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Siegel D.,John Theurer Cancer Center | Martin T.,University of California at San Francisco | Nooka A.,Emory University | Harvey R.D.,Emory University | And 7 more authors.
Haematologica | Year: 2013

Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX- 171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities. © 2013 Ferrata Storti Foundation. Source

Goy A.,John Theurer Cancer Center
Expert Opinion on Orphan Drugs | Year: 2013

Introduction: Mantle cell lymphoma (MCL) responds well to initial therapy but most patients relapse and then respond only briefly to salvage therapy. Nevertheless, the median overall survival of MCL patients has dramatically improved from 30 months in the late 1970s to > 5 years at present. This is largely explained by the use of dose-intensive strategies and/or high-dose therapy upfront, and the development of novel agents for a disease that commonly shows chemoresistance in the relapse/refractory setting. Areas covered: A comprehensive review of published materials on the biology and management of MCL from the past 10 years were the focus for this review. Expert opinion: MCL outcome has definitely improved and achievement of an early deep response (complete remission [CR] or molecular CR) translates into superior survival. High-dose cytosine arabinoside -containing regimens should be used in the frontline setting in younger patients. Relapse/refractory patients still do poorly and an effort for clinical trials in that setting is essential. Three novel therapies have now been approved in MCL: two in the United States-bortezomib (proteasome inhibitor) in 2006 and lenalidomide (IMiDs) in 2013-and one in the Europe-temsirolimus (mammalian target of rapamycin inhibitor) in 2007. A number of new compounds have shown very promising activity in MCL as well: particularly drugs targeting the B-cell receptor pathway-phosphatidylinositol 3-kinase inhibitors (idelalisib, IPI-145) and Bruton's tyrosine kinase inhibitors (ibrutinib) or pan Bcl-2 inhibitors (ABT-199). These molecules provide an opportunity to build up on the regimens used in MCL either in combination or as maintenance and will would without any doubt will revolutionize the landscape in MCL. © 2013 Informa UK, Ltd. Source

Dimopoulos M.A.,National and Kapodistrian University of Athens | Sonneveld P.,Erasmus University Rotterdam | Siegel D.,John Theurer Cancer Center | Palumbo A.,University of Turin | San-Miguel J.,University of Navarra
Annals of Oncology | Year: 2015

While survival times have increased over the last decade, most patients with multiple myeloma (MM) eventually relapse and become refractory to therapy. The treatment of patients with relapsed and/or refractory MM is frequently further complicated by the presence of pre-existing comorbidities that arise from an advanced disease state and of toxicities stemming from prior antimyeloma treatment. Carfilzomib and pomalidomide have recently been approved for the treatment of patients with relapsed and refractory MM. While these agents represent important additions to the available treatment options, the identification of patients who may best benefit from the use of each of therapy is still being investigated. A number of patient-related and disease-related factors may impact treatment efficacy and/or tolerability, and the clinical presentation and medical history of each patient must be carefully considered to optimize treatment. Here, we review results from carfilzomib and pomalidomide clinical trials in patients with relapsed and/or refractory MM who also have baseline comorbidities or treatment-induced or disease-induced complications (including the presence of renal impairment, cardiac risk factors, peripheral neuropathy, or high-risk chromosomal abnormalities) to evaluate the safety and efficacy of the two agents in these difficult-to-treat patients and to provide treatment recommendations specific to each scenario. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

Flaherty A.M.,John Theurer Cancer Center
Oncology nursing forum | Year: 2015

A 65-year-old Polish immigrant named T. J. was diagnosed with metastatic colon cancer in January 2012 when he presented with obstructing sigmoid colon cancer and liver metastases. A diverting colostomy as well as biopsy of his liver metastases was performed and chemotherapy with FOLFOX (5-fluorouracil [5-FU], leucovorin, oxaliplatin) and bevacizumab was initiated. After three months, he transitioned to maintenance therapy with infusional 5-FU and bevacizumab until he progressed in August 2012. Oxaliplatin was reintroduced and he responded until he developed progressive neuropathy in November and his therapy was changed to FOLFIRI (5-FU, leucovorin, irinotecan) and bevacizumab. T. J. developed liver progression after three months and, because he was Kras wild type, irinotecan and panitumumab were initiated. Liver-directed therapy also was pursued and he underwent radioembolization with yittrium-90 followed by chemoembolization with irinotecan-eluded beads. At the time of these procedures, T. J.'s portal and hepatic venous systems were patent (i.e., no thrombosis or obstruction causing portal hypertension). Source

Jakubowiak A.J.,University of Chicago | Jakubowiak A.J.,University of Michigan | Dytfeld D.,University of Michigan | Dytfeld D.,Poznan University of Medical Sciences | And 17 more authors.
Blood | Year: 2012

This phase 1/2 study in patients with newly diagnosed multiple myeloma (N = 53) assessed CRd - carfilzomib (20, 27, or 36 mg/m2, days 1, 2, 8, 9, 15, 16 and 1, 2, 15, 16 after cycle 8), lenalidomide (25 mg/d, days 1-21), and weekly dexamethasone (40/20 mg cycles 1-4/5+) - in 28-day cycles. After cycle 4, transplantation-eligible candidates underwent stem cell collection (SCC) then continued CRd with the option of transplantation. The maximum planned dose level (carfilzomib 36 mg/m2) was expanded in phase 2 (n = 36). Thirty-five patients underwent SCC, 7 proceeded to transplantation, and the remainder resumed CRd. Grade 3/4 toxicities included hypophosphatemia (25%), hyperglycemia (23%), anemia (21%), thrombocytopenia (17%), and neutropenia (17%); peripheral neuropathy was limited to grade 1/2 (23%). Most patients did not require dose modifications. After a median of 12 cycles (range, 1-25), 62% (N = 53) achieved at least near-complete response (CR) and 42% stringent CR. Responses were rapid and improved during treatment. In 36 patients completing 8 or more cycles, 78% reached at least near CR and 61% stringent CR. With median follow-up of 13 months (range, 4-25 months), 24-month progression-free survival estimate was 92%. CRd was well tolerated with exceptional response rates. This study is registered at http://www.clinicaltrials.gov as NCT01029054. © 2012 by The American Society of Hematology. Source

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