Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma

Abstract

This phase 1, dose-finding study investigated ibrutinib and carfilzomib ± dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (≥2 lines of therapy including bortezomib and an immunomodulatory agent). Of 43 patients enrolled, 74% were refractory to bortezomib and 23% had high-risk cytogenetics. No dose-limiting toxicities were observed. The recommended phase 2 dose was ibrutinib 840 mg and carfilzomib 36 mg/m² with dexamethasone. The most common ≥ grade 3 (>10%) treatment-emergent adverse events were hypertension, anemia, pneumonia, fatigue, diarrhea, and thrombocytopenia. Overall response rate was 67% (very good partial response, 21%; stringent complete response, 2%), with an additional 9% minimal response. Median progression-free survival was 7.2 months and was not inferior in refractory nor high-risk patients. Median overall survival was not reached. Ibrutinib plus carfilzomib demonstrated encouraging responses with a manageable safety profile in this advanced population.

Keywords:

• Ibrutinib
• carfilzomib
• Bruton’s tyrosine kinase
• multiple myeloma
• hematologic neoplasms

Acknowledgments

We thank Juthamas Sukbuntherng, PhD, for support and oversight in the pharmacokinetic/pharmacodynamic analysis and Brian Haas, PhD, for medical writing support funded by Pharmacyclics LLC, an AbbVie Company.

Author contributions

All authors: writing—reviewing and editing, resources. Ajai Chari: conceptualization, methodology, investigation. Sarah Larson, Beata Holkova, Robert F. Cornell, Cristina Gasparetto, Chatchada Karanes, Jeffrey V. Matous, Ruben Niesvizky, Jason Valent, Matthew Lunning, Saad Z. Usmani, Larry D. Anderson, Saurabh Chhabra: investigation. Lipo Chang: project administration. Yihua Lee: formal analysis, data curation, project administration. Yvonne Pak: formal analysis, data curation. Zeena Salman, Thorsten Graef, Elizabeth Bilotti: conceptualization, methodology, project administration.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2018.1443337.