[Show abstract][Hide abstract] ABSTRACT: Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (20%) and absolute number (2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.Leukemia advance online publication, 4 January 2013; doi:10.1038/leu.2012.336.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2012; 27(4). DOI:10.1038/leu.2012.336 · 9.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Carfilzomib, an irreversible proteasome inhibitor, has a favorable safety profile and significant anti-tumor activity in patients with relapsed and refractory multiple myeloma (MM). Here we summarize the clinical pharmacokinetics (PK), metabolism, and drug-drug interaction (DDI) profile of carfilzomib. The PK of carfilzomib, infused over 2-10 min, was evaluated in patients with solid tumors or MM. Metabolites of carfilzomib were characterized in patient plasma and urine samples. In vitro drug metabolism and DDI studies were conducted in human liver microsomes and hepatocytes. A clinical DDI study was conducted in patients with solid tumors to evaluate the effect of carfilzomib on cytochrome (CYP)3A activity. Plasma concentrations of carfilzomib declined rapidly and in a biphasic manner following intravenous administration. The systemic half life was short and the systemic clearance rate was higher than hepatic blood flow. Carfilzomib was mainly cleared by extrahepatic metabolism via peptidase cleavage and epoxide hydrolysis. CYP-mediated metabolism played a minor role, suggesting that co-administration of CYP inhibitors or inducers is unlikely to change its PK profile. Carfilzomib showed direct and time-dependent inhibition of CYP3A in human liver microsome preparations and exposure to carfilzomib resulted in reductions in CYP3A and 1A2 gene expression in cultured human hepatocytes. However, administration of carfilzomib did not affect the PK of midazolam in patients with solid tumors, and there were no safety signals indicative of potential drug interactions. We conclude that the unique PK properties of carfilzomib limit clinically significant DDI.
Drug metabolism and disposition: the biological fate of chemicals 11/2012; 41(1). DOI:10.1124/dmd.112.047662 · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The introduction of bortezomib, a first-generation proteasome inhibitor, changed the standard-of-care for newly diagnosed and relapsed multiple myeloma patients. The next generation of proteasome inhibitors, such as carfilzomib, provides a novel pharmacokinetic and pharmacodynamic profile. In vitro data suggest a more specific and irreversible inhibition of the proteasome. Based on the clinical trials conducted to date, carfilzomib has activity in heavily pretreated as well as bortezomib-refractory/relapsed patients. The safety profile, specifically a lower incidence of peripheral neuropathy, efficacy in the high-risk setting, as defined cytogenetically, and the durability of responses indicate a great potential for carfilzomib as a promising therapy. Several trials are underway involving carfilzomib in the newly diagnosed setting and in combination with other active myeloma drugs such as immunomodulatory derivatives of thalidomide, alkylating agents and targeted therapies such as histone deacetylase inhibitors. The introduction of this agent is yet another step in improving the overall outcome of multiple myeloma patients.
[Show abstract][Hide abstract] ABSTRACT: Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years, and time from diagnosis to T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0–8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including partial response in 69 (32%). The median overall survival and event-free survival from T0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.Keywords: multiple myeloma; relapse; natural history; survival
[Show abstract][Hide abstract] ABSTRACT: Peripheral neuropathy is a common and severe dose-limiting side effect of the chemotherapy agent, bortezomib, in multiple myeloma patients. Treatment with narcotics, antidepressants, and anticonvulsants has limited response and potential significant side effects. Acupuncture has been reported to be effective in treating diabetic neuropathy and chemo-induced peripheral neuropathy. There has not been report on the effect of acupuncture in treating bortezomib-induced peripheral neuropathy specifically. Here, we report a successful case of using acupuncture to relieve bortezomib-induced peripheral neuropathy symptoms.
Pain Research and Treatment 03/2011; 2011(2090-1542):920807. DOI:10.1155/2011/920807
[Show abstract][Hide abstract] ABSTRACT: Multiple Myeloma is a molecularly heterogeneous disease with a high degree of genomic instability in which specific genetic changes can be linked to clinical presentation and prognosis. Despite recent improvements in event-free survival and overall survival with the use of high dose chemotherapy and stem cell support as well as the development of novel agents such as thalidomide, lenalidomide and Bortezomib, MM remains an incurable disease. The development of effective targeted therapies requires a detailed knowledge of various genetic and signaling pathways governing MM genesis. This review will focus on the current understanding of the molecular pathogenesis of MM and the intracellular signaling pathways and their regulations, with emphasis on the rationale for identifying therapeutic targets that can be applied in the clinic.
[Show abstract][Hide abstract] ABSTRACT: In a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, 14.6-24.7 months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4(+) T-cell counts and a lower percentage of FOXP3(+) T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. This study was registered at www.clinicaltrials.gov as NCT00499577.
[Show abstract][Hide abstract] ABSTRACT: This study aimed to determine the activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenström Macroglobulinemia (WM). Patients with no prior therapy and symptomatic disease were eligible. Patients received bortezomib IV weekly at 1.6 mg/m(2) on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m(2) weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response (MR). Twenty-six patients were treated. At least MR was observed in 23/26 patients (88%) (95% CI: 70-98%) with 1 complete response (4%), 1 near-complete response (4%), 15 partial remission (58%), and 6 MR (23%). Using IgM response evaluated by nephlometry, all 26 patients (100%) achieved at least MR or better. The median time to progression has not been reached, with an estimated 1-year event free rate of 79% (95% CI: 53, 91%). Common grade 3 and 4 therapy related adverse events included reversible neutropenia in 12%, anemia in 8%, and thrombocytopenia in 8%. No grade 3 or 4 neuropathy occurred. The combination of weekly bortezomib and rituximab exhibited significant activity and minimal neurological toxicity in patients with untreated WM.
American Journal of Hematology 09/2010; 85(9):670-4. DOI:10.1002/ajh.21788 · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tanespimycin (17-allylamino-17-demethoxygeldanamycin, 17-AAG) disrupts heat shock protein 90 (HSP90), a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival and drug resistance. In previous studies, tanespimycin monotherapy was well tolerated and active in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). Preclinical data have shown antitumour synergy between tanespimycin and bortezomib, with more pronounced intracellular accumulation of ubiquitinated proteins than either drug alone, an effect attributed to the synergistic suppression of chymotryptic activity in the 20S proteasome. HSP70 induction has been observed in all Phase 1 tanespimycin studies in which it has been measured, with several separate reports of HSP70 overexpression protecting against peripheral nerve injury. In this Phase 2, open-label multicentre study, we compared 1.3 mg/m2 bortezomib + three doses of tanespimycin: 50, 175 and 340 mg/m2 in heavily pretreated patients with relapsed and refractory MM and measured HSP70 expression and proteasome activity levels in plasma of treated patients. The study was closed prematurely for resource-based reasons, precluding dose comparison. Nonetheless, antitumour activity was observed, with promising response rates and promising severity of peripheral neuropathy.
British Journal of Haematology 08/2010; 150(4):428-37. DOI:10.1111/j.1365-2141.2010.08264.x · 4.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy.
Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course.
There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m(2), and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m(2), owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis.
SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.
[Show abstract][Hide abstract] ABSTRACT: Venous thromboembolism (VTE), osteonecrosis of the jaw, renal failure, and anemia are all common complications of multiple myeloma therapy. Many of these adverse events have been documented only in the past 5 to 10 years, in conjunction with the introduction of a series of the newer therapies thalidomide, bortezomib, and lenalidomide. This article discusses these complications in detail and provides strategies for health care providers to best prevent, identify, and manage them. Preventive measures, such as VTE prophylaxis and appropriate dental hygiene, as well as patient education, dose adjustments, limited duration of drug treatment, and consideration of therapies that are associated with less burdensome adverse-event profiles, can contribute to substantially improved outcomes and quality of life.
Journal of the National Comprehensive Cancer Network: JNCCN 02/2010; 8 Suppl 1:S13-20. · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenström macroglobulinemia (WM).
Patients who had at least one previous therapy were eligible. All patients received bortezomib intravenously weekly at 1.6 mg/m(2) on days 1, 8, and 15, every 28 days for six cycles and rituximab 375 mg/m(2) weekly on cycles 1 and 4. The primary end point was the percentage of patients with at least a minor response.
Thirty-seven patients were treated. The majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI, 65% to 92%), with two patients (5%) in complete remission (CR)/near CR, 17 patients (46%) in partial response, and 11 patients (30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4 to 21.1 months). Death occurred in one patient due to viral pneumonia. The most common grade 3 and 4 therapy-related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade 3 peripheral neuropathy occurred in only two patients (5%). The median progression-free (PFS) is 15.6 months (95% CI, 11 to 21 months), with estimated 12-month and 18-month PFS of 57% (95% CI, 39% to 75%) and 45% (95% CI, 27% to 63%), respectively. The median overall survival has not been reached.
The combination of weekly bortezomib and rituximab showed significant activity and minimal neurologic toxicity in patients with relapsed WM.
[Show abstract][Hide abstract] ABSTRACT: Bisphosphonate-associated osteonecrosis (BON) is a recently recognized oral complication of bisphosphonate (BP) therapy. Currently, research into the pathogenesis of BON has been hampered by being deficient in studies capable of measuring the level of BP in saliva or at the bone-soft tissue interface. The objective of this current study was to develop a novel bioassay model representative of the oral levels of BPs in patients presenting with or at risk for BON.
Zoledronic acid (ZA) injectable was used to develop standardized MTS cell proliferation assay curves at concentrations of 0-10 microM, which were used either in a dilution in normal media, mimicking BP freed from bone or used to "spike" saliva individuals not taking BPs and mimicking BP levels being excreted. This bioassay was then used to estimate BP levels from samples of saliva and bone ex vivo from patients with and without BON.
Saliva and bone from patients with existing BON showed levels of BP ranging from 0.4 to 4.6 microM, while patients receiving IV infusion of BP and naïve to BON showed levels in saliva ranging from 0.4 to 5 microM. All control specimens and patients naïve to BP showed levels at 0 microM.
Given the fact that BPs are poor candidates for detection using standard methods (HPLC), this bioassay provides us with the ability to estimate clinically relevant concentrations of BP capable of producing apoptosis and the inhibition cell proliferation of oral mucosal cells based on previous studies. Subsequently, apoptosis and the inhibition of proliferation could lead to BON, secondary to the exposure of the bone in the unique microenvironment of the oral cavity.
Supportive Care in Cancer 09/2009; 17(12):1553-7. DOI:10.1007/s00520-009-0710-7 · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vorinostat, a histone deacetylase inhibitor, enhances cell death by the proteasome inhibitor bortezomib in vitro. We sought to test the combination clinically.
A phase I trial evaluated sequential dose escalation of bortezomib at 1 to 1.3 mg/m2 i.v. on days 1, 4, 8, and 11 and vorinostat at 100 to 500 mg orally daily for 8 days of each 21-day cycle in relapsed/refractory multiple myeloma patients. Vorinostat pharmacokinetics and dynamics were assessed.
Twenty-three patients were treated. Patients had received a median of 7 prior regimens (range, 3-13), including autologous transplantation in 20, thalidomide in all 23, lenalidomide in 17, and bortezomib in 19, 9 of whom were bortezomib-refractory. Two patients receiving 500 mg vorinostat had prolonged QT interval and fatigue as dose-limiting toxicities. The most common grade >3 toxicities were myelo-suppression (n = 13), fatigue (n = 11), and diarrhea (n = 5). There were no drug-related deaths. Overall response rate was 42%, including three partial responses among nine bortezomib refractory patients. Vorinostat pharmacokinetics were nonlinear. Serum Cmax reached a plateau above 400 mg. Pharmacodynamic changes in CD-138+ bone marrow cells before and on day 11 showed no correlation between protein levels of NF-kappaB, IkappaB, acetylated tubulin, and p21CIP1 and clinical response.
The maximum tolerated dose of vorinostat in our study was 400 mg daily for 8 days every 21 days, with bortezomib administered at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11. The promising antimyeloma activity of the regimen in refractory patients merits further evaluation.
Clinical Cancer Research 09/2009; 15(16):5250-7. DOI:10.1158/1078-0432.CCR-08-2850 · 8.19 Impact Factor