A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma

Richardson, Paul G.; Barlogie, Bart; Berenson, James R.; Singhal, Seema; Jagannath, Sundar; Irwin, David; Rajkumar, S. Vincent; Srkalović, Gordan; Alsina, Melissa; Alexanian, Raymond; Siegel, David S.; Orłowski, Robert Z.; Kuter, David J.; Limentani, Steven; Lee, Stephanie J.; Hideshima, Teru; Esseltine, Dixie Lee; Kauffman, Michael; Adams, Julian; Schenkein, David P.; Anderson, Kenneth C.

doi:10.1056/nejmoa030288

Cited by 2,417 publications

(1,910 citation statements)

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“…Bortezomib (Velcade™; PS-341) is a potent inhibitor of myeloma cell growth and survival in vitro and results indicate striking therapeutic efficacy and acceptable toxicity profile of intravenous bortezomib in myeloma patients when administered alone or in combination with dexamethasone and/or chemotherapeutic agents, after relapse or at first presentation (70)(71)(72)(73)(74). In addition to myeloma cells, osteoblasts are also sensitive to proteasome inhibitors, and we have recently shown that structurally-unrelated inhibitors of the ubiquitin-proteasome pathway (including bortezomib) have beneficial anabolic effects on the skeleton in vivo (60,75).…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

The pathogenesis of the bone disease of multiple myeloma

Edwards

Zhuang

Mundy

2008

Bone

152

120

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Multiple myeloma is a fatal hematologic malignancy associated with clonal expansion of malignant plasma cells within the bone marrow and the development of a destructive osteolytic bone disease. The principal cellular mechanisms involved in the development of myeloma bone disease are an increase in osteoclastic bone resorption, and a reduction in bone formation. Myeloma cells are found in close association with sites of active bone resorption, and the interactions between myeloma cells, and other cells within the specialized bone marrow microenvironment are essential, both for tumor growth and the development of myeloma bone disease. This review discusses the many different factors which have been implicated in myeloma bone disease, including the evidence for their role in myeloma and subsequent therapeutic implications.

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Section: Proteasome Inhibitorsmentioning

confidence: 99%

The pathogenesis of the bone disease of multiple myeloma

Edwards

Zhuang

Mundy

2008

Bone

152

120

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“…Due to generally higher levels of proteasome activity in cancer cells, inhibition of the proteasome elicits pro‐apoptotic effects preferentially in malignant cells compared with normal cells, and is a well‐validated target in multiple myeloma (MM). Three proteasome inhibitors (PIs), bortezomib (BTZ: Kane et al , 2003; Richardson et al , 2003, 2005), carfilzomib (CFZ) and ixazomib (IXZ) are currently approved for the treatment of MM, with several others in development. Although important therapeutic advances, these PIs are associated with significant and dose‐limiting off‐target toxicities (Lonial et al , 2005; Richardson et al , 2006; Cai et al , 2014; Harvey, 2014; Atrash et al , 2015; Wanchoo et al , 2015) and the development of acquired resistance (Fall et al , 2014; Huber et al , 2015; Niewerth et al , 2015).…”

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confidence: 99%

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

Levin¹,

Spencer

Harrison

et al. 2016

Br J Haematol

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SummaryProteasome inhibitors (PIs) are highly active in multiple myeloma (MM) but resistance is commonly observed. All clinical stage PIs effectively inhibit chymotrypsin‐like (CT‐L) activity; one possible mechanism of resistance is compensatory hyperactivation of caspase‐like (C‐L) and trypsin‐like (T‐L) subunits, in response to CT‐L blockade. Marizomib (MRZ), an irreversible PI that potently inhibits all three 20S proteasome subunits with a specificity distinct from other PIs, is currently in development for treatment of MM and malignant glioma. The pan‐proteasome pharmacodynamic activity in packed whole blood and peripheral blood mononuclear cells was measured in two studies in patients with advanced solid tumours and haematological malignancies. Functional inhibition of all proteasome subunits was achieved with once‐ or twice‐weekly MRZ dosing; 100% inhibition of CT‐L was frequently achieved within one cycle at therapeutic doses. Concomitantly, C‐L and T‐L activities were either unaffected or increased, suggesting compensatory hyperactivation of these subunits. Importantly, this response was overcome by continued administration of MRZ, with robust inhibition of T‐L and C‐L (up to 80% and 50%, respectively) by the end of Cycle 2 and maintained thereafter. This enhanced proteasome inhibition was independent of tumour type and may underlie the clinical activity of MRZ in patients resistant to other PIs.

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“…45,46 Common toxicities include sometimes severe gastrointestinal effects (usually diarrhea and less often constipation), sensory peripheral neuropathy, and orthostatic hypotension. Studies have shown that administering bortezomib once weekly instead of twice weekly reduces gastrointestinal and neuropathic toxicity by roughly 30%, 47 and subcutaneous instead of intravenous administration similarly reduces toxicity.…”

Section: Side Effects and Supportive Carementioning

confidence: 99%