A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma

Jakubowiak, Andrzej; Dytfeld, Dominik; Griffith, Kent A.; Lebovic, Daniel; Vesole, David H.; Jagannath, Sundar; Al-Zoubi, Ammar; Anderson, Tara; Nordgren, Brian K.; Detweiler-Short, Kristen; Stockerl-Goldstein, Keith; Ahmed, Asra; Jobkar, Terri L.; Durecki, Diane; McDonnell, Kathryn; Mietzel, Melissa A.; Couriel, Daniel R.; Kaminski, Mark; Vij, Ravi

doi:10.1182/blood-2012-04-422683

Cited by 393 publications

(338 citation statements)

References 32 publications

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“…Similar CBRs were observed among the four therapeutic classes combined with carfilzomib. The observation of clinical benefit across all effective anti-MM agent classes is promising and is consistent with recent studies showing that carfilzomib is safe and effective when used in combination with a variety of drugs, including lenalidomide and dexamethasone, 17,18,[23][24][25] pomalidomide and dexamethasone, 26 melphalan and prednisone, 27 cyclophosphamide and dexamethasone, 28 thalidomide and dexamethasone, 29 and cyclophosphamide, thalidomide and dexamethasone. 30 Results from those studies also compare favorably with bortezomib-based regimens, including bortezomib in combination with lenalidomide and dexamethasone.…”

Section: Discussionsupporting

confidence: 81%

“…In this context, carfilzomib treatment for patients that failed bortezomib therapy in an otherwise novel treatment combination has shown clinical activity, 4,6 yet the concept of substituting PI with another into an otherwise unchanged combination treatment in an attempt to overcome PI resistance has not been investigated in the clinic. Given that single-agent carfilzomib can produce responses in some bortezomib refractory patients 4 and shows high response rates when combined with other agents, 17,18 we hypothesized that carfilzomib would be an effective and well-tolerated replacement for bortezomib among MM patients who had failed bortezomibcontaining combination regimens. In this study, we investigated the feasibility of replacing bortezomib with carfilzomib in an otherwise identical combination regimen for MM patients who had progressed on or within 12 weeks of receiving their most recent bortezomib-based combination regimen.…”

Section: Introductionmentioning

confidence: 99%

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Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy

et al. 2014

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In this open-label, intra-patient phase I/II trial, bortezomib was replaced with carfilzomib (escalated from 20 to 45 mg/m 2 on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle) for multiple myeloma (MM) patients who progressed while on or within 12 weeks of receiving a bortezomib-containing combination regimen. Study objectives included determination of the maximum tolerated dose (MTD), overall response rate (ORR), clinical benefit rate (CBR), time to progression, time to response, duration of response, progression-free survival and overall survival (OS). Of 38 registered patients, 37 were treated and evaluable for efficacy and safety. Thirty-one carfilzomib-based regimens using 14 different drug combinations were tested. One regimen (carfilzomib (45 mg/m 2 ), ascorbic acid (1000 mg) and cyclophosphamide (2.2 mg/kg)) reached MTD. ORR and CBR were 43.2 and 62.2%, respectively. Median progressionfree survival, time to progression and OS were 8.3, 9.9 and 15.8 months, respectively. Hematologic adverse events (AEs; Xgrade 3) included lymphopenia (35.1%), thrombocytopenia (24.3%), anemia (10.8%) and neutropenia (10.8%). Nonhematologic AEs (Xgrade 3) included fever (5.4%) and hypokalemia (5.4%). These results demonstrate that replacing bortezomib with carfilzomib is safe and can be effective for MM patients failing bortezomib-containing combination regimens. This trial was registered at

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy

et al. 2014

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“…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]. An upcoming ECOG Phase III trial will compared CRd and VRD in newly diagnosed myeloma.…”

Section: Treatment Of Relapsed Multiple Myelomamentioning

confidence: 99%

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

2013

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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.

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“…CFZ is well tolerated with acceptable toxicity profiles and few instances of dose limiting toxicity resulting in cessation of treatment (13,14). Both single agent and combination therapies with CFZ have demonstrated good response profiles for patients with relapsed/refractory multiple myeloma and CFZ is now undergoing trials for use as a first-line treatment (11,(15)(16)(17)(18)(19)(20)(21)(22). However, an unanswered question for CFZ, and for the field of covalent inhibitors in general, is the extent to which the elec-trophilic warhead in a covalent inhibitor produces off-target damage to proteins.…”

mentioning

confidence: 99%

Specificity of Protein Covalent Modification by the Electrophilic Proteasome Inhibitor Carfilzomib in Human Cells

Federspiel

Codreanu

Goyal

et al. 2016

Molecular & Cellular Proteomics

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Carfilzomib (CFZ) is a second-generation proteasome inhibitor that is Food and Drug Administration and European Commission approved for the treatment of relapsed or refractory multiple myeloma. CFZ is an epoxomicin derivative with an epoxyketone electrophilic warhead that irreversibly adducts the catalytic threonine residue of the ␤5 subunit of the proteasome. Although CFZ produces a highly potent, sustained inactivation of the proteasome, the electrophilic nature of the drug could potentially produce off-target protein adduction. To address this possibility, we synthesized an alkynyl analog of CFZ and investigated protein adduction by this analog in HepG2 cells. Using click chemistry coupled with streptavidin based IP and shotgun tandem mass spectrometry (MS/MS), we identified two off-target proteins, cytochrome P450 27A1 (CYP27A1) and glutathione S-transferase omega 1 (GSTO1), as targets of the alkynyl CFZ probe. We confirmed the adduction of CYP27A1 and GSTO1 by streptavidin capture and immunoblotting methodology and then site-specifically mapped the adducts with targeted MS/MS methods. Although CFZ adduction of CYP27A1 and GSTO1 in vitro decreased the activities of these enzymes, the small fraction of these proteins modified by CFZ in intact cells should limit the impact of these offtarget modifications. The data support the high selectivity of CFZ for covalent modification of its therapeutic targets, despite the presence of a reactive electrophile. The approach we describe offers a generalizable method to evaluate the safety profile of covalent protein-modifying

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A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma

Cited by 393 publications

References 32 publications

Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy

Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy

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

Specificity of Protein Covalent Modification by the Electrophilic Proteasome Inhibitor Carfilzomib in Human Cells

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