Search

Preclinical studies have shown that targeted combination therapy consisting of vorinostat and bortezomib has antitumor activity in multiple myeloma (MM). We examined this drug combination in advanced relapsing and/or refractory MM patients (n = 34). Although the maximum tolerated dose was not reached, the study found this combination regimen generally well tolerated and clinically active in relapsed and/or refractory MM patients.Development of targeted therapies for MM has improved response rates and increased patient survival, but ultimately the disease becomes refractory and progresses. Vorinostat combined with bortezomib has demonstrated synergistic antiproliferative and proapoptotic activity in preclinical models of MM. The objectives of this study were to determine the maximum tolerated dose for vorinostat with bortezomib in patients with advanced MM and to evaluate the clinical benefit of this new drug combination.Patients ≥ 18 years old with relapsed and/or refractory MM were enrolled into escalating dose cohorts of vorinostat and bortezomib combination therapy. Thirty-four patients were enrolled and were evaluable for safety and efficacy analyses.All patients reported adverse events, 89% of which were mild to moderate in severity. Thirteen patients experienced 29 serious adverse events, 12 (41%) of which were considered drug-related. The maximum tolerated dose was not reached. Partial responses were observed in 9 (27%) patients. Minimal responses were observed in 2 additional patients (6%), and another 20 patients (59%) experienced disease stabilization.Vorinostat with bortezomib is generally well-tolerated and has clinical activity in patients with relapsed and/or refractory MM. Response rates were similar in patients previously exposed to bortezomib and patients who were naive to bortezomib therapy.

Prior studies of myeloma treated with conventional chemotherapy or autologous stem cell transplantation have shown immunohistochemistry for cyclin D1, fibroblast growth factor receptor 3, and p53 to be prognostically significant. The clinical significance of these phenotypic abnormalities in thalidomide-based regimens is currently unknown. We examined the clinical significance of immunohistochemistry for cyclin D1, fibroblast growth factor receptor 3, p53, and cyclin D3 in 94 patients treated with pegylated doxorubicin, vincristine, dexamethasone, and thalidomide, including 49 newly diagnosed and 45 relapsed/refractory patients. The incidence of positivity for cyclin D1, fibroblast growth factor receptor 3, p53, and cyclin D3 was similar in newly diagnosed versus relapsed/refractory groups (37%, 8%, 4%, and 2% versus 42%, 7%, 11%, and 2%, respectively). In contrast to prior studies of other therapeutic regimens, cyclin D1 negativity or fibroblast growth factor receptor 3 positivity did not convey an adverse progression-free or overall survival. p53 positivity, although uncommon, was associated with shorter progression-free and overall survival in newly diagnosed cases. The findings suggest that a thalidomide-based regimen may overcome the poor prognosis associated with a cyclin D1-negative or fibroblast growth factor receptor 3-positive phenotype.

Cancer impacts each patient and family differently. Our current understanding of the disease is primarily limited to clinical hallmarks of cancer, but many specific molecular mechanisms remain elusive. Genetic markers can be used to determine predisposition to tumor development, but molecularly targeted treatment strategies that improve patient prognosis are not widely available for most cancers. Individualized care plans, also described as personalized medicine, still must be developed by understanding and implementing basic science research into clinical treatment. Proteomics holds great promise in contributing to the prevention and cure of cancer because it provides unique tools for discovery of biomarkers and therapeutic targets. As such, proteomics can help translate basic science discoveries into the clinical practice of personalized medicine. Here we describe how biological mass spectrometry and proteome analysis interact with other major patient care and research initiatives and present vignettes illustrating efforts in discovery of diagnostic biomarkers for ovarian cancer, development of treatment strategies in lung cancer, and monitoring prognosis and relapse in multiple myeloma patients.

Multiple myeloma is an incurable disease for which there are 2 clinical research strategies. One strategy is to focus on managing the disease as a chronic process aiming to minimize the negative impact on survival with minimal or no compromise of the quality of life. The other strategy is to pursue total eradication of the malignant clone, thus achieving cure for the disease. Over the past decade, the myeloma communities have seen several new agents approved for the therapy of multiple myeloma. Although these agents do not result in cure, they target the disease microenvironment, allowing for a better overall response rate and improved quality of response. The latter appears to be influencing the disease outcome in improved progression-free survival, translating into a longer overall survival. Despite the advances in the discovery of immune modulator compounds, chemotherapy continues to be an important part of the myeloma therapeutic armamentarium. Recently, several investigators have explored combining traditional chemotherapeutic agents with proteasome inhibitors and immune modulators.

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.

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.

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.

IFNs were the first new therapeutic products resulting from recombinant DNA technology. IFNs were also the first human proteins effective in cancer treatment. There is however much to be discovered which will lead to new clinical applications. Areas which represent major research challenges for full understanding and application of the IFN system are: (i) the diversity of the IFN family; (ii) the role of induction; (iii) molecular mechanism of action; (iv) cellular modulatory effects; (v) advantages of combinations, and (vi) identification of new therapeutic indications. This review will emphasize the diversity of the IFN family and chemical modifications which will result in second-generation IFNs. Pre-clinical and clinical findings form the basis for new therapeutic directions in chronic myelogenous leukemia, lymphomas, myelomas, melanoma, urologic malignancies, primary brain tumors, and ovarian carcinoma.