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Multiple Myeloma, Gammopathies

Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia

Leukemia volume 29, pages 2338–2346 (2015)Cite this article

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Abstract

We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1–16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76–96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38–67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12–not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.

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Acknowledgements

Supported in part by 1R01FD003743, Novartis Inc., Millenium/Takeda Inc. and the International Waldenstrom Macroglobulinemia Foundation (IWMF).

Author Contributions

Irene M Ghobrial: initiated and wrote the clinical trial and was the principal investigator at DFCI. She conducted the clinical trial, analyzed the data and wrote the manuscript, Robert Redd: performed the statistical analysis; Philippe Armand: enrolled patients and reviewed the manuscript; Erica Boswell: entered and analyzed the data and reviewed the manuscript; Stacey Chuma: was the research nurse of the study; Antonio Sacco: performed the mutation studies for MYD88 and CXCR4, Kimberly Noonan: assessed patients during therapy and follow-up; Ranjit Banwait: entered and analyzed the data and reviewed the manuscript; Houry Leblebjian: pharmacist of the study and reviewed treatment and dose modifications of the study; Diane Warren: project manager of the clinical study; Megan MacNabb: assistant project manager, managed the regulatory components of the study; Aldo M Roccaro: performed the mutation studies for MYD88 and CXCR4; Daisy Huynh: performed the mutation studies for MYD88 and CXCR4; Adriana Perilla-Glen performed the mutation studies for MYD88 and CXCR4; Patrick Henrick: entered and analyzed the data and reviewed the manuscript; Jorge Castillo: cared for patients in the study and reviewed the manuscript; Paul G Richardson: input in the design and conduct of the study and reviewed the manuscript; Jeffrey Matous enrolled patients and reviewed the manuscript; Edie Weller: performed the statistical analysis; Steven P Treon: input in the design and conduct of the study, enrolled patients and reviewed the manuscript.

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Authors and Affiliations

  1. Medical Oncology, Dana–Farber Cancer Center, Boston, MA, USA

    I M Ghobrial, P Armand, R Banwait, E Boswell, S Chuma, D Huynh, A Sacco, A M Roccaro, A Perilla-Glen, K Noonan, M MacNabb, H Leblebjian, D Warren, P Henrick, J J Castillo, P G Richardson & S P Treon

  2. Department of Biostatistics, Dana–Farber Cancer Institute, Boston, MA, USA

    R Redd & E Weller

  3. Colorado Blood Cancer Institute, Denver, CO, USA

    J Matous

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  1. I M Ghobrial
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Correspondence to I M Ghobrial.

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Competing interests

Irene M Ghobrial: Consultant for Novartis, Millennium, Celgene and BMS. Philip Armand: received funding from BMS, Merck, Otsuka, Sigma Tau and Sequenta; consultant for Merck. Paul Richardson: Consultant for Novartis, Millennium and Celgene. The rest of the authors declare no conflict of interest.

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Ghobrial, I., Redd, R., Armand, P. et al. Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia. Leukemia 29, 2338–2346 (2015). https://doi.org/10.1038/leu.2015.164

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