Emerging Treatment Options for Relapsed / Refractory Multiple - PowerPoint PPT Presentation

Emerging Treatment Options for Relapsed / Refractory Multiple Myeloma William Bensinger, MD Myeloma & Transplant Program Swedish Cancer Institute Seattle, WA

Outline • Targeting apoptosis • Venetoclax • Targeting BCMA • CAR T cells • Bispecific monoclonal antibodies • Antibody drug conjugates • Individualized Medicine • Conclusions

Bcl-2 Inhibition in Multiple Myeloma • The Bcl-2 specific inhibitor venetoclax has preclinical activity in a subset of human myeloma cell lines (HMCLs) • Predictors of activity: • t(11;14)+ • High Bcl2 / Mcl1 mRNA ratio Touzeau C et al. Leukemia 2014;28:210-212

Venetoclax Monotherapy for Relapsed / Refractory Multiple Myeloma Phase I study • 66 patients • Median age: 63 (31 – 79) • t(11;14)+: 30 patients • 5 with del(17p) • t(11;14)-: 36 patients • Median no. of prior therapies: 5 (1 – 15) • Lenalidomide + bortezomib refractory: 61% • Carfilzomib refractory: 38% • Pomalidomide refractory: 59% • Refractory to the last prior therapy: 79% • * Patients treated with 50 – 400 mg of venetoclax daily with doses titrated up to 300 – 1200 mg by week 3. * 2 responses: 1 in a pt with an IgH translocation with unknown partner, 1 in a pt with unknown CGs Shaji Kumar et al. Blood 2017;130:2401-2409

Venetoclax Monotherapy for Relapsed / Refractory Multiple Myeloma • Median TTP: 2.6 months (95% CI 1.9 – 4.7) Median TTP 11.5 • Median DOR: 9.7 months months Median TTP 6.6 months (95% CI 7.0 – NR) Median TTP 1.9 months Median TTP 1.9 months Shaji Kumar et al. Blood 2017;130:2401-2409

Combined Bcl-2 / Proteasome Inhibition in Multiple Myeloma Bortezomib treatment of human myeloma cell lines leads to upregulation of proapoptotic Noxa and down-regulation of apoptotic Mcl-1 Punnoose E et al. Mol Cancer Ther 2016;15:1132-1144

Venetoclax, Bortezomib and Dexamethasone for Relapsed / Refractory Multiple Myeloma Phase I study • 66 patients • Median age: 64 (38 – 79) • t(11;14)+: 9 patients • Del(17p): 15 patients • Median no. of prior therapies: 3 (1 – 13) • Bortezomib refractory: 39% • Lenalidomide refractory: 53% • Refractory to the last prior therapy: 61% • Patients treated with 100 – 1200 mg of venetoclax daily. Philippe Moreau et al. Blood 2017;130:2392-2400

Venetoclax, Bortezomib and Dexamethasone for Relapsed / Refractory Multiple Myeloma BCL2 level predictive of response and TTP Median TTP 11.6 months Median TTP 5.7 months Philippe Moreau et al. Blood 2017;130:2392-2400

Venetoclax, Bortezomib and Dexamethasone for Relapsed / Refractory Multiple Myeloma • Median TTP: 9.5 months (95% CI 5.7 – 10.4) Bortezomib non-refractory • Median DOR: 9.7 months (95% CI 7.4 – 15.8) • Median TTP best in less 1 – 3 heavily pretreated patients and those with 4 - 6 >6 Bortezomib refractory bortezomib sensitive disease Philippe Moreau et al. Blood 2017;130:2392-2400

Venetoclax, Carfilzomib and Dexamethasone in Relapsed / Refractory Multiple Myeloma Phase II Study, 1 – 3 prior lines therapy, carfilzomib naive 42 pts enrolled • sC R C R V G P R PR 30 evaluable (≥3 cycles or PD) • O R R = 1 0 0 % 28-day cycle • 1 0 0 O R R = 8 8 % 1 4 % P e rc e n ta g e o f P a tie n ts Vtx 400 or 800 mg daily O R R = 8 3 % O R R = 8 2 % • O R R = 7 8 % CFZ 27 or 56 mg/m 2 IV on days 1, 8 0 7% • 9 % 4 % 2 5 % 2 9 % 2, 8, 9, 15 and 16 or 70 mg/m 2 on 1 7 % 1 3 % 1 4 % 8 6 % 4 8 % 6 3 % 5 5 % 5 7 % 6 0 days 1, 8 and 15 3 0 % 3 2 % 3 8 % 3 3 % Median age: 67 (37 – 79) 4 0 • 4 3 % Median prior line of therapy: 2 (1 – 3) • 2 0 PI Refractory: 50% 2 7 % 3 0 % • 2 7 % 2 5 % 1 4 % IMID refractory: 62% • 0 All P a tie n ts t(1 1 ;1 4 )+ n o n -t(1 1 ;1 4 ) H ig h S ta n d a rd Double refractory: 33% • N = 3 0 N = 7 N = 2 3 C y to g e n e tic R is k C y to g e n e tic R is k N = 8 N = 2 2 Costa L et al. ASCO 2018

BCMA in Multiple Myeloma • B cell maturation antigen • Expressed on late memory B cells committed to PC differentiation and PCs • BCMA is critical for survival of long-lived PCs Cho SF et al. Front Immunol 2018;10:1821

BCMA CAR T Cell Therapy in Relapsed / Refractory Multiple Myeloma: bb2121 Flu 30 m/m 2 Cy 300 mg/m 2 Dose Escalation (N=21) Dose Expansion (N=22) ≥50% BCMA expression <50% BCMA expression (n=10) 150 × 450 × 800 × ≥50% BCMA expression (n=12) 50 × 10 6 10 6 10 6 10 6 Dose range: 150–450 × 10 6 CAR+ cells Raje N et al. ASCO 2018

BCMA CAR T Cell Therapy in Relapsed / Refractory Multiple Myeloma: bb2121 Escalation Expansion (N=21) (N=22) Median (min, max) prior regimens 7 (3, 14) 8 (3, 23) Exposed Refractory Exposed Refractory Prior therapies, n (%) Bortezomib 21 (100) 14 (67) 22 (100) 16 (73) Carfilzomib 19 (91) 12 (57) 21 (96) 14 (64) Lenalidomide 21 (100) 19 (91) 22 (100) 18 (82) Pomalidomide 19 (91) 15 (71) 22 (100) 21 (96) Daratumumab 15 (71) 10 (48) 22 (100) 19 (86) Exposed/Refractory, n (%) Bort/Len 21 (100) 14 (67) 22 (100) 14 (64) Bort/Len/Car/Pom/Dara 15 (71) 6 (29) 21 (96) 7 (32) Raje N et al. ASCO 2018

BCMA CAR T Cell Therapy in Relapsed / Refractory Multiple Myeloma: bb2121 Tumor Response By Dose a Tumor Response By BCMA Expression a ORR=95.5% ORR=100% mDOR =10.8 mo 100 100 ORR=91% sCR/CR sCR/CR 90 90 VGPR VGPR Objective Response Rate, % Objective Response Rate, % 80 37.5 80 PR PR ORR=57.1% 70 50.0 70 mDOR =NE 54.5 60 60 50 50 ORR=33.3% 40 mDOR =1.9 mo 40 50.0 42.9 30 30 36.4 27.3 20 20 33.3 7.1 10 10 12.5 9.1 9.1 7.1 0 0 450 × 10 6 50 × 10 6 150 × 10 6 >150 × 10 6 450 × 10 6 50 x 106 150 x 106 >150 x 106 450 x 106 low 450 x 106 high Low High BCMA (n=3) (n=14) (n=22) BCMA (n=11) (n=8) Median follow-up 84 87 194 Median follow-up 311 168 (min, max), d (59, 94) (36, (46, (min, max), d (46, 556) (121, 184) 638) 556) Raje N et al. ASCO 2018

BCMA CAR T Cell Therapy in Relapsed / Refractory Multiple Myeloma: bb2121 PFS at Inactive (50 × 10 6 ) and Active (150–800 × 10 6 ) Dose PFS in MRD-Negative Patients Levels a 50 × 10 6 150–800 × 150–800 × 10 6 10 6 (n=18) (n=3) (n=16) Events 3 10 mPFS (95% CI), 17.7 mPFS (95% CI), 2.7 11.8 mo (5.8–NE) mo (1.0–2.9) (8.8–NE) mPFS = 11.8 mo mPFS = 17.7 mo mPFS = 2.7 mo Raje N et al. ASCO 2018

BCMA CAR T Cell Therapy in Relapsed / Refractory Multiple Myeloma: bb2121 Cytokine Release Syndrome By Dose Level Cytokine Release Syndrome Parameters Dosed Patients 100 Parameter (N=43) Maximum Toxicity Grade a 82% 90 Patients with a CRS event, n (%) 27 (63) 80 3 2 1 9.1 70 Maximum CRS grade a Patients, % 22.7 60 None 16 (37) 50 1 16 (37) 39% 40 2 9 (21) 30 3 2 (5) 22.2 50.0 20 4 0 10 16.7 Median (min, max) time to onset, d 2 (1, 25) 0 150 × 10 6 >150 × 10 6 Median (min, max) duration, d 6 (1, 32) 150 x 106 >150 x 106 (n=18) (n=22) Tocilizumab use, n (%) 9 (21) Dose Level b Corticosteroid use, n (%) 4 (9) Raje N et al. ASCO 2018

Bispecific T-Cell Engagers (BiTEs): Patrick A. Baeuerle, and Carsten Reinhardt Cancer Res 2009;69:4941-4944

BCMA-Targeted BiTEs: AMG 420 • First-in-human, phase I dose escalation study • 35 patients • 6-week cycle • 4-week continuous infusion followed by a 2-week break • Up to 10 cycles of therapy • Doses from 0.2 – 800 mcg / day • CRS seen in 3 patients (2 grade 1, 1 grade 3) • 6 CRs ( 1 each at 6.5, 100, and 200 mcg / day, 3 at 400 mcg / day) • 3/3 CRs at 400 mcg / day are MRD negative • 1 PR (50 mcg / day), 1 VGPR (800 mcg / day) • Confirmation cohort (400 mcg / day): 2 of 3 with PRs Topp M et al. ASH 2018

GSK285916: a BCMA-Targeted Antibody Drug Conjugate ADC • GSK2857916 is a humanized, ADCC afucosylated IgG1 anti-BCMA Fc BCMA – Target specific Receptor Fc region of antibody conjugated to a Lysosome BCMA the Antibody – Enhanced ADCC Effector microtubule disrupting agent Cell BCMA MMAF via a stable, protease BCMA GSK2857916 resistant maleimidocaproyl Linker – Stable in circulation x linker Malignant Plasma – MMAF (non cell – Preclinical studies Cell Drug permeable, highly demonstrate its potent auristatin) selective and potent activity 1 Cell death Mechanisms of Action: 1. ADC mechanism 2. ADCC mechanism ADC, antibody-drug conjugate; ADCC, antibody-dependent cell-mediated cytotoxicity; BCMA, B -cell maturation antigen; Fc, Fragment crystallizable; IgG, 3. Immunogenic cell immunoglobulin G; MMAF, monomethyl auristatin-F death 1 Tai YT, et al. Blood 2014;123(20):3128-38.

DREAMM-1: Efficacy Response Progression-Free Survival ORR = 60% (21/35; 95% CI: 42.1%, 76.1%) • 1 sCR, 2 CR, 15 VGPR, 3 PR Median PFS 7.9 months * Trudel S et al. ASH 2017