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Myeloma

The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects

Leukemia volume 27, pages 430–440 (2013)Cite this article

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Abstract

Proteasome inhibitors (PIs), namely bortezomib, have become a cornerstone therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting pathologic bone destruction. In clinical trials, carfilzomib, a next generation epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. Interactions between myeloma cells and the bone marrow (BM) microenvironment augment the number and activity of bone-resorbing osteoclasts (OCs) while inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth and osteolytic lesions. At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzomib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.

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Acknowledgements

We are grateful to the Washington University MM/MGUS Research Program and Tissue Bank and to Lindsay Goddard, Montserrat Martín, Isabel Isidro, Teresa Prieto and Almudena Martín for their excellent technical work. This research was supported by grants from the National Institutes of Health (T32CA113275:MAH; P01CA100730:KNW; P50CA94056:DP-W), the St Louis Men’s Group Against Cancer (KNW), the Holway Myeloma Fund (KNW), the Spanish MICINN-ISCIII (PI081825), the Fundación de Investigación Médica Mutua Madrileña (AP27262008), the Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, the Spanish Myeloma Network Program (RD06/0020/0006 and RD06/0020/0041) and Spanish FIS (PS09/01897). MicroCT services were provided by the WU musculoskeletal core (P30AR057235).

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  1. M A Hurchla, A Garcia-Gomez, M Garayoa and K N Weilbaecher: These authors contributed equally to this work.

  2. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA

    M A Hurchla, M C Hornick, A Li, R Vij, M H Tomasson & K N Weilbaecher

  2. Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain

    A Garcia-Gomez, E M Ocio, A Pandiella, J F San Miguel & M Garayoa

  3. Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain

    A Garcia-Gomez, J F San Miguel & M Garayoa

  4. Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain

    A Garcia-Gomez, E M Ocio, J F Blanco, A Pandiella, J F San Miguel & M Garayoa

  5. BRIGHT Institute and Molecular Imaging Center, Mallinkrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA

    L Collins & D Piwnica-Worms

  6. ONYX Pharmaceuticals, South San Francisco, CA, USA

    C J Kirk

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Hurchla, M., Garcia-Gomez, A., Hornick, M. et al. The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Leukemia 27, 430–440 (2013). https://doi.org/10.1038/leu.2012.183

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