Multiple Myeloma and Engineered Cell Therapy

Multiple Myeloma and Engineered Cell Therapy

Multiple Myeloma and Engineered Cell Therapy Sarah M. Larson, MD Assistant Professor of Medicine September 2018 Spectrum of Disease Morgan GJ Nat Cancer 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 •Elotuzumab with len/dex • >3 Prior lines •Carfilzomib, dex •Daratumumab •Daratumumab, •Chemotherapy based bortezomib, 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 • Melanoma, 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 .

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