Institute for Myeloma and Bone Cancer Research

West Hollywood, CA, United States

Institute for Myeloma and Bone Cancer Research

West Hollywood, CA, United States
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Terpos E.,National and Kapodistrian University of Athens | Berenson J.,Institute for Myeloma and Bone Cancer Research | Cook R.J.,University of Waterloo | Lipton A.,Pennsylvania State University | Coleman R.E.,University of Sheffield
Leukemia | Year: 2010

Skeletal-related events (SREs) are common in patients with osteolytic lesions from multiple myeloma (MM), and result in substantial morbidity. We report herein a comprehensive, retrospective, multivariate analysis of prognostic factors for survival and first on-study SRE in MM patients using data from the phase III, randomized study comparing zoledronic acid with pamidronate in MM or breast cancer. Cox regression analyses were used to assess 22 variables for prognostic significance (defined as associations with P<0.05) in patients with bone metabolism marker assessments and complete baseline variable data. Of 510 evaluable MM patients, 282 had complete covariate information and were included in models. Reduced Cox multivariate models identified five significant prognostic factors for first SRE (weight, race, high N-terminal cross-linked telopeptide of type I collagen (NTX), high pain score, and need for narcotic analgesics) and seven for survival (age, SRE history, myeloma subtype, anemia, high lactate dehydrogenase, high NTX, and low albumin levels). High NTX was the only variable associated with elevated risks of both first SRE and death (P ≤ 0.02 for each). These analyses identified prognostic factors for SREs and survival in patients with MM. Taken together with current staging systems, these factors could further facilitate decision making for optimal treatment of myeloma bone disease, although further prospective assessments are needed. © 2010 Macmillan Publishers Limited All rights reserved.

Berenson J.,Institute for Myeloma and Bone Cancer Research | Pflugmacher R.,Universitatskinikum Bonn | Jarzem P.,McGill University | Zonder J.,Barbara Ann Karmanos Cancer Institute | And 5 more authors.
The Lancet Oncology | Year: 2011

Background: Non-randomised trials have reported benefits of kyphoplasty in patients with cancer and vertebral compression fractures (VCFs). We aimed to assess the efficacy and safety of balloon kyphoplasty compared with non-surgical management for patients with cancer who have painful VCFs. Methods: The Cancer Patient Fracture Evaluation (CAFE) study was a randomised controlled trial at 22 sites in Europe, the USA, Canada, and Australia. We enrolled patients aged at least 21 years who had cancer and one to three painful VCFs. Patients were randomly assigned by a computer-generated minimisation randomisation algorithm to kyphoplasty or non-surgical management (control group). Investigators and patients were not masked to treatment allocation. The primary endpoint was back-specific functional status measured by the Roland-Morris disability questionnaire (RDQ) score at 1 month. Outcomes at 1 month were analysed by modified intention to treat, including all patients with data available at baseline and at 1 month follow-up. Patients in the control group were allowed to crossover to receive kyphoplasty after 1 month. This study is registered with, NCT00211237. Findings: Between May 16, 2005, and March 11, 2008, 134 patients were enrolled and randomly assigned to kyphoplasty (n=70) or non-surgical management (n=64). 65 patients in the kyphoplasty group and 52 in the control group had data available at 1 month. The mean RDQ score in the kyphoplasty group changed from 17·6 at baseline to 9·1 at 1 month (mean change -8·3 points, 95% CI -6·4 to -10·2; p<0·0001). The mean score in the control group changed from 18·2 to 18·0 (mean change 0·1 points; 95% CI -0·8 to 1·0; p=0·83). At 1 month, the kyphoplasty treatment effect for RDQ was -8·4 points (95% CI -7·6 to -9·2; p<0·0001). The most common adverse events within the first month were back pain (four of 70 in the kyphoplasty group and five of 64 in the control group) and symptomatic vertebral fracture (two and three, respectively). One patient in the kyphoplasty group had an intraoperative non-Q-wave myocardial infarction, which resolved and was attributed to anaesthesia. Another patient in this group had a new VCF, which was thought to be device related. Interpretation: For painful VCFs in patients with cancer, kyphoplasty is an effective and safe treatment that rapidly reduces pain and improves function. Funding: Medtronic Spine LLC. © 2011 Elsevier Ltd.

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 as #NCT00963820. © 2014 by The American Society of Hematology.

Andreu-Vieyra C.,Oncotherapeutics | Berenson J.R.,Oncotherapeutics | Berenson J.R.,Institute for Myeloma and Bone Cancer Research | Berenson J.R.,Berenson
Expert Opinion on Biological Therapy | Year: 2014

Introduction: Advances in drug therapy for multiple myeloma (MM) during the previous decade have improved survival outcomes; however, the disease remains incurable as patients eventually relapse or become refractory to all available therapies. Therefore, there is a clear need for more effective and well-tolerated treatments. Areas covered: We review preclinical and clinical data regarding the use of carfilzomib, a proteasome inhibitor that is structurally and mechanistically distinct from bortezomib, for the treatment of MM patients. Carfilzomib pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are summarized, based on Phase I/II trial data. Expert opinion: Carfilzomib represents a significant advance in the management of relapsed and/or refractory MM patients, including those intolerant or resistant to bortezomib. High response rates have been demonstrated with carfilzomib as a single agent or in combination with alkylating agents, immunomodulators and corticosteroids, even among patients who have failed multiple prior therapies. Carfilzomib also has significant potential in the frontline setting, with encouraging response and survival rates observed for combination regimens. Further evaluation of carfilzomib-containing regimens is ongoing in Phase III trials and investigator-sponsored studies, which include combinations with novel investigational agents. These findings will shape the future role of carfilzomib for MM patients across multiple settings. © 2014 Informa UK, Ltd.

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.

Eshaghian S.,Institute for Myeloma and Bone Cancer Research | Berenson J.R.,Institute for Myeloma and Bone Cancer Research
Current Opinion in Supportive and Palliative Care | Year: 2012

Purpose of review Nearly all patients with multiple myeloma will eventually relapse; and, thus, it is critical to identify new treatments that increase therapeutic options for these patients. This review highlights the newest approaches with already approved drugs for treating this common B-cell malignancy. Recent findings Most patients with multiple myeloma in both the frontline and relapsed/refractory settings are now treated with a combination of dexamethasone with the proteasome inhibitor bortezomib and/or an immunomodulatory agent thalidomide or lenalidomide. However, alkylating agents including melphalan, cyclophosphamide and most recently bendamustine as well as anthracyclines, especially the pegylated liposomal doxorubicin, have shown high response rates and prolonged remissions when combined with these agents. There are emerging data showing the importance of maintenance therapy especially with lenalidomide. Because of the marked improvement in survival of multiple myeloma during the past decade, there has been a renewed emphasis on developing therapies that are not only effective but also well tolerated. Alternative dosing, scheduling and routes of administration of already approved drugs have proven effective in accomplishing these goals. Summary The availability of drugs with different mechanisms that produce anti-multiple myeloma effects and also show synergistic effects has paved the way for more effective and safer combinations and led to multiple myeloma patients living longer with improved quality of lives. © 2012 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.

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.

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.

Meads M.B.,H. Lee Moffitt Cancer Center and Research Institute | Li Z.-W.,Institute for Myeloma and Bone Cancer Research | Dalton W.S.,H. Lee Moffitt Cancer Center and Research Institute
Journal of Immunology | Year: 2010

GM-CSF, IL-3, and IL-5 are proinflammatory cytokines that control the production and function of myeloid and lymphoid cells. Their receptors are composed of a ligand-specific α subunit and a shared common signal-transducing β subunit (β common receptor or GM-CSFR β [βc]). The pleiotropic nature of biologic outcomes mediated by βc and the presence of large, uncharacterized regions of its cytoplasmic domain suggest that much remains to be learned about its downstream signaling pathways. Although some previous work has attempted to link βc with NF-κB activation, a definitive mechanism that mediates this pathway has not been described and, to date, it has not been clear whether the receptor can directly activate NF-κB. We demonstrate that NF-κB activation by βc is dependent on TNFR-associated factor 6 (TRAF6) and that association of TRAF6 with βc requires a consensus-binding motif found in other molecules known to interact with TRAF6. Furthermore, point mutation of this motif abrogated the ability of βc to mediate NF-κB activation and reduced the viability of an IL-3-dependent hematopoietic cell line. Because this receptor plays a key role in hematopoiesis and the βc cytoplasmic domain identified in this work mediates hematopoietic cell viability, this new pathway is likely to contribute to immune cell biology. This work is significant because it is the first description of a TRAF6-dependent signaling pathway associated with a type I cytokine receptor. It also suggests that TRAF6, a mediator of TNFR and TLR signaling, may be a common signaling intermediate in diverse cytokine receptor systems. Copyright © 2010 by The American Association of Immunologists, Inc.

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