2019 Sc ie ntific Re tre a t F RI DAY, APRI L 26, 2019 MUL T - PowerPoint PPT Presentation

2019 Sc ie ntific Re tre a t F RI DAY, APRI L 26, 2019 MUL T I PL E MYE L OMA – T RANSF ORMI NG T HE APPROACH T O AN I NCURABL E DI SE ASE Siegfried Janz, MD, DSc William G. Schuett, Jr., Multiple Myeloma Endowed Chair Professor, HemOnc, Department of Medicine Member, Discovery and Developmental Therapeutics Program Member, MCW Cancer Center T o g e the r, T a king o n Ca nc e r’ s T o ug he st Cha lle ng e s

MUL T I PL E MYE L OMA I S A MAJOR CL I NI CAL T o g e the r, PROBL E M AT MCW…AND GL OBAL L Y T a king o n Ca nc e r’ s Definition: Multiple Myeloma (MM) is a blood cancer derived from T o ug he st immunoglobulin-producing plasma cells that reside in the bone marrow Cha lle ng e s and cause CRAB symptoms: hyperCalcemia, Renal failure, Anemia and Bone loss. Public health relevance: MM is the 2 nd most common blood cancer in 2019 the US. Accounts for approximately 1% of all cancers but 2% of all Sc ie ntific cancer deaths. Estimated 30,000 new cases in US in 2017 and 14,000 Re tre a t deaths. MCW: ~300 new patients per year with plasma cell malignancies (in Wisconsin ~600 new cases p.a. and 200 deaths). Circa 130 BMTs for myeloma annually; i.e., 45% of all HSC transplants. Milwaukee area features high proportion of African American patients with myeloma. Addressing disparities in care and innovation is therefore an institutional priority.

MM AND DI SPARI T I E S T HI NK T ANK : NCI WASHI NGT ON, DC, MARCH 5-6, 2018 1 2 • Prevalence of MGUS in African American (AA) patients 2-3 times higher than in Caucasian American (CA) patients • Earlier age of onset (~4 yrs) in AA patients and higher prevalence of IgA MGUS, a high-risk of progression subtype

I MPROVE ACCRUAL OF AA PAT I E NT S I N CL I NI CAL T RI AL S F OR MYE L OMA Meta-analysis of minority accrual in • Underrepresentation of US myeloma trials minorities results in data Ratio of Observed to Expected minority deficit, which poses a threat participation to external validity of trial results. • External validity of a clinical trial (well designed, carried out and analyzed and thus internally valid) indicates whether results are applicable to affected populations at large. • Meta-analysis of 51 clinical trialsincluding 4,853 patients. Ideal O-to-E ratio is 1. Costa LJ, Hari PN and Kumar SK Leuk Lymphoma 12:2827-2832, 2016

E NHANCE UNDE RST ANDI NG OF GE NE T I C BASI S OF RACI AL DI SPARI T Y I N MYE L OMA • We evaluate the 7p15.3 risk allele with support of a supplemental NCI R01 award . • More strongly associated with MM in AA compared to CA patients. • C risk allele leads to elevated CDCA7L expression (eQTL analysis) – a prognosticator of poor OS, particularly for Blacks. • Our project relies on a variety of preclinical experimental model systems : HMCLs, Human-in-mouse xenografts, Mouse-in-mouse allografts, and GEMMs.

DE SI GN AND T E ST I NG OF NOVE L MYE L OMA I MMUNOT HE RAPI E S • Four (4) ongoing cellular therapy trials for myeloma • PI: Dr. P. Hari, HemOnc, DOM, MCW • Based on the experience of the MCW trial of first-in-human dual targeted CD20 and CD19 CAR-T cells for NHL, we are now proceeding with bispecific CD19 and BCMA targeted CAR-T cell therapies for myeloma. • Preclinical support provided by the Bryon Johnson and Siegfried Janz Labs Myeloma cell CD19 BCMA CAR-T cell

DE VE L OPI NG COMPANI ON DI AGNOST I CS F OR NOVE L MYE L OMAT RE AT ME NT S • Developing new methods for predicting proteolysis VCAN cytotoxic immune responses in the post-ASCT bone marrow TME of myeloma CD8 T cell abundance • Proteolytic cleavage of versican (VCAN) is associated with lack of immune response to myeloma • Clinical project initiated by Dr. Binod Dhakal in 100 collaboration with UW Madison 80 High VCAN Percent OS 60 • Next step: Ancillary project led by Dhakal for breakdown BMT CTN 1401 MM Vaccine Study is 40 approved. Low VCAN 20 breakdown 0 • MCW is the highest accruing site. 0 2 4 6 8 10 Dhakal B et al. Years Leuk Lymphoma 8:1-5, 2019

DI SCOVE RI NG NE W MOL E CUL AR T ARGE T S F OR MYE L OMA T RE AT ME NT • Surface antigen discovery program in collaboration with the Jeff Medin Lab and mass spec core directed by Rebekah Gundry • Relies on myeloma cell membrane protein capture and characterization Workflow diagram Waas et al. , J Proteome Res 18(4):1644, 2019 Fujinaka et al. , Methods Mol Biol 1722:57, 2018 Haverland et al. , Proteomics 17(19), 2017

DI SCOVE RI NG NE W MOL E CUL AR T ARGE T S… CONT ’ D:COMPARAT I VE ONCOGE NOMI CS Late stage MM & Early stage MM & Fast mouse tumors Slow mouse tumors Candidate myeloma genes such as: Multiple myeloma hnRNPA1 5R01CA214246 PI: A. Lichtenstein, UCLA FOXM1 2R01CA151354 PI: S. Janz, MCW Plasma cell tumors from GEMMs of Park et al., BMC Genomics 2007; 8:302 human myeloma LeGrand et al., Blood 2012; 119(4):1018-28 Tompkins et al., PLoSOne 2013; 8(10):e76889

• FOXM1 is a bona fide high-risk myeloma gene • Genetic knockdown of FOXM1 inhibits growth of myeloma cells - both in vitro and in vivo • Enforced expression of FOXM1 promotes growth and survival of myeloma cells - both in vitro and in vivo • Repurposing FOXM1-inhibiting, FDA-approved drugs for myeloma therapy and prevention • Combining FOXM1 and proteasome inhibitors for myeloma therapy and prevention Gu et al., Leukemia 30(4):873-882, 2016

OXM1 I S F URT HE R UPRE GUL AT E D I N F RE L APSE D MYE L OMA (rMM) A B Gu et al., Blood Cancer J. 8(2):22, 2018

F OXM1 E XPRE SSI ON I S ASSOCI AT E D WI T H MYE L OMA CE L L PROL I F E RAT I ON, AN ADVE RSE PROGNOST I CAT OR OF OUT COME A B Gu et al., Blood Cancer J. 8(2):22, 2018

OXM1 Hig h T a rg e ting CDK 4/ 6 ma y re -se nsitize F mye lo ma to c he mo the ra py • Enforced expression of FOXM1 leads to diminished drug sensitivity of myeloma in vitro and in vivo • FOXM1 engages the CDK4/6-Rb-E2F pathway, a regulator of myeloma senescence Gu et al., BMC Cancer 18(1):1152, 2018

Clinic a l tria l o f CDK 4/ 6-ta rg e te d the ra pie s fo r OXM1 Hig h mye lo ma a t MCW? pa tie ntswith F

ROBUST ONGOI NG MCWCC T RI AL T o g e the r, PROGRAM F OR MYE L OMA T a king o n Ca nc e r’ s T o ug he st Phase 1 : n = 9 Cha lle ng e s Phase 2 : n = 6 2019 Phase 3 : n = 4 Sc ie ntific Re tre a t Improving clinical care for all, including minority myeloma patients!

I f yo u wa nt to g o fa st, ACK NOWL E DGE ME NT S g o a lo ne . Myeloma Care Binod Dhakal I f yo u wa nt to g o fa r, Anita D’Souza Saurabh Chhabra g o to g e the r. Parameswaran Hari Schuett Foundation – Afric a n Pro ve rb Janz Lab Fumou Sun & Yan Cheng Michael Pisano & Krista Lingle Mullen Collaborators Frank Zhan, Univ of Iowa Guido Tricot, UAMS Hartmut Goldschmidt, Germany Dirk Hose, Germany Brian Van Ness, UoMinnesota Ye Yang, Nanjing, China CANCE R COL L ABORAT I VE Others