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Original Articles: Research

Enzymatic activities of circulating plasma proteasomes in newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide and dexamethasone

Elisabet E. ManasanchMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; ;Department of Lymphoma/Myeloma, Division of Cancer Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA;

Carlos Fernández de LarreaMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; ;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic, Barcelona. Institut D’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain;

Adriana ZingoneMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Seth M. SteinbergBiostastistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Mary KwokMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Nishant TagejaMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Manisha BhutaniMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Dickran KazandjianMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Mark RoschewskiMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Peter WuMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

George CarterMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Diamond ZuchlinskiMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Marcia MulquinMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Liz LampingMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Rene CostelloMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Deborah BurtonMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Lindsay A. GilMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

William D. FiggMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Irina MaricLaboratory of Hematology, Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USA;

Katherine R. CalvoLaboratory of Hematology, Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USA;

Constance YuanFlow Cytometry Unit, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Maryalice Stetler-StevensonFlow Cytometry Unit, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

Neha KordeMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; ;Myeloma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Ola LandgrenMultiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; ;Myeloma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USACorrespondence[email protected]

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Abstract

The proteasome inhibitor carfilzomib is highly effective in the treatment of multiple myeloma. It irreversibly binds the chymotrypsin-like active site in the β5 subunit of the 20S proteasome. Despite impressive response rates when carfilzomib is used in combination with immunomodulatory agents in newly diagnosed multiple myeloma patients; no biomarker exists to accurately predict response and clinical outcomes. We prospectively assessed the activity in peripheral blood of the chymotrypsin-like (CHYM), caspase-like (CASP) and trypsin-like (TRYP) proteolytic sites in 45 newly diagnosed multiple myeloma patients treated with eight cycles of carfilzomib, lenalidomide and dexamethasone (CRd) (NCT01402284). Samples were collected per protocol and proteasome activity measured through a fluorogenic assay. Median CHYM levels after one dose of carfilzomib decreased by >70%. CHYM and CASP activity decreased throughout treatment reaching a minimum after eight cycles of treatment. Higher levels of proteasome activity associated with higher disease burden (r > 0.30; p < 0.05) and higher disease stage (0.10 < p <0.20). No association was found with the probability of achieving a complete response, minimal residual disease negativity or time to best response. Further studies evaluating proteasome activity in malignant plasma cells may help elucidate how proteasome activity can be used as a biomarker in multiple myeloma.

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Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.1080/10428194.2016.1214953

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Enzymatic activities of circulating plasma proteasomes in newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide and dexamethasone

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Enzymatic activities of circulating plasma proteasomes in newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide and dexamethasone

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