Phase II Study: Pembrolizumab Plus Pomalidomide and Dexamethasone Active in R/R 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. R/R, relapsed/refractory. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

Pembrolizumab, Pomalidomide, Dexamethasone for R/R MM: Background PD-1/PD-L1 pathway blockade being exploited in several cancers to restore cytotoxic T-cell activity and anticancer immunity[1] Pembrolizumab: humanized anti–PD-1 monoclonal antibody Pomalidomide: immunomodulatory thalidomide analogue indicated in combination with dexamethasone for pts with MM and ≥ 2 previous treatments including lenalidomide and a PI with progression ≤ 60 days of last regimen Current study evaluates the safety and efficacy of pembrolizumab combined with pomalidomide and dexamethasone in pts with relapsed/refractory MM[2] MM, multiple myeloma; PI, proteasome inhibitor; R/R, relapsed/refractory. Slide credit: clinicaloptions.com 1. Boussiotis VA. N Engl J Med. 2016;375:1767-1778. 2. Badros AZ, et al. ASH 2016. Abstract 490.

Pembrolizumab, Pomalidomide, Dexamethasone for R/R MM: Study Design Exploratory trial Primary endpoint: safety Secondary endpoints: ORR, PFS, OS Exploratory endpoints: correlation of BL levels of PD-1 and PD-L1 in BM with response Mo 24 Pts with R/R MM and 2 lines of previous tx including IMid and PI; ECOG PS < 2 and adequate organ function; no active autoimmune disease requiring treatment or history of severe autoimmune disease (N = 48) Pembrolizumab* 200 mg IV Days 1, 14 + Pomalidomide 4 mg PO Days 1-21 + Dexamethasone 40 mg† PO Days 1, 7, 14, 21 Q28D Pembrolizumab 200 mg IV/mo + Pomalidomide 4 mg PO + Dexamethasone 40 mg† PO Responders *First 6 pts received pembrolizumab on Day 1 only. †Pts > 70 yrs of age received 20 mg. BL, baseline; BM, bone marrow; ECOG, Eastern Cooperative Oncology Group; IMiD, immunomodulatory drug; MM, multiple myeloma; PI, proteasome inhibitor; PS, performance status; R/R, relapsed/refractory; tx, treatment. Slide credit: clinicaloptions.com Badros AZ, et al. ASH 2016. Abstract 490.

Pembrolizumab, Pomalidomide, Dexamethasone for R/R MM: Baseline Characteristics Pts (N = 48) Median age, yrs (range) < 65 yrs, % 65-74 yrs, % ≥ 75 yrs, % 64 (35-83) 54 37 13 Male sex, % 66 Race, % White Black Other 38 8 ECOG PS 0-1, % 92 Isotype, % IgG isotype IgA isotype IgD isotype Light chain in urine Light chain in serum only 60 15 2 Characteristic Pts (N = 48) Median LDH IU/L (range) > ULN, % 509 (139-4800) 8 Median creatinine, mg/dL (range) 1 (0.5-1.8) Median BM plasmacytosis, % (range) 20 (15-100) Standard-risk cytogenetics, % Normal Hyperdiploid t(11;14) 38 21 13 4 High-risk cytogenetics, % del(17p) t(14;16) t(14;20) t(4;14) 1q+ 62 10 27 BM, bone marrow; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; MM, multiple myeloma; PI, proteasome inhibitor; PS, performance status; R/R, relapsed/refractory; ULN, upper limit of normal. Slide credit: clinicaloptions.com Badros AZ, et al. ASH 2016. Abstract 490.

Pembrolizumab, Pomalidomide, Dexamethasone for R/R MM: Prior Therapy Characteristic Pts (N = 48) Median time from diagnosis to study, yrs (range) 4 (1.2-26) Median lines of earlier therapy (range) 2 lines, % 3 lines, % > 3 lines, % 3 (2-5) 35 38 27 Previous therapy, % ASCT Bortezomib Carfilzomib Lenalidomide Thalidomide 72 100 50 98 2 Refractory, % Proteasome inhibitors IMiDs + proteasome inhibitors 79 90 73 ASCT, autologous stem cell transplantation; IMiD, immunomodulatory drug; MM, multiple myeloma; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Badros AZ, et al. ASH 2016. Abstract 490.

Pembrolizumab, Pomalidomide, Dexamethasone for R/R MM: Adverse Events All Grades Grade > 3 In > 30% of pts Fatigue Neutropenia Hyperglycemia Thrombocytopenia Anemia Dizziness Constipation URT infection Dyspnea Edema In > 20% to 30% of pts Lymphopenia Muscle spams Rash Diarrhea Infection Pneumonia Nausea In ≥ 10% to 20% of pts Hypotension Peripheral neuropathy Arrhythmia irAEs in any pt Pneumonitis (12%)* Hypothyroidism (10%) Adrenal Hepatitis Vitiligo Hypothyroidism Pneumonitis irAE, immune-related adverse event; MM, multiple myeloma; R/R, relapsed/refractory; URT, upper respiratory tract. *With ground glass opacification in 6 pts who presented with cough, shortness of breath, low-grade fever. Slide credit: clinicaloptions.com Badros AZ, et al. ASH 2016. Abstract 490.

Pembrolizumab, Pomalidomide, Dexamethasone for R/R MM: Safety Outcome Pts (N = 48) Median no. of cycles (range) Median follow-up, mos 8 (3-23) 9.6 Dose reduction, n (%) Pembrolizumab, n* Pomalidomide, n† Dexamethasone, n‡ 22 (49) 2 13 7 Discontinuation due to regimen toxicity, n (%) Pneumonitis, n Shortness of breath, n Fatigue, n 5 (11) 3 1 Deaths, n 9 Disease progression, n 23 MM, multiple myeloma; R/R, relapsed/refractory. *Pneumonitis, n = 2 †Fatigue, n = 5; neutropenia, n = 3; rash, n = 2; palpitation, n = 1; muscle spasm, n = 1; peripheral neuropathy, n = 1. ‡Uncontrolled hyperglycemia, n = 3; weight gain, n = 2; cellulitis, n = 1; lack of sleep, n = 1. Slide credit: clinicaloptions.com Badros AZ, et al. ASH 2016. Abstract 490.

Pembrolizumab, Pomalidomide, Dexamethasone for R/R MM: Efficacy Response, % Full Efficacy Population (N = 45) Refractory to 2 Classes (n = 32) High-Risk Cytogenetics (n = 27) ORR 65 68 56 Clinical benefit 72 69 60 Best response sCR CR VGPR PR MR SD PD 7 2 20 36 23 5 3 18 44 22 4 41 31 sCR + CR+ VGPR, % 29 24 15 MM, multiple myeloma; MR, minimal response; PD, progressive disease; R/R, relapsed/refractory, sCR, stringent; SD, stable disease; VGPR, very good PR. Slide credit: clinicaloptions.com Badros AZ, et al. ASH 2016. Abstract 490.

Full Efficacy Population Pembrolizumab, Pomalidomide, Dexamethasone for R/R MM: Duration of Response and Survival Outcome, Mos (95% CI) Full Efficacy Population (N = 45) Median duration of response 16.3 (9.9-19.1) Median PFS 17.4 (11.7-18.8) Median OS Not reached (18.8-not reached) PFS significantly longer in low-risk vs high-risk subgroups (P = .0366) MM, multiple myeloma; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Badros AZ, et al. ASH 2016. Abstract 490.

PD-L1 Marker Expression T-Cell Infiltrate Marker Expression Pembrolizumab, Pomalidomide, Dexamethasone for R/R MM: Biomarker Expression and Efficacy PD-L1 Marker Expression Response Negative (n = 10) Weakly Positive (n = 6) Positive (n = 27) ORR, % sCR CR VGPR PR MR + SD + PD 60 20 40 50 77 8 38 23 sCR + CR+ VGPR, % 54* Median PFS, mos (95% CI) 17.4 (10.6-18.4) 17.5 (6.4-17.5) NR (3.7-NR)† T-Cell Infiltrate Marker Expression Response, % CD3+/ PD1+ (n = 6) PD1- (n = 10) CD3-/ (n = 22) Best response sCR CR VGPR PR MR + SD + PD 33 67 70 10 40 20 30 73 14 9 50 23 sCR + CR+ VGPR, % 23%‡ Median PFS, mos (95% CI) 6.3 (2.6-NR) 16.5 (10.6-17.9) 17.5¶ (11.7-NR) MM, multiple myeloma; MR, minimal response; NR, not reached; PD, progressive disease; R/R, relapsed/refractory; sCR, stringent CR; SD, stable disease; VGPR, very good PR. *P = .05 vs PD-L1 negative. †P = .5 vs PD-L1 negative. ‡P = .12 vs CD3+/PD-1+. ¶P = .05 vs CD3+/PD-1+. Slide credit: clinicaloptions.com Badros AZ, et al. ASH 2016. Abstract 490.

Pembrolizumab, Pomalidomide, Dexamethasone for R/R MM: Investigator Conclusions In this small study of pts with R/R MM, the combination of pembrolizumab/pomalidomide/dexamethasone appears active AEs occurred in ~ 50% of the study population Discontinuation in 10%; most AEs manageable These results suggest that future studies are warranted to further understand the role of PD-1/PD-L1 inhibitors in pts with MM AE, adverse events; MM, multiple myeloma; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Badros AZ, et al. ASH 2016. Abstract 490.

Go Online for More CCO Coverage of ASH 2016! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Leukemias Lymphomas/CLL Myeloma/plasma cell disorders MDS and myeloproliferative neoplasms clinicaloptions.com/oncology