1. New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida First-in-Human Trial: BCMA- Targeted CAR T Cells in Advanced R/R MM *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from Amgen, Celgene Corporation, Merck, Incyte, Seattle Genetics, and Takeda Oncology.

2. CAR-BCMA T Cells in MM: Background  BCMA: protein in TNF superfamily expressed by normal and malignant plasma cells and B cells [1]  Autologous T cells can be genetically modified to express CARs targeted to malignancy-associated antigens –BCMA a potential target for myeloma CAR T-cell therapy –BCMA expressed uniformly on malignant plasma cells from 60% to 70% of pts with MM  Current study evaluated CAR-BCMA T-cell infusion for treatment of advanced MM [2] –Autologous T cells were stimulated, transduced with CAR-BCMA retroviruses, and cultured for 9 days before infusion 1. Carpenter RO, et al. Clin Cancer Res. 2013;19:2048-2060. 2. Ali SA, et al. ASH 2015. Abstract LBA-1. Slide credit: clinicaloptions.comclinicaloptions.com

3. CAR-BCMA T Cells in MM: Study Design  First-in-human phase I trial  CAR-BCMA expression determined by flow cytometry Slide credit: clinicaloptions.comclinicaloptions.com Pts with advanced R/R MM; ≥ 3 prior lines of therapy; normal organ function; clear, uniform BCMA expression on MM cells (N = 12) CAR-BCMA T cells* Single infusion Cyclophosphamide 300 mg/m 2 Fludarabine 30 mg/m 2 QD for 3 days *Dose escalation of CAR+ T cells/kg 0.3 x 10 6 1.0 x 10 6 3.0 x 10 6 9.0 x 10 6 Ali SA, et al. ASH 2015. Abstract LBA-1.

4. CAR-BCMA T Cells in MM: Response Slide credit: clinicaloptions.comclinicaloptions.com Ali SA, et al. ASH 2015. Abstract LBA-1. PtMyeloma Type CAR-BCMA Dose (T cells/kg) ResponseResponse Duration, Wks 1κ light chain only0.3 x 10 6 PR2 2IgA λ0.3 x 10 6 SD6 3κ light chain only0.3 x 10 6 SD6 4κ light chain only1.0 x 10 6 SD12 5IgG κ1.0 x 10 6 SD4 6IgG λ1.0 x 10 6 SD2 7IgG λ3.0 x 10 6 SD7 8κ light chain only3.0 x 10 6 VGPR8 9κ light chain only3.0 x 10 6 SD16 10IgA λ9.0 x 10 6 sCR12+ 11IgG λ9.0 x 10 6 PR6+ 12IgA λ3.0 x 10 6 SD2

5. CAR-BCMA T Cells in MM: Pt 10  Pt 10: chemotherapy-resistant IgA MM with 3 prior lines of therapy –Relapse 3 mos after ASCT + melphalan 200 mg/m 2 conditioning with 90% bone marrow plasma cells –BCMA expression on pt’s myeloma cells was uniform but dim  After CAR-BCMA T-cell infusion, the pt experienced cytokine release syndrome (including fever, hypotension, tachycardia, high creatinine kinase, liver enzymes) which resolved within 2 wks –ANC < 500/µL at time of infusion and for 40 days after –Pt was platelet transfusion dependent for 9 wks after infusion  Pt achieved ongoing sCR after CAR-BCMA T-cell infusion –Serum, urine immunofixation negative at 14 wks post infusion –Bone marrow negative by flow cytometry 14 wks post induction  MM eliminated from bone marrow cells after infusion with CAR-BCMA Slide credit: clinicaloptions.comclinicaloptions.com Ali SA, et al. ASH 2015. Abstract LBA-1.

6. CAR-BCMA T Cells in MM: Pt 11  Pt 11: advanced MM with 5 prior lines of therapy  After CAR-BCMA infusion, pt experienced significant AEs; however, dramatic reduction in disease did occur –Toxicities included fever, delirium, dyspnea, hypotension, tachycardia, acute kidney injury, prolonged thrombocytopenia –All toxicities completely resolved  Pt achieved PR with M-protein still decreasing –Markers of MM decreased rapidly after infusion –Evidence of MM comprising 80% of Pt 11’s bone marrow cells eliminated after CAR-BCMA infusion Slide credit: clinicaloptions.comclinicaloptions.com Ali SA, et al. ASH 2015. Abstract LBA-1.

7. CAR-BCMA T Cells in MM: IL-6 Elevation  Significant antimyeloma responses associated with highest blood levels of CAR-BCMA T cells  Serum IL-6 elevations observed in pts with clinical signs of cytokine-release syndrome –Pts 10 and 11, with the most severe cytokine-release syndrome, had markedly higher serum IL-6 levels as compared with other pts Slide credit: clinicaloptions.comclinicaloptions.com Ali SA, et al. ASH 2015. Abstract LBA-1.

8. CAR-BCMA T Cells in MM: Conclusions  First demonstration that CAR T cells have activity in MM  CAR-BCMA T cells eliminated plasma cells without causing direct organ damage  Responses included ongoing sCR in pt with a high disease burden that was chemotherapy-resistant  Substantial but reversible toxicity comparable to that observed in previous CAR T-cell studies –Highest dose level of CAR-BCMA T cells to be reserved for pts with ≥ 50% bone marrow plasma cells  Authors conclude that CAR-BCMA T cells represent a promising novel therapy for MM Slide credit: clinicaloptions.comclinicaloptions.com Ali SA, et al. ASH 2015. Abstract LBA-1.

9. Go Online for More CCO Coverage of ASH 2015! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in:  Acute leukemias/chronic leukemias  Myeloma/plasma cell disorders  Lymphomas  MDS and myeloproliferative neoplasms clinicaloptions.com/oncology