells/mL) < 50% plasma cells > 50% plasma cells < 75,000 < 30,000 < 75,000 < 30,000 Serum creatinine (mg/dL) > 3.0 – Creatinine clearance (mL/min) – < 45 Serum liver transaminase level > 3.0 x upper limit of normal > 3.0 x upper limit of normal Serum calcium (mmol/L) – > 3.5 Serum bilirubin level > 2.0 mg/dL > 34.2 µmol/L DEX, dexamethasone; LEN, lenalidomide; LoDEX, low-dose DEX; MM, multiple myeloma; POM, pomalidomide; pt, patient; Tx, treatment. Assessments • Data cut-off was February 1 2013 for MM-002 and September 1 2013 for MM-003; median follow-up was 14.2 and 10.0 months, respectively • Response rate and efficacy data were evaluated by investigator assessment based on best response assessment using EBMT criteria • Adverse event (AE) severity was graded according to NCI-CTC v3.0 Dose Modification Schedule • Treatment-emergent AEs (TEAEs) were managed using dose reductions, Tx interruptions, and supportive care • The dose modification schedule for POM (per protocol) is shown in Table 2 Table 2. Dose Modification Schedule Per Protocol Toxicity POM dose modification a Gr ≥ 2 hypo-hyperthyroidism Hold dose, initiate appropriate Tx, maintain DL at next cycle at discretion of treating physician Gr 3 rash Hold dose, decrease by 1 DL at next cycle (resolve to Gr ≤ 1) Gr 3 peripheral neuropathy Hold dose, decrease by 1 DL at next cycle (resolve to Gr ≤ 1) Gr ≥ 3 constipation Hold dose, initiate bowel regimen, decrease by 1 DL at next cycle, at discretion of treating physician Gr ≥ 3 venous thromboembolism Hold dose, initiate anticoagulation, maintain DL at next cycle, at discretion of treating physician Gr 4 neutropenia or febrile neutropenia Hold dose, initiate G-CSF, reduce by 1 DL at next cycle if neutropenia was not the only DLT To initiate next cycle of POM: platelet count ≥ 500/μL Gr 4 thrombocytopenia Hold dose, decrease by 1 DL at next cycle To initiate next cycle of POM: platelet count ≥ 50,000/μL Gr 4 rash or rash with blistering Discontinue study drug and discontinue pt from study Gr 4 peripheral neuropathy Discontinue study drug and discontinue pt from study Other Gr ≥ 3 POM-related adverse events Hold dose, decrease by 1 DL at next cycle (resolve to Gr ≤ 2) a POM DL: 4 mg to 3 mg to 2 mg to 1 mg then discontinuation. DL, dose level; DLT, dose-limiting toxicity; G-CSF, granulocyte colony-stimulating factor; Gr, Grade; POM, pomalidomide; pt, patient; Tx, treatment. Baseline Characteristics • In MM-002, the intent-to-treat efficacy analysis included 112 pts in the POM + LoDEX group and 108 pts in the POM alone group – 60% of pts in the POM alone group received LoDEX upon progression – 79% were LEN refractory – 62% were refractory to both LEN and BORT – 39% received LEN as last prior Tx • In MM-003, 302 pts were treated with POM + LoDEX and 153 pts with high- dose dexamethasone (HiDEX) – 50% of pts in the HiDEX group subsequently received POM – 95% were LEN refractory – 75% were refractory to both LEN and BORT – 24% had received LEN as last prior Tx • Baseline characteristics and prior Tx are summarized in Table 3 for pts in both studies receiving POM + LoDEX – The majority of pts (93%) had advanced disease (Durie Salmon stage ≥ II) – The median number of prior Txs was 5 (range 2–14) – Most pts were refractory to LEN (90%) Table 3. Baseline Characteristics MM-002 MM-003 POM + LoDEX (n = 112) POM + LoDEX (n = 302) Male, n (%) 62 (55) 181 (60) Age, median (range), years 64 (34–88) 64 (35–84) ECOG performance status score, n (%) 0–1 100 (88) 248 (82) 2–3 13 (12) 52 (17) Cytogenetic profile, n (%) High risk a 30 (27) 130 (43) Standard risk b 57 (50) 91 (30) Median number of prior Tx (range) 5 (2–13) 5 (2–14) Type of prior Tx, c n (%) LEN/BORT/steroids 113 (100) 300 (100) LEN as last therapy 44 (39) 71 (24) BORT as last therapy 56 (50) 108 (36) Alkylators 105 (93) 300 (100) SCT 82 (74) 214 (71) Thalidomide 77 (67) 173 (57) Anthracycline 55 (49) 172 (57) a High-risk cytogenetic profile is defined as those with abnormalities in 13q14, 17p13, 4p16/14q32, or 14q32/16q23. b Standard risk is defined as any cytogenetic abnormality in 17p13 or 4p16/14q32. c Pts could receive > 1 therapy. BORT, bortezomib; LEN, lenalidomide; LoDEX, low-dose dexamethasone; POM, pomalidomide; pts, patients; SCT, stem cell transplantation; Tx, treatment. Tolerability and Safety • The most common Gr 3/4 TEAEs for pts receiving POM + LoDEX were neutropenia, anemia, thrombocytopenia, and pneumonia (Table 5) – The percentages of pts with neutropenia (all grades) was similar in both trials (49% in MM-002 vs. 51% in MM-003) – In the MM-003 trial there were 26% pts with Gr 3 neutropenia and 22% with Gr 4 neutropenia – A higher percentage of pts with pneumonia (all grades) was seen in the MM-002 trial (33%) vs. MM-003 trial (15%) – Incidence of deep-vein thrombosis was low (all grades: 2.7% in MM-002 and 3.0% in MM-003) – The majority of infections occurred in the absence of neutropenia of any grade (54% in MM-002 and 66% in MM-003) Table 5. Summary of AEs in the Safety Populations of the POM+ LoDEX arms in MM-002 and MM-003 MM-002 MM-003 POM + LoDEX (n = 112) POM + LoDEX (n = 300) Most common hematologic Gr 3/4 AEs, n (%) Neutropenia 46 (41) 147 (49) Anemia 25 (22) 99 (33) Thrombocytopenia 21 (19) 67 (22) Most common nonhematologic Gr 3/4 AEs, n (%) Pneumonia 25 (22) 42 (14) Bone pain 14 (13) 21 (7) Fatigue 16 (14) 16 (5) Hematologic Gr 3/4 TEAEs occurring in ≥ 10% of pts, n (%) Febrile neutropenia 3 (3) 29 (10) Leukopenia 11 (10) 26 (9) Nonhematologic Gr 3/4 TEAEs occurring in ≥ 10% of pts, n (%) Dyspnea 14 (13) 15 (5) Back pain 11 (10) 15 (5) AE of interest (all grades), n (%) DVT/PE 3 (3) 9 (3) Peripheral neuropathy 12 (11) 51 (17) Discontinuation of POM due to any AEs, n (%) 8 (7) 26 (9) PN With POM Tx, n (%) Pts with PN a 20 (18) 45 (15) Pts with improvement/resolution, n (%) 11 (55) 3 (1) Median time to resolution, mos 4.6 (95% CI: 0.5–17.7) 0.1 (range: 0.1–1.1) a PN includes 6 selected preferred terms: hyperesthesia, neuropathy peripheral, peripheral sensory neuropathy, paresthesia, hypoesthesia, and polyneuropathy. AE, adverse event; CI, confidence interval; DVT, deep-vein thrombosis; LoDEX, low-dose dexamethasone; mos, months PE, pulmonary embolism; POM, pomalidomide; PN, peripheral neuropathy ; pts, patients; TEAE, treatment-emergent AE. Response • The survival outcomes and best response rates for the MM-002 and MM-003 trials are shown in Table 4 • Survival outcomes were similar between the 2 trials – MM-002: At a median follow-up of 14.2 months the median PFS was 4.2 months; OS was 16.5 months; and overall response rate (ORR, defined as at least a partial response) was 33% with POM + LoDEX – MM-003: At a median follow-up of 15.4 months the median PFS was 4.0 months; OS was 13.1 months; and ORR was 32% with POM + LoDEX – In both trials, LEN as last prior Tx did not impact response, PFS, or OS vs. the overall population Scan this QR code to receive the PDF file of the poster