First clinical (phase 1b/2a) study of iberdomide (CC-220; IBER), a CELMoD, in combination with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).
Abstract
8006 Background: IBER is a novel cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immunostimulatory activities. Preclinically, IBER overcomes immunomodulatory drug (IMiD) resistance and has synergy with daratumumab (DARA), bortezomib (BORT), and DEX. Methods: A phase 1b/2a multicenter, open-label, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy of IBER. Eligible pts had RRMM and must have received ≥ 2 prior regimens including lenalidomide (LEN) and/or pomalidomide (POM), and a proteasome inhibitor (PI). All pts had progressed on or within 60 days of last MM therapy. Escalating doses of IBER were given on days 1–21, in combination with DEX 40 mg (20 mg in pts age > 75 years) on days 1, 8, 15, and 22, of each 28-day cycle. Dose escalation was reviewed by a dose escalation committee. Results: As of Jan 2019,58 pts received IBER + DEX. Median age was 64.5 years (range 33–79), and median number of prior regimens was 5 (2–12). Prior therapies included autologous stem cell transplant (79%), LEN (100%), POM (69%), PIs (100%), and DARA (66%). IBER dose ranged from 0.3 to 1.2 mg; MTD/RP2D was not reached. Median duration of therapy was 12+ weeks (range 4–109). Grade 3–4 adverse events (AEs) were reported in 41 (72%) pts and were not related to dose. Grade 3–4 neutropenia, thrombocytopenia, neuropathy, and fatigue occurred in 26%, 11%, 2%, and 0% pts, respectively. Three pts discontinued treatment due to AEs. Clinical activity occurred early and was observed across all dose levels (Table); 20 of 51 pts remain on treatment (2–27+ cycles). Conclusions: IBER + DEX showed favorable efficacy and safety in heavily pretreated pts with RRMM who failed multiple prior therapies. This study is ongoing, including combinations of IBER with DARA or BORT. Clinical trial information: NCT02773030. [Table: see text]
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CC-92480 has activity across a variety of MM cell lines resistant to lenalidomide and pomalidomide, even those with low levels of CRBN expression, which has been proposed as a mechanism of drug resistance.
“This agent has activity across a variety of MM cell lines resistant to lenalidomide and pomalidomide, even those with low levels of CRBN expression, which has been proposed as a mechanism of drug resistance (FIG. 3)120.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [120]
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“Consistently, iberdomide induced greater apoptosis than pomalidomide in all MM cell lines tested, at a tenfold lower concentration, estimated to be in the range of clinical activity [4] (Fig.”
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“Recent results with iberdomide, a novel cereblon E3 ligase modulator with enhanced tumoricidal and immunomodulatory activity, further support the beneficial role of continued immunomodulation in MM [34, 35].”
ResultMultiple Myeloma Therapy: Emerging Trends and Challenges
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“label, dose-escalation study of Iberdomide in combination with dexamethasone in heavily pretreated MM patients (mostly IMiD resistant) demonstrated an overall response rate of 32% and good tolerability [43].”
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“To date, with limited clinical experience grade 3/4 neutropenia rates with IBER plus dexamethasone (IBERdex) are ~30% [30].”
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“Also, preliminary results evaluating the novel compound iberdomide (CC-220) have demonstrated favorable efficacy and safety in RRMM patients who failed prior therapies, including lenalidomide and pomalidomide [73].”
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“Iberdomide is a CELMoD with demonstrable activity in MM patients who are refractory to pomalidomide [11,12].”
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“Another CELMoD named Iberdomide (CC-220) was tested in combination with dexamethasone in a Phase Ib/IIa study and found an ORR of 31%, a minimal response rate or better of 51%, and disease control of 88% [37].”
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“Immunomodulatory agents (IMiD) Iberdomide (cereblon E3 ligase modulators (CELMoDs)) Not approved for RRMM [26]”
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“A phase 1b/2a study of iberdomidedexamethasone demonstrated preliminary efficacy and safety in patients who received a median of 5 (range, 2–12) prior lines of therapy [89].”
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“…Iberdomide could also maintain activity in pomalidomide resistant cell lines, and prelim-inary data from the fi rst phase Ib/IIa trial of 58 patients with relapsed/refractory MM indicate that over 50% of patients achieve disease bene fi t with iberdomide in combination with dexamethasone [88,89].”
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“Iberdomide in combination with dexamethasone (DEX), or in combination with DEX and daratumumab (DARA) or bortezomib, are being investigated in CC220-MM-001 as treatment regimens and showed encouraging clinical outcome in patients with heavily pre-treated relapsed and refractory MM (RRMM).(6,10)”
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- Authors
- Lonial, S., van de Donk, N. W. C. J., Popat, R., Zonder, J. A., Minnema, M. C., Larsen, J., Nguyen, T. V., Chen, M. S., Bensmaine, A., Cota, M., & Sonneveld, P.
- Affiliations
- Winship Cancer Institute (US)
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Hematology, Amsterdam, Netherlands;
- University College London Hospitals NHS Foundation Trust (GB)
- The Barbara Ann Karmanos Cancer Institute (US)
- University Medical Center Utrecht (NL)
- Mayo Clinic Hospital (US)
- Celgene (United States) (US)
- Erasmus MC (NL)
- Venue
- Journal of Clinical Oncology
- Published
- 2019-05-20
- Volume
- 37
- Issue
- 15_suppl
- Pages
- 8006-8006
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2955507058
- Cited by
- 49
- References
- 0
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 5 · 2022: 13 · 2021: 14 · 2020: 9 · 2019: 2
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- iberdomide, CELMoD, cereblon E3 ligase modulator, dexamethasone, relapsed/refractory multiple myeloma, combination therapy, maximum tolerated dose, dose escalation, adverse events, neutropenia, thrombocytopenia, lenalidomide, pomalidomide, proteasome inhibitors
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