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Oral azacitidine (CC-486) in combination with lenalidomide and dexamethasone in advanced, lenalidomide-refractory multiple myeloma (ROAR study)
- Source :
- Leukemia & Lymphoma. 60:2143-2151
- Publication Year :
- 2019
- Publisher :
- Informa UK Limited, 2019.
-
Abstract
- In preclinical studies, oral azacitidine (CC-486), a hypomethylating agent, has been shown to have a direct anti-MM effect and in vitro anti-MM synergism when combined with lenalidomide (LEN). We present a phase 1b, single center, 3 × 3 dose escalation study with planned expansion at maximum tolerated dose (MTD), which assessed the safety and efficacy of combining CC-486 with LEN (25 mg d1-21/28) and dexamethasone (DEX) (40 mg weekly) in patients with relapsed/refractory MM who had previously failed LEN. Twenty-four patients were enrolled. The MTD of CC-486 was 150 mg d1-21; recommended expansion dose was 100 mg d1-21. Adverse events were predictable and manageable. ORR was 37.5%; clinical benefit rate was 50%. Median OS was 10.3 m; median PFS was 2.6 m. Correlative proteomics demonstrated that higher MM tumor cell cereblon expression (pretreatment, C1D5) was associated with superior PFS/OS. CC-486, LEN and DEX produced meaningful clinical responses in heavily treated LEN refractory MM patients. Proteomics may have utility in predicting clinical outcomes.
- Subjects :
- Male
Proteomics
Antimetabolites, Antineoplastic
Cancer Research
Maximum Tolerated Dose
Ubiquitin-Protein Ligases
Administration, Oral
Dexamethasone
Drug Administration Schedule
Oral Azacitidine
Epigenesis, Genetic
03 medical and health sciences
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Lenalidomide
Adaptor Proteins, Signal Transducing
Aged
Aged, 80 and over
Dose-Response Relationship, Drug
business.industry
Cereblon
Refractory Multiple Myeloma
Hematology
DNA Methylation
Middle Aged
Prognosis
Progression-Free Survival
Gene Expression Regulation, Neoplastic
Oncology
Hypomethylating agent
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Azacitidine
Cancer research
Female
Neoplasm Recurrence, Local
Multiple Myeloma
business
030215 immunology
medicine.drug
Subjects
Details
- ISSN :
- 10292403 and 10428194
- Volume :
- 60
- Database :
- OpenAIRE
- Journal :
- Leukemia & Lymphoma
- Accession number :
- edsair.doi.dedup.....de79dc8556992e3be7d3337aa9879f18