Multiple Myeloma and Engineered Cell Therapy

Sarah M. Larson, MD Assistant Professor of Medicine September 2018 Spectrum of Disease

Morgan GJ Nat Rev 2012 SMM: Janssen SMM3001

• Patients randomized to dara sc vs active monitoring •Study duration 8 years

• Primary endpoint PFS

• Prior SMM treatment is an exclusion

• NCT03301220

Van de Donk NWCJ Immunol Rev 2016 Multiple Myeloma

• Second most common heme malignancy • 33,000 new cases 2017 • >100,000 people with multiple myeloma • Increasing number of patients • Incidence • Improved survival

SEER database Treatment

Treatment of Initial Consolidation/ ASCT relapsed Therapy Maintenance disease

Supportive Care Minimal Residual Disease (MRD) Undetectable MRD: The Goal of Frontline Therapy?

PFS

OS

Landgren O BMT 2016 IFM2009 • Newly diagnosed patients eligible for transplant • Patients <65 years of age PFS 50 mos (p<0.001) CR 59% Transplant MRD neg 79% (p<0.001) R 2 cycles A Len Main RVD N 3 D Cycles O RVD M PFS 36 mos I CR 48% Z MRD neg 65% E 5 Cycles D RVD Len Main

Attal M NEJM 2017 Response at Each Treatment Phase

Treatment Arm Induction Consolidation Maintenance (%) (%) (%) RVD 45 69 76 Transplant 47 78 85

Attal M NEJM 2017 Conclusions

• Transplant remains a standard therapy • Delayed transplant is reasonable • Collection and storage of stem cell frequently not covered • Following second line of treatment • Trials to improve the transplant course Stem Cell Mobilization Trial

• BL-8040 Phase III, randomized, double-blinded, placebo controlled trial of BL-8040 and G-CSF vs G- CSF and placebo • Key inclusion • Up to age 78 • Key exclusion • > 6 cycles lenalidomide • > 2 cycles alkylating agent combinations Relapsed/Refractory Disease

12 Treatment Options

• 1-3 Prior lines • ≥2 Prior lines •Panobinostat with •Carfilzomib, len, dex len/dex •Carfilzomib, pom, dex •Ixazomib with len/dex •Pomalidomide, dex • with len/dex • >3 Prior lines •Carfilzomib, dex • •Daratumumab, •Chemotherapy based , dex combos •Daratumumab, len, dex Venetoclax

• Phase Ib trial with bortezomib and dex • 3 median prior therapies • ORR 68% with 8.8 months duration • Specific to t(11;14)

Moreau P ASH 2016 Venetoclax/Dex vs Pom/dex

• Phase III, randomized study for relapsed or refractory patients with t(11;14) • 1:1 randomization • Key inclusion • ≥2 prior lines of therapy • Lenalidomide refractory • PI exposure • Key exclusion • Previous pomalidomide Actinium

• Phase I Trial of Lintuzumab-Ac225 in relapsed or refractory multiple myeloma • Alpha particle emitting anti-CD33 immunoconjugate • Key inclusion • > 3 prior lines of therapy • Not candidates for an FDA approved therapy • Key exclusion • Maximum targeted radiation dose Engineered Cell Therapy CAR-T Structure

• Slide 65

J FAP Miller and M Sadelain. Cell Press 2015 CAR-T Structure

Maude et al Blood 2015 Generations of CAR

J FAP Miller and M Sadelain. Cell Press 2015 Dotti G et al. Human Gene Therapy 2009 Myeloma Targets

Giraldo WAS. Rheumatol Clin. 2012;8(4):201-207. Myeloma Targets

Lonial S Leukemia 2016 Kite 585-501 Protocol Anti-BCMA CAR-T Cells: bb2121

• Heavily pretreated patients • Overall response rate 94% • 10/18 patients were in a CR •90% MRD negative • Progression free survival 71% at 9 months • Side effects better tolerated than in ALL or DLBCL Myeloma CAR-T Trials at UCLA

• KITE-585-501 Anti-BCMA CAR-T NCT03318861 • ≥3 prior lines of therapy • Previous imid, PI and anti-CD38 • Celgene bb2121-MM-003 •bb2121 vs triplet therapy •≥2 prior lines of therapy • JUNO JCARH125 Anti-BCMA CAR-T NCT03430011 •>3 prior lines of therapy KITE-585-501

• Phase I trial of anti-BCMA CAR-T cell therapy in patients with relapse/refractory multiple myeloma • Primary outcome is safety • Secondary outcomes: response rate, duration of response, PFS • Key inclusion • ≥3 prior lines of therapy including a proteosome inhibitor and imid • Adequate bone marrow function • Key exclusion • History of DVT or PE within 6 mos of enrollment, CNS disease, plasma cell leukemia, non-secretory Dose Escalation and Expansion Cohorts

3+3 Dose Escalation Expansion Cohorts

1 x 107 CAR T cells

Conditioning 7 3 x 10 CAR T cells Up to 20 subjects with Chemotherapy CrClb 60 mL/min a Cy/Flu (300/30) 1 x 108 CAR T cells MTDc or lower

3 x 108 CAR T cells Up to 20 subjects with CrClb 30-59 mL/min 1 x 109 CAR T cells MTDc or lower aCy/Flu: Cyclophosphamide 300 mg/m 2; Fludarabine 30 mg/m 2 days -5, -4, -3. bCrCl: Creatinine Clearance estimated by Cockgroft-Gault. cMTD: Maximum tolerated dose. Can we improve our current outcomes?

• “Off the Shelf” • Allogeneic CAR-T cells (UCART) • Overcome resistance • Bispecific CAR • Transduction of hematopoietic stem cells • Renewable source of cells • Multi-lineage (CAR) • T cell receptors (TCRs) and CARs • Extensive work at UCLA • Sickle cell disease, Severe Combined Immunodeficiency Allogeneic CAR-T

Donor CAR-T Cell Universal CAR-T

Ruella M Biodrugs 2017 Overcoming Resistance: Bispecific CAR

• Mechanism of resistance is antigen escape • At least 30% relapses are CD19 negative • Additional targets to decrease resistance • CD19 and CD20

Zah E, et al. Cancer Immunol Res 2016 Anti-CD19 and CD20 Bispecific CAR-T

Protocol for relapsed/refractory NHL is in development

Zah E, et al. Cancer Immunol Res 2016 Transduction of HSCs: TCRs and CARs

June CH Science 2018 NY-ESO TCR

• NY-ESO is an intracellular protein • , sarcoma, myeloma • Relapsed or relapsed/refractory multiple myeloma • Modification of HSCs and T cells • Key inclusion • ≥3 prior lines of therapy • Imid, PI, and anti-CD38 • HLA A02:01 • NY-ESO NY-ESO TCR for Multiple Myeloma UCLA Multiple Myeloma Clinical Trials

Transplant ≥2 lines of therapy >3 lines of therapy

BioLineRx-8040 Abbvie M13-494 Actinium AC225-MM01 Mobilization Trial for Venetoclax/dex vs Anti-CD33 alpha Autologous Stem pomalidomide /dex particle Cell Transplant KCP-330 Selinexor in combination with Smoldering MM Celgene bb2121-MM-003 backbone therapies bb2121 vs triplet therapy

Janssen SMM3001: KITE-585-501 Anti- Dara sc vs BCMA CAR T-cell observation NY-ESO TCR Modification of stem cells and T cells with the TCR TRIO US

Juno JCARH125 Anti- In start up BCMA CAR T-cell