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Kumar S.K.,Mayo Medical School | Bensinger W.I.,Fred Hutchinson Cancer Research Center | Zimmerman T.M.,University of Chicago | Reeder C.B.,Mayo Medical School | And 8 more authors.
Blood | Year: 2014

Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m2. Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820. © 2014 by The American Society of Hematology.

Berenson J.R.,Institute for Myeloma and Bone Cancer Research
Seminars in Oncology | Year: 2010

Advanced multiple myeloma is typically accompanied by osteolytic bone lesions resulting from heightened osteolytic activity of osteoclasts and decreased rates of osteogenesis by osteoblasts. Therefore, patients with myeloma bone disease are at increased risk for skeletal-related events (SREs) such as pathologic fracture, the need for radiotherapy or surgery to bone, spinal cord compression, and hypercalcemia of malignancy. Each of these can reduce patients' functional independence, quality of life, and survival. Radiotherapy and surgery are often used to palliate bone pain and to stabilize, repair, or prevent bone fractures. Bisphosphonates (BPs) may reduce the risk of SREs. In particular, clodronate, pamidronate, and zoledronic acid (ZOL) have demonstrated efficacy for delaying the onset of potentially life-threatening SREs. Overall, BPs have a well established tolerability profile. The introduction of BPs for multiple myeloma was practice-changing, and patients now experience far fewer serious fractures and hypercalcemia of malignancy. Ongoing studies will help further refine and optimize the timing and duration of BP therapy in patients with myeloma bone disease. © 2010 Elsevier Inc.

Berenson J.R.,Institute for Myeloma and Bone Cancer Research
Current Opinion in Supportive and Palliative Care | Year: 2011

Purpose of review The use of bisphosphonates has focused on their antibone resorptive effects but recent studies have shown that these drugs also possess a variety of antitumor effects in the laboratory that are now being observed in clinical trials. Recent findings It is becoming increasingly clear that bisphosphonates - especially the more potent nitrogen-containing bisphosphonates (N-BPs) and, in particular, zoledronic acid - show a multitude of antitumor effects in the laboratory. These drugs have been shown to induce apoptosis in a variety of cancer cells and enhance the antitumor effects of a variety of treatments including steroids, chemotherapeutic agents and hormonal therapies as well as many classes of new anticancer drugs. In addition, the agents inhibit vasculogenesis and angiogenesis. The N-BPs also show immunostimulatory effects that have been shown to have potent antitumor effects. They also block tumor cell adhesion making tumor cells more susceptible to the cytotoxic effects of chemotherapy as well as migration and invasion of tumor cells. Recent clinical trials have demonstrated their ability to not only reduce skeletal morbidity but also delay time to progression of the malignant disease in some but not all studies and improve overall survival in other trials. Summary Emerging laboratory and clinical data now support the important antitumor effects of N-BPs in both solid and hematological cancers. It will be important to determine whether the combination of these drugs with other agents with not only chemotherapy but newer agents may enhance these effects. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Berenson J.R.,Institute for Myeloma and Bone Cancer Research
Clinical Advances in Hematology and Oncology | Year: 2015

Multiple myeloma (MM) is the most common primary malignancy of the bone marrow.1 Although the recent approvals of immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) have resulted in a significant improvement in the overall survival (OS) of MM patients, the disease remains incurable and patients eventually relapse.2,3 Long-term maintenance therapy has been suggested as a viable approach to delaying relapse, resulting in longer progression-free survival (PFS) and, more importantly, OS.4 Ideally, maintenance therapy should sustain treatment responses, have good safety and tolerability profiles in long-term use, and be convenient for patients. Importantly, it should not reduce the efficacy or preclude the use of other drugs in future treatments. © 2015 Clinical Advances in Hematology & Oncology All right received.

Migliorati C.A.,University of Tennessee Health Science Center | Epstein J.B.,University of Illinois at Chicago | Abt E.,University of Illinois at Chicago | Berenson J.R.,Institute for Myeloma and Bone Cancer Research
Nature Reviews Endocrinology | Year: 2011

Bisphosphonate-associated osteonecrosis (BON) is a complication that almost exclusively affects the jaw bones. The clinical presentation of BON often mimics that of other conditions, such as routine dental disease, osteoradionecrosis or avascular necrosis; therefore, diagnosis can be difficult. As this complication has only been recognized within the past 10 years, management strategies for patients with BON are poorly defined. Physicians must choose between continuing the bisphosphonate therapy (to reduce the risk of skeletal complications in patients with metastatic bone disease or osteoporosis) and discontinuing the drug (to possibly improve the odds for tissue healing). A conservative or aggressive management strategy must be chosen with limited evidence that the outcome of either strategy will be successful. BON is most prevalent in patients with cancer using intravenous nitrogen-containing bisphosphonates. The pathobiology of this complication is not fully understood and the diagnosis relies on the clinical manifestations of the condition. Future research should focus on the pathobiological mechanisms involved in the development of BON, which could help explain why this complication affects only a small number of those who use bisphosphonates, and also suggest strategies for prevention and management. © 2010 Macmillan Publishers Limited. All rights reserved.

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