Phase II study of carfilzomib in patients with relapsed/refractory multiple myeloma and renal insufficiency.

Badros, A.; Vij, Ravi; Martin, T.; Zonder, Jeff; Wong, Alvin; Woo, Tina M.; Boussina, K.; Wang, Z.; Niesvizky, Rubén

doi:10.1200/jco.2010.28.15_suppl.8128

Cited by 17 publications

(17 citation statements)

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“…Preliminary findings suggest no impact of renal impairment on safety profile or pharmacokinetics, with generally mild and manageable toxicity and encouraging activity [37% ! MR (114)]. The final results from this trial will be important to further define the importance of incorporating a proteasome inhibitor early in the treatment of patients with multiple myeloma and renal dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Novel Therapeutic Agents for the Management of Patients with Multiple Myeloma and Renal Impairment

Chanan‐Khan

Miguel

Jagannath

et al. 2012

Clinical Cancer Research

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Renal impairment is a major complication of multiple myeloma. Patients presenting with severe renal impairment represent a greater therapeutic challenge and generally have poorer outcome. However, once patients with renal impairment achieve remission, their outcomes are comparable with those of patients without renal impairment. Therapies that offer substantial activity in this setting are needed. Bortezomib, thalidomide, and lenalidomide have substantially improved the survival of patients with multiple myeloma. Here we review the pharmacokinetics, activity, and safety of these agents in patients with renal impairment. Bortezomib can be administered at the full approved dose and schedule in renally impaired patients; similarly, no dose reductions are required with thalidomide. The pharmacokinetics of lenalidomide is affected by its renal route of excretion, and dose adjustments are recommended for moderate/severe impairment. Substantial evidence has emerged showing that these novel agents improve outcomes of patients with renal impairment, including impairment reversal. Bortezomib, thalidomide, and lenalidomide (at the recommended doses) are active options for patients with mild to moderate impairment, although limited data are available for thalidomide. Information on lenalidomide-based combinations is still emerging, but the available data indicate considerable activity. Substantial evidence indicates that bortezomib-high-dose dexamethasone with or without a third drug (e.g., cyclophosphamide, thalidomide, or doxorubicin) is an appropriate option for patients with any degree of renal impairment.

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Section: Discussionmentioning

confidence: 99%

Novel Therapeutic Agents for the Management of Patients with Multiple Myeloma and Renal Impairment

Chanan‐Khan

Miguel

Jagannath

et al. 2012

Clinical Cancer Research

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“…In the early phase studies of the drugs, there were a few episodes of deterioration of renal function that was attributed to tumor lysis or other 'inflammatory' reactions. Current data suggest that carfilzomib is not metabolized by the kidneys, although inactive metabolites of the drug are found in urine [76][77][78][79]. However, with the use of the drug it has been shown that carfilzomib may be safe and effective in patients with RI.…”

Section: Other Novel Agents 5141 Carfilzomibmentioning

confidence: 89%

Current treatments for renal failure due to multiple myeloma

Kastritis

Terpos

Dimopoulos

2013

Expert Opinion on Pharmacotherapy

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Bortezomib/dexamethasone-based regimens are the preferred regimens for most patients with multiple myeloma (MM) who present with RI, especially for newly diagnosed patients; however, other novel agents (thalidomide, lenalidomide) in combination with dexamethasone may also improve RI in several patients. Further investigation is needed for the clarification of the role of plasma exchange or extended high cutoff dialysis. Carfilzomib, which was recently approved, may also be a treatment choice for selected patients with relapsed MM and RI.

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“…Toxicities were manageable and independent of renal status; dose adjustment was not necessary. 72,73 In the PX-171-010 trial, the long-term safety of CFZ treatment was assessed. No cumulative toxicities, including late development of peripheral neuropathy or significant emerging renal dysfunction, were observed.…”

Section: Cfz Phase 2 Clinical Trialsmentioning

confidence: 99%

Carfilzomib

Kortuem

Stewart

2013

Blood

184

141

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IntroductionProteasome inhibition is highly effective treatment for multiple myeloma (MM), Waldenström macroglobulinemia, low-grade nonHodgkin lymphomas, and primary amyloidosis. 1 Almost 10 years ago, the US Food and Drug Administration (FDA) approved the dipeptidyl boronic acid derivative proteasome inhibitor bortezomib (BTZ) for the treatment of refractory MM and subsequently frontline therapy for MM, thus opening the door to a new era of improved MM therapy. Indeed, disease-free and overall survival for most MM patients has been significantly extended. Nevertheless primary or secondary BTZ resistance 2 is common, and treatment is often limited by BTZ-induced, dose-limiting side effects, mostly consequent to peripheral neuropathy. 3 Although less frequent BTZ administration at lower doses and using subcutaneous delivery 4,5 may contribute to a lowered BTZ neuropathy incidence and severity without seemingly compromising efficacy, new proteasome inhibitors-the "second generation"-have now been developed and are aimed at being potentially more efficacious and less toxic. The FDA recently granted accelerated approval for carfilzomib (CFZ) injection for the treatment of patients with MM who have received at least 2 prior therapies, including BTZ and an immunomodulatory agent, and who have demonstrated disease progression on or within 60 days of the completion of last therapy. This spotlight review focuses on the data leading to drug approval and provides helpful management tips for treating physicians. Ubiquitin-proteasome pathway inhibition in MM treatmentProteasomes are present in all eukaryotic cells. 6,7 They degrade proteins 8,9 and influence a multitude of cellular processes, [10][11][12][13][14][15][16] including proliferation and DNA repair. [17][18][19] Proteasome inhibition leads to an unfolded protein stress response by accumulation of misfolded proteins in the cell, 20-22 inhibits NF-B, 23 and thus induces cell-cycle arrest 24,25 and apoptosis. [26][27][28] The (malignant) plasma cell in particular is susceptible to proteasome inhibition, even to small changes, 29 because of its inherent function in Ab production. 22,[30][31][32] The proteasomeThe constitutive 26S proteasome consists of protein-recognizing 19S regulatory particles and a 20S proteolytic core 33 that carries 3 protein-specific 29 catalytic sites: the chymotrypsin, trypsin, and caspase-like sites. 34,35 Blocking the chymotrypsin-like site is most effective in cellular growth inhibition in vitro, but coinhibition of other proteasome subunits further increases overall growth retardation. [35][36][37][38] Unique immunoproteasomes exist in cells of immune or hematopoietic origin, where the catalytic sites differ from the constitutive proteasomes. 36 These play an important role in generating antigens for MHC class I presentation. 39 Both constitutive and immunoproteasomes are expressed in MM cells and are targeted by the available inhibitors BTZ and CFZ. It has not been fully elucidated whether the anticancer effects depend on inhibition o...

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Phase II study of carfilzomib in patients with relapsed/refractory multiple myeloma and renal insufficiency.

Cited by 17 publications

References 0 publications

Novel Therapeutic Agents for the Management of Patients with Multiple Myeloma and Renal Impairment

Novel Therapeutic Agents for the Management of Patients with Multiple Myeloma and Renal Impairment

Current treatments for renal failure due to multiple myeloma

Carfilzomib

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