An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma

Vij, Ravi; Wang, Michael; Kaufman, Jonathan L.; Lonial, Sagar; Jakubowiak, Andrzej; Stewart, A. Keith; Kukreti, Vishal; Jagannath, Sundar; McDonagh, Kevin T.; Alsina, Melissa; Bahlis, Nizar J.; Reu, Frederic J.; Gabrail, Nashat; Belch, Andrew R.; Matous, Jeffrey; Lee, Peter P.; Rosen, Peter J.; Sébag, Michaël; Vesole, David H.; Kunkel, Lori; Wear, Sandra; Wong, Alvin; Orłowski, Robert Z.; Siegel, David S.

doi:10.1182/blood-2012-03-414359

Cited by 235 publications

(187 citation statements)

References 25 publications

Supporting

Mentioning

174

Contrasting

Unclassified

Order By: Relevance

“…Carfilzomib has demonstrated anti‐tumour activity in patients with MM at doses ranging from 15 to 56 mg/m 2 (Siegel et al , 2012; Vij et al , 2012a,b; Badros et al , 2013; Papadopoulos et al , 2013, 2015). In phase I and II trials, only the LLVY‐AMC assay was used in a limited number of patient samples to measure CT‐L activity alone (O'Connor et al , 2009; Badros et al , 2013; Niesvizky et al , 2013; Papadopoulos et al , 2013).…”

Section: Resultsmentioning

confidence: 99%

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

et al. 2016

Self Cite

View full text Add to dashboard Cite

SummaryWhile proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme‐linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15–56 mg/m2), dose‐dependent inhibition of c20S and i20S chymotrypsin‐like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow–derived CD138+ tumour cells. Carfilzomib‐induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near‐complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.

show abstract

Section: Resultsmentioning

confidence: 99%

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…The results suggest that the benefit of carfilzomib treatment in reducing disease progression, and even death, outweighs CV risks for most patients. Nonetheless, Month since first dose or randomization 24 …”

Section: Discussionmentioning

confidence: 99%

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials

et al. 2018

Self Cite

View full text Add to dashboard Cite

“…Neuropathy was minimal. In a separate Phase II trial (PX-171-004) that treated 129 patients who were bortezomib naiive, the response rate with single-agent carfilzomib was approximately 50% [112]. Carfilzomib is now being tested in newly diagnosed myeloma, with high activity reported in a Phase II trial of carfilzomib plus Rd (CRd) [113].…”

Section: Treatment Of Relapsed Multiple Myelomamentioning

confidence: 99%

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

2013

View full text Add to dashboard Cite

Disease overviewMultiple myeloma accounts for approximately 10% of hematologic malignancies.DiagnosisThe diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end‐organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end‐organ damage.Risk stratificationIn the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high‐risk myeloma. Patients with t(4;14) translocation are considered intermediate‐risk. All others are considered as standard‐risk.Risk‐adapted initial therapyStandard‐risk patients can be treated with lenalidomide plus low‐dose dexamethasone (Rd), or a bortezomib‐containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate‐risk and high‐risk patients require a bortezomib‐based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard‐risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12–18 months.Maintenance therapyAfter initial therapy, lenalidomide maintenance is considered for standard‐risk patients who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen should be considered in pateints with intermediate or high‐risk myeloma.Management of refractory diseasePatients with indolent relapse can be treated first with two‐drug or three‐drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 88:225–235, 2013. © 2013 Wiley Periodicals, Inc.

show abstract

An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma

Cited by 235 publications

References 25 publications

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

Contact Info

Product

Resources

About