CC-92480, a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD) Agent, in Combination with Dexamethasone (DEX) and Bortezomib (BORT) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Phase 1/2 Study CC-92480-MM-002
Authors: Richardson Paul G. , Ocio Enrique , Raje Noopur S. , Gregory Tara , White Darrell , Oriol Albert , Sandhu Irwindeep , Raab Marc-Steffen , LeBlanc Richard , Rodriguez Cesar , Trudel Suzanne , Wäsch Ralph , Perrot Aurore , Bahlis Nizar J. , Zhou Zehua , Lamba Manisha , Amatangelo Michael , Civardi Tiziana , Katz Jessica , Maciag Paulo , Peluso Teresa , Dimopoulos Meletios A. 
Published: November 2021

Abstract
Introduction: CC-92480 is a potent, novel CELMoD ® compound designed for rapid and maximal degradation of Ikaros and Aiolos, that has shown immunostimulatory effects and enhanced tumoricidal activity in myeloma cells, including those resistant to lenalidomide (LEN) and pomalidomide (POM). CC-92480 has demonstrated potent synergy with DEX, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) (Wong L, et al. Blood 2019;134[suppl 1]:1815). In pts with RRMM, CC-92480 in combination with DEX demonstrated a manageable safety profile with promising preliminary efficacy (Richardson PG, et al. J Clin Oncol 2020;38[suppl 15]:8500). CC-92480-MM-002 (NCT03989414) is an ongoing phase 1/2 study evaluating CC-92480 in combination with standard treatments in pts with RRMM. Here we report preliminary results from the CC-92480 + BORT + DEX cohort.
Methods: Pts with RRMM who had received 2-4 prior regimens, including prior treatment with LEN, and had documented disease progression during or after their last myeloma therapy were eligible. CC-92480, at specified cohort doses (0.3 mg, 0.6 mg, and 1.0 mg), was administered orally on days (D) 1-14 with subcutaneous BORT (1.3 mg/m 2) on D1, 4, 8, and 11 in cycles (C) 1-8 and on D1 and 8 after C8, over a 21-day cycle; DEX (20 mg/day or 10 mg/day if &gt; 75 years of age) was given on D1, 2, 4, 5, 8, 9, 11, and 12 in C1-8 and on D1, 2, 8, and 9 after C8. Primary objectives were to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and to evaluate safety and preliminary efficacy. Pharmacodynamics (PD), Ikaros/Aiolos protein levels, and immunophenotyping were also assessed.
Results: As of May 26, 2021, 19 pts had received CC-92480 + BORT + DEX. Median age was 66 (50-83) years, median time since initial diagnosis was 4.8 (1.9-17.1) years, and median number of prior regimens was 3 (2-4). Prior therapies included stem cell transplantation (57.9%), BORT (78.9%), carfilzomib (CFZ, 21.1%), LEN (100%), POM (47.4%), and anti-CD38 mAbs (36.8%); 21.1% of the pts had extramedullary disease and 21.1% were triple-class refractory (refractory to immunomodulatory drug, PI, and anti-CD38 mAb). Median follow-up was 8 (1.0-19.2) months, with a median number of 10 (1-28) cycles received and 9 (47.4%) pts continue on treatment. Main reason for discontinuation was progressive disease, reported in 5 pts.
All pts experienced ≥ 1 treatment-emergent adverse events (TEAEs) and grade (Gr) 3-4 TEAEs were reported in 18 (94.7%) pts. Most frequent (≥ 10% of pts) Gr 3-4 TEAEs were neutropenia (36.8%, no febrile neutropenia reported), thrombocytopenia (21.1%, no bleeding reported), anemia (10.5%), hyperglycemia (10.5%), and insomnia (10.5%). Gr 3-4 infection was reported in 1 (5.3%) pt. Eight (42.1%) pts had Gr 1-2 peripheral neuropathy. Five (26.3%) pts had serious TEAEs, none considered related to study treatment. Five (26.3%), 7 (36.8%), and 8 (42.1%) pts had dose reductions of CC-92480, BORT, and DEX, respectively; 4 (21.1%) pts had dose reductions due to TEAEs. Two (10.5%) pts discontinued due to TEAEs (dysgeusia and colon neoplasm [pre-existing]). No pt experienced dose-limiting toxicity and the MTD was not reached. Two deaths were reported (due to myeloma progression and colon neoplasm).
The overall response rate across all doses per investigator assessment was 73.7% (14/19 pts), including 3 stringent complete responses and 1 complete response. Responses were observed at all dose levels. Median duration of response was 10.4 (5.5-not reached) months and median time to first response was 0.95 (0.7-3.3) months.
Plasma exposures of CC-92480 + BORT + DEX were consistent with previous pharmacokinetic (PK) analysis of CC-92480 + DEX. Consistent with CC-92480 mechanism of action, PD studies showed potent degradation of substrates 3-6 hours post treatment and a reduction of mature B cells with CC-92480 + BORT + DEX treatment.
Based on safety, efficacy, and PK/PD data, a 1.0 mg dose of CC-92480 was selected as the RP2D.
Conclusions: CC-92480 in combination with BORT and DEX appears to be safe and well tolerated with encouraging preliminary efficacy in pts with RRMM. These results support further development of CC-92480 in combination regimens in RRMM. In the CC-92480-MM-002 study, a CC-92480 + BORT + DEX expansion cohort is ongoing at the RP2D, as well as a CC-92480 + CFZ + DEX cohort. Updated data will be presented at the meeting.

Disclosures
Richardson: Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Ocio: Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy; MSD: Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy; Secura-Bio: Consultancy. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. White: Amgen: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Forus: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sandhu: Celgene/BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Raab: Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. LeBlanc: Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Canada: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Research Funding; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Rodriguez: BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau. Trudel: Sanofi: Honoraria; Roche: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Genentech: Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Wäsch: Pfizer: Consultancy; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Perrot: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria. Bahlis: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Zhou: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lamba: Bristol Myers Squibb: Current Employment; Pfizer: Current equity holder in publicly-traded company. Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Civardi: Bristol Myers Squibb: Current Employment. Katz: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Maciag: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Peluso: Celgene, a Bristol-Myers Squibb Company: Current Employment. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; Amgen: Honoraria.