Dose- and Schedule-Dependent Immunomodulatory Effects of the Novel Celmod Agent CC-92480 in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Wong Lilly , Lamba Manisha , Jiménez Nuñez María Dolores , Bauer Daniel , Richardson Paul G. , Bahlis Nizar J. , Vangsted Annette J. , Ramasamy Karthik , Trudel Suzanne , Martínez-Lopez Joaquín , Mateos María-Victoria , Rodriguez-Otero Paula , Lonial Sagar , Popat Rakesh , Oriol Albert , Karanes Chatchada , Orlowski Robert Z. , Berdeja Jesus G. , Pourdehnad Michael , Pierce Daniel W. 
Published: November 2020

Introduction: CC-92480 is an oral novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent currently in phase 1/2 development in patients with relapsed/refractory multiple myeloma (RRMM). CC-92480 induces rapid degradation of the transcription factors Ikaros and Aiolos, leading to apoptosis of myeloma cells and immune-stimulatory effects. The innovative CC-92480-MM-001 phase 1 study design investigated the effects of a broad range of CC-92480 doses and schedules. The pharmacodynamic effects will be discussed in this analysis with a focus on modulation of immune cell subsets.
Methods: An adaptive Bayesian dose-escalation design was used in the CC-92480-MM-001 study (NCT03374085) that allowed for evaluation of several dosing schedules. The continuous schedules included 10 days on followed by 4 days off × 2, and 21 days on followed by 7 days off in a 28-day cycle. The intensive schedules included 3 days on followed by 11 days off × 2, and 7 days on followed by 7 days off × 2. An intensive biomarker sampling program was included in the study to allow for characterization of pharmacodynamic changes. Peripheral blood and bone marrow aspirates (BMA) were obtained from patients enrolled in part 1 of the dose-escalation study for biomarker analysis. Samples were taken pre-dose and during treatment at multiple time points. Biomarker analyses included Ikaros and Aiolos levels in peripheral blood mononuclear cells by flow cytometry; CRBN, Aiolos, Ikaros, and ZFP91 expression by immunohistochemistry (IHC) in BMA; weekly levels of serum free light chain (sFLC) and soluble B-cell maturation antigen (sBCMA), and effects on immune cells in peripheral blood. CC-92480 plasma exposures were collected at several time points in Cycle 1.
Results: CC-92480 1.0 mg, 21/28-days was selected as the recommended phase 2 dose (RP2D) based on tolerability, efficacy, and pharmacodynamic effects. Degradation of Ikaros and Aiolos was evident at all dose levels in bone marrow plasma cells independent of baseline CRBN staining intensity and prior treatment. In these heavily pretreated patients with RRMM, CC-92480 induced rapid and sustained decreases in sFLC (median 94%) and sBCMA (median 78%) in Cycle 1 at the RP2D. Ikaros and Aiolos degradation in peripheral blood T cells was dose-dependent and reached &gt; 80% degradation at 0.6 mg and above. Substrate recovery occurred during drug holidays, with faster recovery at lower doses, and reached full recovery with ≥ 7-day breaks. Focusing on the immunomodulatory effects, dynamic and dose- and schedule-dependent changes were demonstrated in immune cell subtypes. B cells decreased with increasing dose and reached &gt; 90% at 0.8 mg and above in the continuous schedules. Recovery was evident during drug holidays, especially at lower doses. T-cell proliferation by Ki-67 staining increased between 30% and 350% during treatment and returned toward baseline during drug holidays at lower doses and with longer breaks. NK-cell proliferation by Ki-67 staining was evident at all doses and peaked at approximately 1 week post dose regardless of schedule. T cells demonstrated a shift from naïve to effector phenotype at all doses and schedules, and showed an increase in activation markers, HLA-DR, CD38, and ICOS. Regulatory T cells increased by 90% and 130% at 0.8 mg and 1.0 mg, respectively. At the 1.0 mg dose (RP2D) and more continuous schedules (10/14 days × 2 and 21/28 days), higher percentages of proliferating CD3+CD4+ and CD3+CD8+ T cells associated with a clinical response.
Conclusions: The novel study design and biomarker sampling have allowed us to understand how depth, duration, and recovery of Ikaros and Aiolos degradation lead to specific immune changes. CC-92480 pharmacodynamic activity was dose-dependent from 0.1 mg to 1.0 mg and recovery was dose- and schedule-dependent. These changes were also demonstrated in immune cell subsets. Dynamic changes of immune cell subsets in peripheral blood occurred in concert with Ikaros and Aiolos degradation and recovery, suggesting that immune profiles may be modified and optimized by dose and schedule. This new insight may be utilized to provide the rationale for dose and schedule for specific immune effects when combining with other immunotherapies, such as bispecific antibodies and CAR T cells.

Disclosures
Wong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lamba:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. Jiménez Nuñez:CITRE, a Bristol-Myers Squibb Company, Spain: Current Employment. Bauer:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Bahlis:Sanofi: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria. Ramasamy:Takeda: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Trudel:Pfizer: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Takeda, Karyopharm, AstraZeneca, Sanofi: Honoraria; Janssen: Honoraria, Research Funding; Amgen: Consultancy, Research Funding. Martínez-Lopez:Altum, Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Vivia Biotech: Honoraria; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding. Mateos:EDOMundipharma: Consultancy; Adaptive: Consultancy; Pharmamar: Consultancy; GlaxoSmithKline: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Rodriguez-Otero:Oncopeptides: Consultancy, 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); Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Lonial:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Merck: Consultancy, Honoraria, Other: Personal fees; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Takeda: Consultancy, Other: Personal fees, Research Funding; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; JUNO Therapeutics: Consultancy; Millennium: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Personal fees; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria. Popat:AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, 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); Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Orlowski:Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Berdeja:Amgen: Consultancy, Research Funding; Abbvie: Research Funding; Bluebird: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Vivolux: Research Funding; Kesios: Research Funding; Karyopharm: Consultancy; Glenmark: Research Funding; Genentech, Inc.: Research Funding; EMD Sorono: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; Poseida: Research Funding; Prothena: Consultancy; Kite Pharma: Consultancy; Legend: Consultancy; Lilly: Research Funding; Novartis: Research Funding; Teva: Research Funding; Acetylon: Research Funding; Bioclinica: Consultancy; BMS: Consultancy, Research Funding. Pourdehnad:Celgene: Ended employment in the past 24 months, Patents & Royalties: Various CC-122 patents; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Various CC-122 patents. Pierce:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.