1. Slideset on: Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012;120:1801-9. Carfilzomib/Lenalidomide/Low-Dose Dexamethasone (CRd) Chemotherapy Active and Well Tolerated in Patients With Newly Diagnosed Multiple Myeloma This program is supported by educational grants from

2. clinicaloptions.com/oncology An Online Journal Club Resource for Physician Fellows 1. O’Connor OA, et al. Clin Cancer Res. 2009;15:7085-7091. 2. Mohty B, et al. Haematologica. 2010;95:311-319. 3. Vij R, et al. ASH 2011. Abstract 813. Background  Carfilzomib (PR-171): selective, irreversible proteasome inhibitor with activity in hematologic malignancies, including MM [1] –Durable antitumor activity in patients with relapsed/refractory multiple myeloma [1] –Active in patients refractory to bortezomib [2] –Decreased incidence of peripheral neuropathy compared with bortezomib [3]

3. clinicaloptions.com/oncology An Online Journal Club Resource for Physician Fellows Jakubowiak AJ, et al. Blood 2012;120:1801-9. Phase I: CRd MTD Lenalidomide 25 mg/day on Days 1-21 + Dexamethasone 40 mg/wk for cycles 1-4, 20 mg/wk for cycles 5+ Carfilzomib 28-day cycles: Days 1, 2, 8, 9, 15, 16 for cycles 1-8 (induction); Days 1, 2, 15, 16 for cycles 9-24 (maintenance) All patients receive carfilzomib 20 mg/m 2 on Days 1, 2 for cycle 1, then proceed to investigational dose (remainder of study) Phase II: MTD not reached; dosing as before with carfilzomib 36 mg/m 2 Primary endpoint: response rate ≥ nCR; secondary endpoints: ORR, duration, PFS, OS, TTP, and feasibility of stem cell collection after cycle 4 ≤ 1 DLT ≥ 2 DLT MTD: 20 mg/m² 20 mg/m² MPD: 36 mg/m² 27 mg/m²36 mg/m² ≤ 1 DLT MTD: 27 mg/m² ≥ 2 DLT Phase I/II Study Design

4. clinicaloptions.com/oncology An Online Journal Club Resource for Physician Fellows ORR With CRd  Rapid, durable responses improve with continued treatment  Depth and rate of response not affected by ISS stage or cytogenetic profile  PFS: 97% (12 mos), 92% (24 mos) 0 10 20 30 40 50 60 70 80 90 100 All Patients (N = 53) 4+ Cycles (n = 49) 8+ Cycles (n = 36) 12+ Cycles (n = 29) sCR = nCR = VGPR = PR Patients With ORR (%) Jakubowiak AJ, et al. Blood 2012;120:1801-9.

5. clinicaloptions.com/oncology An Online Journal Club Resource for Physician Fellows CRd Impact on Stem Cell Collection  35 patients underwent stem cell collection after 4 cycles  28 patients used only growth factors; 7 patients used chemotherapy and growth factors  Collection unsuccessful in 1 patient (older than 70 yrs of age, collection attempted after 8 cycles)  Median number of CD34+ cells: 6.9 x 10 6 /kg (range: 0.6- 27.8 x 10 6 /kg) Jakubowiak AJ, et al. Blood 2012;120:1801-9.

6. clinicaloptions.com/oncology An Online Journal Club Resource for Physician Fellows Safety of CRd Regimen  MTD not reached  31% of patients required CRd dose modification  No grade 3/4 adverse events during maintenance phase Treatment-Emergent Adverse Events During Induction, %Any GradeGrade 3/4 Nonhematologic  Hyperglycemia7223  Hypophosphatemia4525  Elevated liver function test288  Rash288  Peripheral neuropathy23*0  Pulmonary embolism66 Hematologic  Thrombocytopenia6817  Anemia6021  Neutropenia3017 *Peripheral neuropathy: 3 grade 2 events, 20 grade 1 events. Jakubowiak AJ, et al. Blood 2012;120:1801-9.

7. clinicaloptions.com/oncology An Online Journal Club Resource for Physician Fellows CRd Summary  Carfilzomib combined with lenalidomide and low-dose dexamethasone produces rapid, durable responses in patients with newly diagnosed MM –Response improved with continued treatment –≥ sCR: 45% (4 cycles), 61% (8 cycles), 62% (12 cycles) –Well tolerated –No grade 3/4 neuropathy; manageable hematologic toxicity; hyperglycemia, hypophosphatemia, liver dysfunction, rash, edema, dyspnea, DVT/PE noted –No adverse effects on stem cell collection –Median number of CD34+ cells: 6.9 x 10 6 /kg (range: 0.6-27.8 x 10 6 /kg) Jakubowiak AJ, et al. Blood 2012;120:1801-9.