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1358 Preclinical and Translational Support for Clinical Development of Iberdomide in Combination with Proteasome Inhibitors: Mechanism of Synergy in Clinical Trial CC-220-MM-001

Program: Oral and Poster Abstracts
Session: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy: Poster I
Hematology Disease Topics & Pathways:
multiple myeloma, Biological, Diseases, immune cells, Plasma Cell Disorders, Cell Lineage, Lymphoid Malignancies
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Michael Amatangelo1*, Chad Bjorklund1*, Jian Kang1*, Archana Mukhopadhyay1*, María Dolores Jiménez Nuñez2*, Lilly Wong1*, William Pierceall1*, Sagar Lonial, MD3, Niels W.C.J. Van De Donk4, Rakesh Popat5*, Sundar Jagannath, MD6*, Jeffrey Zonder7, Monique C. Minnema8, Albert Oriol9*, Jeremy Larsen10, Ashraf Z. Badros, MD11, Paula Rodriguez-Otero, MD, PhD12*, Pieter Sonneveld, MD, PhD13, Tuong Vi Nguyen1*, Kevin Hong1*, April Sorrell1* and Anjan Thakurta1*

1Bristol Myers Squibb, Princeton, NJ
2Celgene Research S.L.U., a Bristol-Myers Squibb Company, Seville, Spain
3Winship Cancer Institute of Emory University, Atlanta, GA
4Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, Netherlands
5NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, United Kingdom
6The Mount Sinai Hospital, New York, NY
7Karmanos Cancer Institute, Detroit, MI
8Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
9Institut de Recerca contra la Leucèmia Josep Carreras and Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain
10Mayo Clinic, Scottsdale, AZ
11The University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD
12Clínica Universidad de Navarra, CIMA, IDISNA, CIBERONC, Pamplona, Spain
13Erasmus Medical Center, Rotterdam, Netherlands

Introduction: Iberdomide (IBER; CC-220) is a potent, novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent under investigation in a phase 1/2 dose-escalation study for relapsed/refractory multiple myeloma (MM) (CC-220-MM-001; NCT02773030). IBER modulates CRBN to induce ubiquitination and proteasome-dependent degradation of Ikaros/Aiolos, resulting in antimyeloma and immunomodulatory activity. Compared with immunomodulatory drugs (IMiDs); IBER binds to CRBN with 20-fold higher affinity and is more efficient at degrading Ikaros/Aiolos. Additionally, IBER can overcome IMiD drug resistance. Here, we compare the preclinical activity of IBER versus IMiD drugs + proteasome inhibitors (PIs), and assess the pharmacodynamic (PD) activity of IBER in patients treated with IBER + dexamethasone (DEX), IBER + DEX + bortezomib (BORT), and IBER + DEX + carfilzomib (CFZ).

Methods: MM cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were analyzed. Cell lines treated with PIs (BORT and CFZ) were pulsed with drug for 1 h, and then treated with clinically relevant concentrations of lenalidomide (LEN; 1 μM), pomalidomide (POM; 300 nM), or IBER (20 nM). Biomarker data for PD analyses were obtained from blood samples of patients enrolled in the IBER + DEX, IBER + DEX + BORT, and IBER + DEX + CFZ cohorts of the CC-220-MM-001 study. Degradation of Ikaros/Aiolos in peripheral blood was analyzed on Cycle (C) 1 Day (D) 1, pre-dose, and post IBER/IBER + PI dose by flow cytometry. Immune profiling was evaluated by flow cytometry from peripheral blood at C1D1, C2D15, C4D1, and C4D15.

Results: Proteasome inhibition in cell lines after 1 h pulse of PI was maintained after washout. However, substrate degradation by IBER was affected only minimally by combination with PIs, and was more potent than by LEN or POM. These results correlate with synergistic antiproliferative activity and more potent tumoricidal activity in cell lines treated with IBER + PI than IMiD + PI combinations. Furthermore, ex vivo treatment of PBMCs with IBER + PIs minimally affected cytokine induction by IBER. Analysis of patient samples from the CC-220-MM-001 study confirmed preclinical observations showing minimal inhibition of IBER PD with the addition of PIs to the treatment regimen. In patient T cells, Ikaros and Aiolos protein levels decreased by > 50% and > 70%, respectively, with IBER + DEX, and by > 30% and > 45% (at lower IBER doses) with IBER + DEX + BORT or IBER + DEX + CFX. In all cohorts, the nadir of substrate expression was determined to be 6 h. After repeated dosing (mid-C1) patients treated with IBER + PIs showed > 70% decreases in both Ikaros and Aiolos expression. Furthermore, immune profiling of patients showed that the addition of PIs to the IBER treatment regimen did not inhibit immune-stimulatory activity of IBER, including induction of NK and T cell proliferation.

Conclusions: Preclinically, IBER induced substrate degradation in the presence of PIs, and treatment with IBER + PIs resulted in substantially increased tumoricidal activity. Deeper substrate degradation and increased apoptosis were also observed when PIs were combined with IBER versus IMiD drugs. Clinically, IBER led to rapid decreases in substrate levels, even in the presence of PIs, and levels were reduced further with repeated dosing, suggesting that concurrent administration of PIs minimally affects proteasomal degradation of substrates mediated by IBER. Furthermore, increases in NK and T cell proliferation in IBER-treated patients were consistent whether or not they also received a PI, further confirming that IBER has immune-stimulatory activity in combination with PIs. These data support continued clinical development of IBER in combination with PIs for the treatment of MM.

Disclosures: Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bjorklund: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kang: Bristol Myers Squibb: Current Employment. Mukhopadhyay: Bristol Myers Squibb: Other: Contract scientist, Research & Early Development. Jiménez Nuñez: CITRE, a Bristol-Myers Squibb Company: Current Employment. Wong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pierceall: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lonial: Merck: Consultancy, Honoraria, Other: Personal fees; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Millennium: Consultancy, Honoraria; JUNO Therapeutics: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria. Van De Donk: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Popat: GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Jagannath: BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Zonder: Caelum: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Oncopeptide: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Research Funding; Janssen: Consultancy, Other: Personal fees; Prothena: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; BMS: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Minnema: Celgene: Other: travel support, Research Funding; Servier: Consultancy; Amgen: Consultancy; Kite, a Gilead Company: Speakers Bureau. Oriol: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Larsen: Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Badros: Amgen: Consultancy; University of Maryland: Current Employment. Rodriguez-Otero: Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Amgen: Consultancy, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Oncopeptides: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Sonneveld: Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Nguyen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hong: Bristol Myers Squibb: Current Employment. Sorrell: Children's Oncology Group: Other: Non-member; Previous Study Chair AAML08B1; Bristol Myers Squibb: Current Employment. Thakurta: Oxford University: Other: visiting professor; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

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