DEVELOPMENTAL THERAPEUTICS

University Of Arkansas Med Scis Ltl Rock, Little Rock AR

Investigators

Linked publications & trials

Abstract

DESCRIPTION: (Applicant's Description) Myeloma cells are associated with complex karyotypic abnormalities leading to a multiplicity of antiapoptotic mechanisms that are additionally supported by autocrine and paracrine loops, exercised in concert with the tumor microenvironment. In the last 4 years, we have reported on the efficacy of high-dose therapy, the grave prognostic significance of cytogenetic changes, and the role of combination chemotherapy and thalidomide in patients who have relapsed after transplantation. Also, we have demonstrated the therapeutic benefit of immune-based therapy. Based on these results, we hypothesize that a curative strategy for myeloma requires multi-agent therapy directed at both tumor cells and accessory elements that support myeloma cell growth. Our goal is to develop new and improved therapies, including cytotoxics, immunotherapy (idiotype or dendritic cell vaccination, donor lymphocyte infusions), antiangiogenic therapy (thalidomide), antistromal cell treatments (bisphosphonates), and assess newer agents in previously treated patients. To achieve this goal, the following aims will be pursued. Specific Aim 1: Compare the efficacy of multi-agent angiochemotherapy (DT-PACE) with that of tandem transplant with high-dose single-agent chemotherapy (melphalan) in a randomized phase III clinical trial for previously treated patients. The rationale is to evaluate whether patients will have superior response to multi-agent chemotherapy when compared with single-agent high-dose therapy. Specific Aim 2: Evaluate the role of immunological approaches in achieving or maintaining CR or partial remission (PR). Patients achieving CR/PR status will be enrolled on one of the currently ongoing idiotype (UARK-94-008) and dendritic cell vaccination protocols (UARK-96-023) to investigate clinical humoral and cellular responses. Additionally, patients with inadequate response or relapse will undergo "micro-allotransplants" or receive tumor-specific cytotoxic T lymphocytes. Specific Aim 3: Evaluate novel agents or their combinations in phase II studies in resistant or relapsing patients. The proposed, investigator-initiated clinical studies are likely to provide answers to important questions regarding the novel therapeutic approaches directed at various molecular targets and to provide information regarding the role of single-agent high-dose chemotherapy in MM.