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Berenson J.R.,Oncotherapeutics | Berenson J.R.,Berenson | Berenson J.R.,Institute for Myeloma and Bone Cancer Research | Yellin O.,Oncotherapeutics | And 10 more authors.
Leukemia | Year: 2012

Our previous studies have shown that lowering the dose of pegylated liposomal doxorubicin (PLD) and bortezomib in combination with intravenous dexamethasone on a longer 4-week cycle maintained efficacy and improved tolerability in both previously untreated and relapsed/refractory (R/R) multiple myeloma (MM) patients. Lenalidomide has shown efficacy in combination with bortezomib and dexamethasone but this combination has been poorly tolerated. We conducted this phase 2 study (clinicaltrials.gov identifier: NCT01160484) to evaluate whether a longer 4-week schedule using modified doses and schedules of IV dexamethasone (40 mg), bortezomib (1.0 mg/m 2) and PLD (4.0 mg/m 2) administered on days 1, 4, 8, and 11 with lenalidomide 10 mg daily on days 1-14 (DVD-R) would be effective and tolerated for patients with R/R MM. A total of 40 heavily pretreated patients were enrolled and 84.6% showed clinical benefit (complete response, 20.5%; very good partial response, 10.3%; partial response, 17.9%; minimal response, 35.9%) to the combination regimen. An additional 10.3% showed stable disease and 5.1% progressed while on study. The regimen was well tolerated, with a low incidence of adverse events such as fatigue (40%), thrombocytopenia (35%), neutropenia (35%), anemia (30%), peripheral neuropathy (25%) and pneumonia (15%). Thus, the DVD-R regimen is well tolerated and produces high response rates for patients with R/R MM. © 2012 Macmillan Publishers Limited.


Subramanian A.,Carnegie Mellon University | Shackney S.,Oncotherapeutics | Schwartz R.,Carnegie Mellon University
IEEE/ACM Transactions on Computational Biology and Bioinformatics | Year: 2013

Computational cancer phylogenetics seeks to enumerate the temporal sequences of aberrations in tumor evolution, thereby delineating the evolution of possible tumor progression pathways, molecular subtypes, and mechanisms of action. We previously developed a pipeline for constructing phylogenies describing evolution between major recurring cell types computationally inferred from whole-genome tumor profiles. The accuracy and detail of the phylogenies, however, depend on the identification of accurate, high-resolution molecular markers of progression, i.e., reproducible regions of aberration that robustly differentiate different subtypes and stages of progression. Here, we present a novel hidden Markov model (HMM) scheme for the problem of inferring such phylogenetically significant markers through joint segmentation and calling of multisample tumor data. Our method classifies sets of genome-wide DNA copy number measurements into a partitioning of samples into normal (diploid) or amplified at each probe. It differs from other similar HMM methods in its design specifically for the needs of tumor phylogenetics, by seeking to identify robust markers of progression conserved across a set of copy number profiles. We show an analysis of our method in comparison to other methods on both synthetic and real tumor data, which confirms its effectiveness for tumor phylogeny inference and suggests avenues for future advances. © 2013 IEEE.


Berenson J.R.,Oncotherapeutics | Berenson J.R.,Berenson | Berenson J.R.,Institute for Myeloma and Bone Cancer Research | Hilger J.D.,Oncotherapeutics | And 12 more authors.
Annals of Hematology | Year: 2014

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination. © 2013 Springer-Verlag Berlin Heidelberg.


Waterman G.N.,Berenson | Yellin O.,Oncotherapeutics | Swift R.A.,Berenson | Mapes R.,Berenson | And 3 more authors.
Annals of Hematology | Year: 2011

Preclinical and clinical studies have demonstrated synergy between bortezomib and pegylated liposomal doxorubicin (PLD) for relapsed/refractory (R/R) multiple myeloma (MM) patients compared to bortezomib as a single agent. This retrospective study evaluated the efficacy and safety of a more frequent low-dose schedule of PLD, bortezomib, and intravenous dexamethasone (DVD) for patients with R/R MM, many of whom were previously treated with bortezomib. Twenty-eight patients with R/R MM were treated, and 23 (83%) had been previously treated with ≤1 bortezomib-containing regimen. Treatment consisted of dexamethasone 40 mg intravenously, bortezomib 1.0 mg/m2, and PLD 5.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle for a maximum of eight cycles. Patients ranged from 33 to 81 years of age (median, 67) and had received 1-14 prior therapies (median, 5). At baseline, ten, nine, and nine patients were in stages I, II, and III, respectively, as defined by the International Staging System, and eight (29%) patients had elevated serum creatinine levels. The overall response rate was 61%, which included one (4%) complete response, three (11%) very good partial responses, eight (29%) partial responses, and five (18%) minimal responses. Of the 23 patients who had previously received bortezomib, 12 (52%) responded. The regimen was well tolerated with only six patients (21%) who showed worsening of their baseline peripheral neuropathy (PN). One patient discontinued this regimen due to an adverse event (grade II PN). DVD appears to represent a well-tolerated regimen with a high response rate for the treatment of R/R MM patients. © 2010 Springer-Verlag.


Berenson J.R.,Institute for Myeloma and Bone Cancer Research | Berenson J.R.,Berenson | Hilger J.D.,Oncotherapeutics | Yellin O.,Oncotherapeutics | And 10 more authors.
Leukemia | Year: 2014

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 progression-free survival, time to progression and OS were 8.3, 9.9 and 15.8 months, respectively. Hematologic adverse events (AEs; ≥grade 3) included lymphopenia (35.1%), thrombocytopenia (24.3%), anemia (10.8%) and neutropenia (10.8%). Nonhematologic AEs (≥grade 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. © 2014 Macmillan Publishers Limited.


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.


PubMed | Oncotherapeutics, Institute for Myeloma & Bone Cancer Research and Berenson
Type: | Journal: Haematologica | Year: 2016

B-cell maturation antigen is expressed on plasma cells. In this study, we have identified serum B-call maturation antigen as a novel biomarker that can monitor and predict outcomes for multiple myeloma patients. Compared to healthy donors, patients with multiple myeloma showed elevated serum B-cell maturation antigen levels (P < 0.0001). Serum B-cell maturation antigen levels correlated with the proportion of plasma cells in bone marrow biopsies (Spearman rho = 0.710; P < 0.001), clinical status (P values: 0.0374 complete response vs partial response; < 0.0001 complete response vs. progressive disease), and tracked with changes in M protein levels. Among patients with non secretory disease, serum B-cell maturation antigen levels correlated with bone marrow plasma cell levels and PET scan findings. Kaplan-Meier analysis demonstrated that serum B-cell maturation antigen levels above the median levels were predictive of a shorter progression-free survival (PFS; P = 0.0006) and overall survival (OS; P = 0.0108) among multiple myeloma patients (n = 243). Specifically, patients with serum B-cell maturation antigen levels above the median level at the time of starting frontline (P = 0.0043) or a new salvage therapy (P = 0.0044) were found to have shorter progression-free survival. Importantly, serum B-cell maturation antigen levels did not show any dependence on renal function and maintained independent significance when tested against other known prognostic markers for multiple myeloma such as age, 2M, hemoglobin, and bone disease. These data identify serum B-cell maturation antigen as a new biomarker to manage multiple myeloma patients.


PubMed | Berenson, Wheaton Francis Healthcare, Beaver Medical Group, Oncotherapeutics and 2 more.
Type: Journal Article | Journal: Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer | Year: 2016

Previous studies have shown that low serum vitamin D levels have been associated with many skeletal and non-skeletal disorders. We studied the relationship between 25-hydroxyvitamin D (25D) levels and motor and sensory peripheral neuropathy (PN) among multiple myeloma (MM) patients who have been treated with bortezomib and/or thalidomide.We performed a study of 111 MM patients who had received at least one of these two agents for at least 12weeks by correlating physical exam/neurologic assessment findings with patient self-assessment responses.The median age of study patients was 66years (range 42-89years) and 54% were males. 25D levels were determined, and complete history and physical and neurologic examinations were performed at the same study visit. In addition, study subjects completed questionnaires regarding symptoms related to motor and sensory PN. Overall, patients had a median serum 25D level of only 32ng/ml; 42% of patients were considered either 25D-deficient (<20.0 ng/mL; 16% of patients) or 25D-insufficient (20.0-29.9ng/mL; 26%). Notably, we found that 25D-deficient MM patients were more likely to have severe PN (>grade 2) of both motor (p=0.0415) and sensory (p=0.0086) types although the overall incidence of PN was not higher in this patient population.These results show that the severity of peripheral neuropathy is associated with lower vitamin D levels and provides the rationale for monitoring vitamin D for myeloma patients especially those receiving drugs associated with the development of peripheral neuropathy.


PubMed | Oncotherapeutics
Type: Clinical Trial, Phase III | Journal: Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer | Year: 2015

Fatigue is a common problem among multiple myeloma (MM) patients. Armodafinil is a drug known to promote wakefulness, which is related to modafinil, a compound that improves fatigue in some cancer patients treated with chemotherapeutic agents. We investigated whether armodafinil could reduce cancer-related fatigue in MM patients.This double-blind, placebo-controlled phase 3 trial evaluated the efficacy of armodafinil in MM patients with evidence of moderate fatigue. Patients were randomized to one of two arms: treatment-only, with armodafinil given at 150 mg/daily for 56 days, or placebo-first, with placebo given on days 1-28, followed by armodafinil administered at 150 mg daily on days 29-56. Fatigue was measured on days 1 (pre-dose: baseline), 15, 28, 43, and 56 using seven separate assessments, including four patient-reported outcomes of fatigue and related quality of life measures, as well as three objective measures of cognitive function.Overall toxicities were similar between treatment groups. No significant differences were observed between the placebo-first and the treatment-only arms after 28 days. Treatment with armodafinil for 28 additional days did not produce responses. Both placebo-first and treatment-only patients showed similar significant improvements in three patient-reported measures and one objective task at day 28 compared to baseline. Placebo-first patients improved on eight additional measures (one patient-reported measure, six subscales, and one objective task), suggesting a strong placebo effect in this patient population.Evaluation and treatment of cancer-related fatigue continues to be challenging; a clear definition of this symptom and better assessment tools are needed.


PubMed | Cancer Research and Biostatistics, Berenson, University of Southern California, University of California at Los Angeles and 3 more.
Type: Journal Article | Journal: European journal of haematology | Year: 2016

Immunosuppressed patients are known to have an increased incidence of skin cancer. Patients with multiple myeloma (MM) show impaired immune function. In the past, because of poor survival, the incidence of specific secondary primary malignancies such as skin cancer among these patients was difficult to establish. With more effective MM therapies that have emerged in recent years, these patients are living markedly longer, and therefore, it becomes of increasing importance to determine whether their risk of developing other medical problems such as skin cancer is increased. We performed a retrospective cohort study of 205 myeloma patients and 193 age-, race-, and gender-matched control subjects to assess the incidence of skin cancers among patients with MM and determine the specific types of and risk factors for skin cancer. We found that there is an increased occurrence of skin cancer among patients with MM compared to control subjects (26.8% vs. 16.1% in controls; P = 0.009). Among specific types of skin cancer, the proportion of patients with squamous cell carcinoma (SCC) was higher than controls (P = 0.016). In addition to MM diagnosis, older age and Caucasian ethnicity were predictors of skin cancer of any type. Furthermore, older age was also a predictor of SCC.

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