Biomedical subjects
Publications and source records attributed to Mohamad A Hussein.
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BACKGROUND: Pegylated liposomal doxorubicin has pharmacologic and safety advantages over conventional doxorubicin. METHODS: For this noninferiority trial, 192 patients with newly diagnosed, active multiple myeloma were randomized to receive either combined pegylated liposomal doxorubicin (40 mg/m(2)) and vincristine (1.4 mg/m(2); maximum, 2.0 mg) as an intravenous infusion on Day 1 plus reduced-dose dexamethasone (40 mg) orally on Days 1-4 (DVd) (n = 97 patients) or combined vincristine (0.4 mg per day) and conventional doxorubicin (9 mg/m(2) per day) as a continuous intravenous infusion on Days 1-4 plus reduced-dose dexamethasone (VAd) (n = 95 patients) for at least 4 cycles. Treatment was repeated every 4 weeks until patients either achieved maximal response, disease progression, or unacceptable toxicity or underwent transplantation. The primary endpoints were response and toxicity. RESULTS: Objective response rates (DVd, 44%; VAd, 41%), progression-free survival (hazard ratio, 1.11; P = 0.69), and overall survival (hazard ratio, 0.88; P = 0.67) were similar between the treatment groups. However, DVd was associated with significantly less Grade 3/4 neutropenia or neutropenic fever (10% vs. 24%; P = 0.01), a lower incidence of sepsis, and less antibiotic use. Compared with VAd, DVd also significantly decreased the need for central venous access (P < 0.0001) and growth-factor support (P = 0.03) and resulted in less alopecia (20% vs. 44%; P < 0.001) but more hand-foot syndrome (25% vs. 1%; P < 0.001), mainly Grade 1/2. CONCLUSIONS: The DVd regimen demonstrated similar efficacy with less toxicity and supportive care compared with VAd, which should improve clinical utility and optimize the opportunity for transplantation.
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Multiple myeloma is a clonal disorder of plasma cells which is considered incurable with currently available therapies. Substantial advances have been achieved in the past decade with the identification of cellular mechanisms that confer drug resistance. This has resulted in newer agents such as arsenic trioxide (Trisenoxt), lenalidomide (Revlimid) and bortezomib (Velcade) with promising activity in this disease. In this review article we will outline the history, mechanisms of action, pharmacology, and clinical trials of arsenic trioxide in multiple myeloma.
Deep vein thrombosis and its lethal complication pulmonary embolism are manifestations of venous thromboembolism (VTE), which is typically associated with cancer and recent major surgery. Certain solid tumors and hematologic malignancies impose an inherently elevated risk of VTE that is compounded by chemotherapy and other risk factors. Multiple myeloma (MM) and other plasma cell dyscrasias are thrombogenic as a consequence of their multiple hemostatic effects, including elevated interleukin-6 levels, pro-coagulant antibody formation, paraprotein interference with fibrin structure, activated protein C resistance, and endothelial damage. The oral immunomodulatory drugs thalidomide and lenalidomide have produced major therapeutic responses in patients with MM when used in combination with oral steroids and chemotherapy, but a high incidence of VTE has been reported. Various VTE prophylaxis strategies with thalidomide- and lenalidomide-containing combinations have been investigated in clinical studies. This review discusses emerging results on the use of VTE prophylaxis to minimize VTE risks associated with MM treatment regimens containing thalidomide and lenalidomide.
Multiple myeloma is a malignant process of the plasma cell. There is no cure for this disease and at present the focus is to manage the disease as a chronic process to achieve a good quality of life. Hopefully, with the advancement in the understanding of the pathophysiology of the disease, target therapy should allow for the control of multiple myeloma, its prevention, and/or the reversal of organ damage; therefore prolonging survival. Proteasome inhibitors and immune modulators are the first of new therapies that target the malignant plasma cell microenvironment. In this review, different aspects of these agents are discussed.
The design of innovative, more effective, less toxic therapy for multiple myeloma (MM) is emerging in parallel to a better understanding of the underlying pathophysiology of this common hematologic malignancy. Thalidomide has changed the treatment paradigm for patients with myeloma. Its efficacy, however, has been compromised to some degree by its side effects. Immunomodulatory drugs (IMiDs) are structural and functional analogues of thalidomide that were specifically designed to produce new agents with enhanced immunomodulating and anticancer properties but with less toxicity. In this article, we review the clinical trial development of second-generation IMiDs lenalidomide and CC-4047. Both agents demonstrate potent activity with manageable toxicities and provide another treatment opportunity for patients with MM.
OBJECTIVE: To evaluate the efficacy and safety of adding thalidomide to the pegylated liposomal doxorubicin, vincristine, and decreased-frequency dexamethasone (DVd) regimen for multiple myeloma. PATIENTS AND METHODS: Patients newly diagnosed as having active multiple myeloma and those with relapsed-refractory disease were studied between August 2001 and October 2003. Patients received DVd as previously described. Thalidomide was given at 50 mg/d orally and the dose increased slowly to a maximum of 400 mg/d. At the time of best response, patients received maintenance prednisone, 50 mg orally every other day, and daily thalidomide at the maximum tolerated dose for each patient. The primary end point was the rate of complete responses plus very good partial responses as defined by the European Group for Blood and Marrow Transplantation criteria and the Intergroupe Français du Myélome, respectively. RESULTS: Of 102 eligible patients, 53 were newly diagnosed as having multiple myeloma, and 49 had been previously treated for multiple myeloma. The complete response plus very good partial response rate was 49% and 45%, with an overall response rate of 87% and 90% for patients with newly diagnosed and previously treated multiple myeloma, respectively. Furthermore, better responses were associated with improved progression-free and overall survival. The most common grade 3 and 4 adverse events were thromboembolic events (25%), peripheral neuropathy (22%), and neutropenia (14%). CONCLUSIONS: The addition of thalidomide to the DVd regimen significantly improves the response rate and quality of responses compared with the DVd regimen alone. This improvement is associated with longer progression-free and overall survival. The rate of observed quality responses is comparable to responses seen with high-dose therapy.
BACKGROUND: Coagulation problems in amyloidosis are historically associated with bleeding tendencies (mostly Factor X abnormalities). Increased clotting was observed in isolated cases diagnosed with low-grade disseminated intravascular coagulation (DIC). Problem of venous thromboembolic disaease (VTD) in amyloidosis was not systematically investigated. METHODS: We evaluated frequency of VTD and risk factors for VTD in 56 consecutive amyloidosis patients with a documented disease evaluated and followed up at our Center from 1991-2001. Data was collected in 5 categories: (a) demographics, (b) disease and treatment, (c) thrombosis case information, (d) major risk factors for thrombosis and (e) baseline laboratory data. Univariable correlates of VTD were assessed using Kaplan-Meier analysis and Cox proportional hazards analysis. RESULTS: Mean age of the patients was 67 (years range 21-83). Male/female percentage ratio was 70/30. 29% of the patients had high creatinine level (> 1.4 mg/dl). Personal or family history of VTD was recorded in 2 and 0% of patients, respectively. Known hypercoagulable state was present in 1 patient (2%). 8% of patients were smokers. Of 56 patients, 6 developed VTD (11%). Median time from diagnosis of amyloidosis to VTD was 12.5 month (range 1-107). Treatment was given within a median of 1 month (range 0-4) from the development of thrombosis. Only sites of VTD were lower extremities. No cases were associated with I.V. line. 1 case (17%) was identified postoperatively. We identified several univariable correlates of VTD in amyloid patients, including greater age at diagnosis (HR-2.99, P = .041), personal history of DVT (HR-47.7, P = .006) and immobility (HR-11.78, P = .006). Presence of circulating serum M-protein had protective role in our analysis (HR-.08, P = .031). There was no correlation with the type of treatment patients were receiving. CONCLUSION: Risk for thromboembolic diseases in patients with amyloidosis is similar to one previously described for multiple myeloma. Additional studies with higher number of thromboembolic events could help to further elucidate risk factors for VTD in this population of patients.
Experience with thalidomide has underscored the need for diligent monitoring and management of side effects to achieve optimal therapeutic benefit. Initial phase II and III results with lenalidomide, a thalidomide analogue, have confirmed impressive response rates with a significantly more favorable toxicity profile. The Cleveland Clinic experience with lenalidomide alone or in combination with pegylated liposomal doxorubicin, vincristine, and reduced schedule dexamethasone will be described. Peripheral neuropathy and deep venous thrombosis (DVT). Low-dose aspirin alleviated DVT when lenalidomide was used in combination with anthracycline-containing chemotherapy. Strategies for managing these toxicities and for recognition and management of lenalidomide-associated myelosuppression are reviewed.
Multiple myeloma continues to be an incurable disease. The understanding of the disease's pathophysiology has significantly improved over the past few years, partly due to the discovery of the role of immunomodulatory agents and the study of their mechanism of action. Thalidomide, the first of the immunomodulatory family to be used in the management of multiple myeloma, proved not only to be effective in the treatment of multiple myeloma, but also instigated a wide range of in vitro and in vivo studies to define the pathophysiology of the plasma cell dyscrasia. The attention thalidomide has received in the past and recent history has not been without a price. The drug has a side-effect profile that, if managed appropriately, provides the most unique active molecule in the management of the disease, where it maintains the same response rate in newly diagnosed patients as in advanced relapsed/refractory multiple myeloma patients.
Progressive bone destruction is the hallmark of multiple myeloma (MM) and is responsible for principal morbidity in the disease. The spine is the most afflicted skeletal organ, and vertebral fractures have significantly contributed to its poor prognosis. The principal underlying pathologic mechanism causing bone disease in MM is a shift in the balance of bone formation and bone resorption toward bone resorption, and eventually total dissociation between the 2 processes occurs in latter stages of the disease. During the past decade bisphosphonates have become an important adjunctive treatment in the management of MM, in which they have shown the ability to reduce bony complications associated with the disease. Advances in minimally invasive surgical techniques, such as percutaneous vertebroplasty and kyphoplasty, offer these patients less-invasive options for the treatment of vertebral collapse and restoration of their normal function. This report reviews recent advances in the understanding of bone disease in MM, the role of bisphosphonates in the prevention of skeletal events, and available data regarding percutaneous vertebroplasty and kyphoplasty.
OBJECTIVE: To study the efficacy of daily low-dose aspirin (81 mg orally) in decreasing the incidence of venous thromboembolic events (VTEs) in patients with multiple myeloma receiving pegylated doxorubicin, vincristine, and decreased-frequency dexamethasone, plus thalidomide (DVd-T). PATIENTS AND METHODS: In this phase 2 clinical trial of DVd-T, conducted by the Cleveland Clinic Foundation from August 2001 to October 2003, 105 patients were enrolled. The first 35 patients experienced increased numbers of VTEs. von Willebrand levels and platelet aggregation to ristocetin before and after treatment with DVd-T increased significantly, suggesting a pathophysiology involving platelet-endothelial interaction. Aspirin was added to the regimen, thus generating 3 patient groups: group 1 received aspirin from the start of DVd-T treatment before the study began (58 patients), group 2 received aspirin after the start of DVd-T treatment and after the study began (26 patients), and group 3 did not receive daily low-dose aspirin during the study (19 patients). Two patients being treated with warfarin for other indications were excluded from the study. The primary end point for this study was the incidence of VTE in the form of either deep venous thrombosis or pulmonary embolism. Secondary end points were the time to the first VTE, time to the composite end point of death or first VTE, and incidence of bleeding complications. RESULTS: After a median follow-up of 24 months, on an intent-to-treat basis, 26 posttreatment VTEs occurred after a median of 90 days, with 19% occurring in group 1, 15% in group 2, and 58% in group 3. Following multivariate time-to-event analysis, aspirin use continued to be associated with lower relative risk of VTE (hazard ratio, 0.22; confidence interval, 0.10-0.47; P<.001) and of the composite end point (hazard ratio, 0.28; confidence interval, 0.15-0.51; P<.001). CONCLUSION: Daily low-dose aspirin (81 mg orally) given to patients with newly diagnosed and relapsed/refractory multiple myeloma who were receiving DVd-T reduced the incidence of VTEs without an increase in bleeding complications.
BACKGROUND: To the authors' knowledge, the prevalence of vitamin B12 deficiency among patients with plasma cell dyscrasias (PCD) is largely unknown. Identifying this vitamin deficiency in such patients could help improve their anemia and increase their tolerance to potentially neurotoxic agents. METHODS: The authors retrospectively reviewed the charts and laboratory results of 664 consecutive patients diagnosed with PCD who had their vitamin B12 and folate status evaluated between 1997 and 2001 at the Cleveland Clinic Multiple Myeloma Research Program. The patients were screened for vitamin B12 deficiency using serum vitamin B12 and methylmalonic acid. RESULTS: Of the 664 patients whose medical charts were reviewed, information on vitamin B12 status was available for 522 patients (78%). Among these 522 patients, 71 (13.6%) had laboratory-defined vitamin B12 deficiency and the remaining 451 patients (86.4%) did not. On univariate analysis, vitamin B12 deficiency correlated with immunoglobulin A (IgA) PCD (P = 0.04), higher mean corpuscular volume (P = 0.008), and longer follow-up (P = 0.048). In a covariate adjusted model, only the presence of IgA PCD was associated with an increased prevalence of vitamin B12 deficiency (P = 0.003). CONCLUSIONS: Vitamin B12 deficiency was prevalent in patients with PCD, especially in patients with the IgA subtype. Serum vitamin B12 measurements should be part of the initial evaluation and subsequent workups for anemia in patients with PCD.
Current therapy of primary systemic (AL) amyloidosis with oral melphalan and prednisone remains unsatisfactory, with a median survival of only 13 months. Between 1996 and 2003, 93 patients with biopsy-proven AL amyloidosis were enrolled in a prospective US national cooperative group trial. Treatment schema consisted of induction therapy with pulse dexamethasone (DEX), followed by maintenance therapy with DEX and alpha interferon. Hematologic complete remissions were observed in 24% and improvement in AL amyloidosis-related organ dysfunction occurred in 45% of patients evaluable for response. Median survival of the entire cohort is 31 months, with an estimated 2-year overall survival (OS) and event-free survival (EFS) of 60% and 52%, respectively. Presence of congestive heart failure and increased level of serum beta2 microglobulin (>/= 0.0035 g/L [3.5 mg/L]) were dominant predictors of adverse outcome. Estimated 2-year OS in patients who are eligible to receive transplants with this approach was 78%. These data demonstrate for the first time in the context of a US multicenter prospective clinical trial that front-line therapy with a DEX-based regimen in AL amyloidosis can lead to durable reversal of AL amyloidosis-related organ dysfunction and prolonged survival.
BACKGROUND: Venous thromboembolic disease (VTD) is a recently recognized complication of thalidomide in combination therapy for patients with multiple myeloma (MM). The authors assessed the frequency of VTD and its risk factors in 612 consecutive patients with plasma cell dyscrasia (PCD) who were evaluated and followed from 1991 to 2001. METHODS: In the current study, 404 patients were diagnosed with multiple myeloma (MM), 174 with monoclonal gammopathy of undetermined significance (MGUS), and 34 with other forms (excluding amyloidosis). Univariable correlates of VTD were assessed using Kaplan-Meier analysis and Cox proportional hazards analysis. RESULTS: The authors identified several univariable correlates of VTD in patients with MGUS, including a family and medical history of VTD, immobility, low serum albumin level, and high leukocyte count. Patients with MGUS with immunoglobulin (Ig) G monoclonal immunoglobulin were found to be less prone to develop VTD. In patients with MM, a family and medical history of VTD and the presence of a hypercoagulable state were factors identified in univariable analysis to be associated with an increased risk of VTD. In patients with MM, for each unit increase in serum albumin, the risk of VTD was lower. The type of the treatment regimen did not appear to correlate with the development of VTD. CONCLUSIONS: In the current study, the risk for thromboembolic diseases among patients with PCD was increased compared with the risk in the general population. Further studies are necessary to define the mechanisms involved.
Multiple myeloma remains an incurable disease despite aggressive, high-dose therapy and intensive supportive care. Newer therapies with good safety profiles are needed for patients with multiple myeloma to improve the quality of responses and prolong survival. Novel treatment strategies for multiple myeloma include replacing conventional doxorubicin with pegylated liposomal doxorubicin and reducing the dexamethasone dose (DVd) in the widely accepted VAD (vincristine, conventional doxorubicin, dexamethasone) regimen to improve the safety profile. Because of its antiangiogenic and immunomodulatory effects, thalidomide has also been explored for use in the treatment of multiple myeloma and has demonstrated increased response rates when used in combination with dexamethasone. These findings subsequently led to the evaluation of the role of thalidomide in combination with pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone (the DVd-T regimen). This regimen was associated with response rates greater than 80% in patients with both newly diagnosed and relapsed/refractory multiple myeloma. Future applications of this and similar regimens for the treatment of multiple myeloma are currently being explored.
Patients with multiple myeloma (MM) typically respond to initial chemotherapy, but almost all patients relapse with a median survival of approximately 5 years. Combining vincristine and conventional doxorubicin with oral dexamethasone (VAD) or reduced-dose dexamethasone (VAd) provides rapid response in many patients, but its use is limited by toxicity concerns and the inconvenience of continuous infusions in each cycle. Use of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) and vincristine intravenous injection with oral dexamethasone (DVD) or reduced-dose dexamethasone (DVd) is safe and effective for the management of newly diagnosed or relapsed/refractory MM. Controlled trials showed that DVD/DVd is at least as effective as VAD/VAd for the treatment of MM, but DVd is associated with less neutropenia and alopecia in addition to requiring fewer days in the hospital or clinic for drug administration. DVd therapy has also been reported to be associated with an antiangiogenic effect not observed with VAD. Another liposomal anthracycline, liposomal daunorubicin (DaunoXome [DNX]), has been investigated in MM and preliminary data suggest that it is safe and effective, but studies comparing it with other regimens have not been reported. Early results from ongoing trials suggest that adding thalidomide, bortezomib, or other immune modulators to PLD-based chemotherapy may improve efficacy.