Phase Ib PAVO Study: Subcutaneous Daratumumab in Relapsed/Refractory Multiple Myeloma New Findings in Hematology: Independent Conference Coverage of ASH 2016*; December 3-6, 2016; San Diego, California *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 activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

PAVO: Background Daratumumab, recently approved anti-CD38 IgG1k monoclonal antibody, effective MM treatment in combination with Rd or Vd in the second-line setting and beyond or as single agent in MM after ≥ 3 lines of therapy[1-3] Currently administered IV Most IV-associated infusion-related reactions with daratumumab occur during first infusion but are grade 1/2[2] Current phase Ib trial sought to determine safety, pharmacokinetics, and efficacy of SC daratumumab + recombinant human hyaluronidase enzyme (rHuPH20) in pts with relapsed/refractory MM[4] rHuPH20 allows for more rapid absorption of SC injected agents MM, multiple myeloma; RD, lenalidomide/dexamethasone; Vd, bortezomib/dexamethasone. 1. Dimopoulos MA, et al. N Engl J Med. 2016;375:1319-1331. 2. Palumbo A, et al. N Engl J Med. 2016;375:754-766. 3. Lonial S, et al. Lancet. 2016;387:1551-1560. 4. Usmani SZ, et al. ASH 2016. Abstract 1149. Slide credit: clinicaloptions.com

PAVO: Study Design Open-label, multicenter, dose-finding, proof-of-concept phase Ib study Next stage of study will randomize pts to recommended SC dose vs daratumumab IV 16 mg/kg Recommended SC dose will be derived from pharmacokinetic and safety results from above design Primary endpoints: Ctrough of daratumumab at cycle 3/Day 1 and safety Secondary endpoints: ORR, CR, DoR, time to response 4-wk treatment cycles Every wk for 8 wks Every 2 wks for 16 wks Every 4 wks thereafter Infusion time 1200 mg: 20 min (60 mL) 1800 mg: 30 min (90 mL) Daratumumab 1200 mg SC + rHuPH20 30,000 U SC (n = 8)* Pts with measurable R/R MM, ≥ 2 lines of therapy, no prior anti-CD38 therapy (N = 53) Daratumumab 1800 mg SC + rHuPH20 45,000 U SC (n = 45)* *Pre/postinfusion medication includes acetaminophen, diphenhydramine, montelukast, and methylprednisolone. DoR, duration of response; MM, multiple myeloma; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Usmani SZ, et al. ASH 2016. Abstract 1149.

PAVO: Baseline Demographics Characteristic 1200 mg (n = 8) 1800 mg (n = 45) Median age, yrs (range) ≥ 75 yrs, % 66 (49-78) 13 63 (36-79) 9 Median weight, kg (range) 75.0 (53.0-82.5) 74.8 (48.0-133.0) Baseline ECOG PS, % 1 2 25 63 24 73 ISS stage, % I II III 17 50 33 47 20 Median time from diagnosis, yrs (range) 6.55 (1.19-10.3) 5.94 (1.1-15.2) Characteristic 1200 mg (n = 8) 1800 mg (n = 45) Prior lines of therapy, median (range) ≤ 3 lines, % > 3 lines, % 5 (2-10) 33 63 4 (2-11) 36 64 Prior ASCT, % 82 Prior PI, % Prior bortezomib 100 96 Prior IMiD, % Prior lenalidomide Refractory, % PI only IMiD only Both PI and IMiD Last line of therapy 13 88 4 20 58 71 ASCT, autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group; IMiD, immunomodulatory drug; ISS, International Staging System; PI, proteasome inhibitor; PS, performance status. Slide credit: clinicaloptions.com Usmani SZ, et al. ASH 2016. Abstract 1149.

PAVO: Pt Disposition Median follow-up Median duration of treatment 1200 mg: 6.4 mos (range: 1.6-12.0) 1800 mg: 4.3 mos (range: 0.8-8.6) Median duration of treatment 1200 mg: 2.6 mos (range: 0.7-12.0) 1800 mg: 3.4 mos (range: 0.7-8.6) 1200 mg (n = 8) 1800 mg (n = 45) Patients who discontinued treatment, % 88 33 Progressive disease 63 27 Withdrawal by consent 13 Physician decision 4 Death 2 Slide credit: clinicaloptions.com Usmani SZ, et al. ASH 2016. Abstract 1149.

PAVO: Treatment-Related AEs AE profile with SC daratumumab consistent with IV daratumumab Treatment-Related AEs, % 1200 mg (n = 8) 1800 mg (n = 45) Drug-related 63 62 Serious drug-related 13 7 Grade ≥ 3 40 All-grade hematologic > 25% Anemia Thrombocytopenia 25 38 31 18 All-grade nonhematologic > 25% Upper respiratory tract infection Insomnia Decreased appetite 9 Grade 3/4 Treatment-Related AEs, % 1200 mg (n = 8) 1800 mg (n = 45) Anemia 13 Thrombocytopenia 7 Neutropenia Lymphopenia Hypertension 25 4 Fatigue 2 Device-related infection Hyponatremia AE, adverse event. Slide credit: clinicaloptions.com Usmani SZ, et al. ASH 2016. Abstract 1149.

PAVO: Infusion-Related Reactions 1200 mg (n = 8) 1800 mg (n = 45) Overall 13 24 Chills 9 Pyrexia Pruritus 4 Dyspnea Flushing 2 Hypertension Hypotension Nausea Infusion-Related Reaction, n (%) 1200 mg (n = 8) 1800 mg (n = 45) Noncardiac chest pain 13 Oropharyngeal pain 2 Paresthesia Rash Sinus headache Tongue edema Vomiting Wheezing IRR, infusion-related reaction. No grade 4 IRRs in either dosing group; 1 grade 3 IRR (dyspnea) in 1200-mg group All IRRs occurred during first infusion and within first 4 hrs Slide credit: clinicaloptions.com Usmani SZ, et al. ASH 2016. Abstract 1149.

PAVO: Efficacy PK for 1800-mg SC dose similar to that of 16-mg/kg IV dose Mean concentration-time outcomes for daratumumab 1800 mg SC Cmax similar to 16 mg/kg IV dose Cmax lower during initial weekly administration Ctrough higher than with 1200-mg SC dose Response, % 1200 mg (n = 8) 1,00 mg (n = 45) ORR 25 38 sCR 2 CR VGPR 7 PR 29 MR 13 11 SD 50 PD 12 MR, minimal response; PD, progressive disease; PK, pharmacokinetic; sCR, stringent CR, VGPR, very good PR. Slide credit: clinicaloptions.com Usmani SZ, et al. ASH 2016. Abstract 1149.

PAVO: Conclusions SC administration of daratumumab + rHuPH20 safe and effective Both dose groups showed responses to SC daratumumab 1800-mg group had deeper responses vs 1200-mg group Preliminary efficacy similar to IV daratumumab: 38% ORR, including 1 sCR AEs for SC daratumumab + rHuPH20 similar to IV daratumumab with no new safety signals Low IRR incidence and intensity with SC daratumumab PK of SC daratumumab 1800 mg similar to 16 mg/kg IV administration AE, adverse event; IRR, infusion-related reaction; PK, pharmacokinetic; sCR, stringent CR. Slide credit: clinicaloptions.com Usmani SZ, et al. ASH 2016. Abstract 1149.

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