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Last Updated: 02/21/17

SPORE in Multiple Myeloma

The University of Texas MD Anderson Cancer Center

Principal Investigator:
Robert Z. Orlowski, M.D., Ph.D.

OVERALL ABSTRACT

Multiple myeloma is a clonal plasma cell malignancy which, despite recent treatment advances, remains incurable in the vast majority of the over 59,000 patients in the United States afflicted with this disease. Therefore, The University of Texas M. D. Anderson Cancer Center, in collaboration with The University of Pennsylvania and the Virginia Commonwealth University, is proposing this Specialized Program of Research Excellence (SPORE) in Multiple Myeloma. The primary goal of this program will be to translate promising new strategies from the bench to the bedside to reduce the morbidity and mortality, and improve the quality of life of multiple myeloma patients. To do so, a multidisciplinary, collaborative group of experienced investigators will be pursuing four highly innovative Projects:

  • Project 1 — Combination Activated T-Cell and Vaccine Therapy in Myeloma (Kwak/Giralt/June/Stadtmauer)

  • Project 2 — AntH32-microglobulin Antibodies as Therapeutic Agents for Multiple Myeloma (Yi/Wang)

  • Project 3 — Targeting the HDM-2 E3 Ligase in Multiple Myeloma (Orlowski/Weber)

  • Project 4 — Targeting Multiple Myeloma by Combining CDK Inhibitors and Bcl-2 Antagonists (Grant/Wang/Dai/Dent)

To provide the specialized expertise needed to maximize the success of the Projects, they will be supported by five Core Facilities:

  • Core A — Administrative Core Facility (Orlowski/Kwak)

  • Core B — Myeloma Tissue Core Facility (Kornblau!Wang/Davis/Lin)

  • Core C — Animal Models Core Facility (Yi/Yang)

  • Core D — Clinical Trials Core Facility (Weber/Stadtmauer/Mclaughlin)

  • Core E — Biostatistics and Bioinformatics Core Facility (Berry/Baladandayuthapani/Aimeida/ Ramakrishnan)

Also, the SPORE will attract new investigators with additional novel ideas, and train the next generation of myeloma researchers, through the following Programs:

  • Developmental Research Program (Orlowski/Yi)

  • Career Development Program (Kwak/Aggarwai!Stadtmauer)

This SPORE will therefore serve as a nexus for its Investigators and the myeloma research community to foster the kind of multidisciplinary efforts that are necessary to bring us closer to a cure for this disease.

PROJECT 1: COMBINATION ACTIVATED T-CELLS AND VACCINE THERAPY IN MYELOMA

Project Leaders:
Larry W. Kwark, M.D. Ph.D. (basic)
Sergio A. Giralt, M.D. (clinical)

Project Co-Leaders:
Carl H. June, M.D. (basic)
Edward A. Stadtmauer, M.D. (clinical)

Our team has made significant progress in our efforts to develop and validate methods to induce immunity in patients with hematologic malignancies. A central hypothesis of this application is that multiple biologic and immunologic maneuvers will be required in order to achieve long-term control of hematologic malignancies; similar to the finding that combination chemotherapy has been required to significantly improve survival in most tumors. We have developed a candidate vaccine termed ld KLH, that targets the patient specific and tumor specific M-protein that is produced by myeloma cells. This vaccine, given as a single agent, has been demonstrated to have safety and clinical activity in phase II and phase Ill trials in follicular lymphoma. Complementing the vaccine studies, our recent randomized phase III studies in subjects with advanced myeloma showed adoptive immunotherapy with vaccine primed T cells resulted in an encouraging immunologic reconstitution following high dose chemotherapy and autologous hematopoietic stem cell transplantation (SCT). Furthermore, we provided the first evidence in humans that adoptive immunotherapy combined with vaccination could result in the generation of protective immunity within weeks following the SCT. Based on these promising clinical results, and on the safety and feasibility of this clinical trial, we now propose a series of clinical trials to induce tumor-specific immunity in patients with myeloma. To build on our combined progress, the following two specific aims will test the hypothesis that vaccines can be combined with adoptive immunotherapy in patients with myeloma with the goal of generating a molecularly targeted and potent antitumor immunity:

  • Specific Aim 1. Conduct a phase II clinical trial to study the feasibility and immunogenicity of post-transplant effector T cell reconstitution and ldiotype-KLH vaccination in patients with advanced myeloma. Obtain full regulatory clearance to open the protocol, and conduct the clinical trial. The protocol will be opened at the MD Anderson Cancer Center and the University of Pennsylvania, and closed to enrollment when -60 patients are enrolled.

  • Specific Aim 2. Determine whether the combination immunotherapy regimen augments myeloma immunity and decreases tumor burdens. We will determine (a) cellular and (b) humoral immune responses and (c) learn whether this correlates with the degree of paraprotein reduction for all patients regardless of whether they received the vaccine or not and then amongst vaccine recipients alone. Based upon our preliminary data, we expect to see a trend between ld-specific immunity and a reduction of paraprotein levels.

PROJECT 2: ANTI-β2-MICROGLOBULIN ANTIBODIES AS THERAPEUTIC AGENTS FOR MULTIPLE MYELOMA

Project Leaders:
Qing Yi, M.D., Ph.D. (basic)
Michael Wang, M.D. (clinical)

Multiple myeloma (MM) is still incurable 8-cell malignancy affecting more than 14,000 Americans annually. Myeloma tumor cells can survive even the most aggressive treatment available today, leading to disease relapses. The long-term goal of this project is to develop more effective cytostatic therapies to eradicate myeloma cells. We recently made a novel and exciting discovery that anti-β2-microglobulin (β2M) monoclonal antibodies (mAbs) had strong apoptotic activity in both established myeloma cell lines and primary myeloma cells from patients. The mAbs selectively target and kill myeloma cells in coculture with normal hematopoietic cells without damaging normal blood cells, including CD34+ stem cells. Anti- β2M mAb­ induced apoptosis in myeloma cells were not blocked by soluble β2M (10-100 µg/mL, 3- to 30-fold higher than that in most MM patients, which are about 3 µg/mL), IL-6, or other myeloma growth and survival factors. The mAbs induced cell death via inhibiting PI3K/Akt and ERK, activating JNK, and compromising mitochondrial integrity, leading to cytochrome c release and activation of a caspase-9-dependent cascade. Furthermore, the mAbs were also active and therapeutic in vivo in xenograft mouse models of myeloma. Thus, we hypothesize that anti- β2M mAbs may be used as therapeutic agents to treat patients with MM. This hypothesis will be tested by the following aims. Aim 1 will examine the mechanisms of anti- β2M mAb­ induced apoptosis in myeloma cells. Using normal plasma or B cells as controls, we will define the role of surface MHC class I and class I-like molecules in these responses, and examine surface proteins binding to, the downstream kinases, and intracellular signaling and apoptosis pathways induced by anti- β2M mAbs. Aim 2 will utilize immune effector cells or molecules to enhance the efficacy of anti- β2M mAbs, Aim 3 will develop strategies to enhance the efficacy of anti- β2M mAbs to induce apoptosis in myeloma cells by combining with novel antimyeloma agents, and Aim 4 will perform pre-clinical and clinical studies to examine the safety and toxicity profiles of the mAbs.

PROJECT 3: TARGETING THE HDM-2 E3 LIGASE IN MULTIPLE MYELOMA

Project Leaders:
Robert Z. Orlowski, M.D., Ph.D. (basic)
Donna M. Weber, M.D. (clinical)

The ubiquitin-proteasome pathway has been validated as a therapeutic target for multiple myeloma (MM) by our group and others through the demonstration of the activity of bortezomib in both the relapsed/refractory and up-front settings. Because of its broad impact on intracellular proteolysis, however, this proteasome inhibitor induces anti-apoptotic effects at the molecular level that decrease its efficacy, and at the clinical level it induces toxicities such as peripheral neuropathy that limit its utility. A more targeted approach, therefore, such as by inhibiting a specific E3 ubiquitin ligase responsible for ubiquitination of only a small subset of client proteins, would likely be more effective and better tolerated. We have obtained evidence that second-generation small molecule inhibitors of the HDM-2 E3 ligase, which is best known for its role in p53 ubiquitination, induce anti-proliferative effects in MM models irrespective of their p53 status; that these agents activate a p53-dependent type I cell death program, as well as p53-independent type II cell death, or autophagy; and that they interact synergistically with different classes of chemotherapeutics in wild type and mutant p53 backgrounds. These and other findings led us to our central hypothesis, that HDM-2 inhibitors are promising novel agents that can be used as chemosensitizers in a p53 status-adapted approach to personalize MM therapy. To evaluate this possibility, and to translate these agents into the clinic, our proposed specific aims will: 1. Further define the molecular mechanisms of action of HDM-2 inhibitors in MM, including their impact on type I and II cell death, and the role of p53 and HDM-2 in these processes; 2. Delineate the pathways by which HDM-2 inhibitors sensitize MM to type I-inducing chemotherapeutics such as anthracyclines, death receptor agonists, and Bcl-2 inhibitors in wild type p53 models, and to mTOR inhibitors in mutant p53 models; and 3. Pilot an HDM-2 inhibitor as a single agent in a phase I study evaluating its impact and mechanism of cell death induction in patients with relapsed/refractory MM in preparation for later studies of an individualized p53 status-adapted approach.

PROJECT 4: TARGETING MULTIPLE MYELOMA BY COMBINING CDK INHIBITORS AND BCL-2 ANTAGONISTS

Project Leaders:
Steven Grant, M.D. (basic)
Michael Wang, M.D. (clinical)

Co-Investigators:
Yun Dai, M.D., Ph.D. (basic)
Paul Dent, Ph.D. (basic)

Evidence linking dysregulation of cell cycle and Bcl-2 family proteins in the molecular pathogenesis of multiple myeloma (MM) has prompted intense interest in cyclin-dependent kinase (CDK) inhibitors and Bcl-2 antagonists in this disease. Furthermore, recent findings suggest that certain CDK inhibitors (e.g., flavopiridol; FP) act as transcriptional repressors by inhibiting the CDK9/cyclinT pTEFB complex, and by extension, phosphorylation of the carboxy-terminal domain of RNA PollI. Such agents down-regulate expression of short-lived proteins including Mcl-1, a critical survival factor in MM. Significantly, CDK inhibitors have recently been found to enhance the lethality of Bcl-2 antagonists (e.g. ABT-737) in human leukemia cells by unleashing Bak from Bcl-xL and Mcl-1, leading to a dramatic potentiation of apoptosis. Notably, a novel FP schedule has recently been developed which displays significant activity in another B-cell malignancy (CLL). We therefore hypothesize that clinically relevant CDK inhibitors such as FP, seliciclib (R­ roscovitine), and SCH727965, an agent with an IC50 of 1 nM toward CDK9, represent logical candidate agents to enhance the activity of clinically relevant Bcl-2 antagonists (e.g., GX15-070, ABT-737) in MM. Indeed, preliminary evidence suggests a high degree of synergism between FP and GX15070, as well as other CDKI/Bcl-2 antagonist regimens, in MM cells. Evidence also suggests that such regimens induce up­ regulation of pro-apoptotic proteins (e.g., Bim, NOXA, and BIK) which may cooperate with Mcl-1 down­ regulation to trigger apoptosis. In specific aim #1, we will employ genetic tools to test the hypothesis that synergistic interactions between CDK inhibitors and Bcl-2 antagonists stem from Mci-1/XIAP downregulation, upregulation of Bim, NOXA, and BIK, release of Bak and BIM from both Bcl-xL and Mcl-1, Bax/Bak activation, and induction of mitochondrial injury. This information will guide the selection of correlative laboratory studies in subsequent planned clinical trials. In Specific Aim #2, we will determine whether and by what mechanism(s) this strategy overcomes conventional drug resistance, stromal/cell adhesion- or growth factor-mediated drug resistance, and bortezomib or lenalidomide resistance in MM cells. In specific aim #3, we will evaluate the selectivity of this strategy by comparing its activity against primary, patient-derived CD138+ MM versus their normal counterparts (e.g., CD138-, CD34+ cells), and testing its in vivo efficacy using flank and systemic xenograft MM models. In Specific Aim #4, we will use this information as a foundation for initiating one or more Phase I trials of CDKIs (e.g., FP) and Bcl-2 antagonists (e.g., GX15-070) in patients with refractory MM. Collectively, these studies will provide a rational foundation for a novel approach to MM therapy in which the activity of clinically relevant Bcl-2 antagonists (e.g., GX15-070 or ABT- 737) is enhanced through rational combination with transcriptionally repressive CDK inhibitors that disrupt the pTEFb complex (e.g., FP or SCH727965) in patients with refractory MM.

CORE A: ADMINISTRATIVE CORE

Core Director:
Robert Z. Orlowski, M.D., Ph.D.

Core Co-Director:
Larry W. Kwak, M.D., Ph.D.

The M. D. Anderson Cancer Center Administrative Core Facility will serve as a nexus for this SPORE in Multiple Myeloma, as the latter strives to develop novel approaches to the prevention, early detection, diagnosis, staging, and treatment of this hematologic malignancy. This Core's overall goals will be to provide coordination and oversight of SPORE activities, to facilitate internal and external collaborations, as well as intramural and extramural communications, and to thereby expedite in every way possible the translational mission of the SPORE. Specific aims of this Core will include: 1. To assure the overall scientific quality and function of all of the SPORE components, including the four Projects, five Cores, and the Developmental Research and Career Development Programs; 2. To establish and monitor compliance of SPORE activities with all applicable local, state, national, and international regulations and requirements; 3. To oversee SPORE expenditures, and maintain and distribute budget information on a regular basis; 4. To organize and convene all necessary SPORE meetings, including those of the Internal and External Scientific Advisory Boards, utilizing the M. D. Anderson conference and videoconference capabilities, and provide summaries thereof to applicable personnel; 5. To assist the SPORE Developmental Research Program and Career Development Program Directors and Co-Directors in administering these vital components; 6. To support the preparation of all SPORE publications and other external communications; 7. To coordinate, obtain, and maintain Institutional commitments to the SPORE from the participating centers; 8. To encourage and facilitate intra- and inter-SPORE communications, collaborations, and data and resource sharing; and 9. To promote communications and collaborations with other SPORE partners in both academia and industry. Through these activities, the Administrative Core will help both established and developmental projects to clearly focus on their translational goals, and to identify and implement steps required to translate the research to and from the clinic to produce objective evidence of improving clinically relevant endpoints in multiple myeloma.

CORE B: MYELOMA TISSUE CORE

Core Director:
Steven Kornblau, M.D.

Core Co-Directors:
Michael Wang, M.D.
R. Eric Davis, M.D.
Pei Lin, M.D.

Basic, translational, and clinical scientists focusing on multiple myeloma must have access to molecularly characterized cell line model systems, and especially to clinically-annotated fresh and frozen primary tissue samples, to test and validate their hypotheses. The main objective of the Myeloma Tissue Core is to work with each SPORE Project, Core, and Program to insure efficient procurement, storage, and distribution of laboratory and clinical tissue samples at the M.D. Anderson Cancer Center. Validated standardized operating procedures have been established for all activities, and continuous communication between the investigators, research nurses, biostatisticians and hematopathologists will provide for optimal tissue collection, standardized processing, accurate analysis, and safe storage of each sample. These samples will be associated with relevant patient clinical and laboratory data obtained and maintained in accordance with all applicable regulatory guidelines. This Tissue Core will also be used for novel and robust biomarker development and accurate testing of translational hypotheses.

There are four specific aims for this Core:

  • Specific Aim 1: To develop and maintain a repository of intact cells, serum, DNA, RNA, and protein derived from blood, bone marrow, and other tissue specimens obtained from patients with plasma cell dyscrasias at the M.D. Anderson Cancer Center. Samples are collected and processed at the time of diagnosis, during therapy, in remission, or at relapse. This Core will distribute tissue specimens to SPORE investigators for analysis, while providing comprehensive hematopathologic characterization with detailed annotation of parameters of collection and preservation. The Tissue Core also maintains a collection of myeloma cell lines, and will act as a centralized repository for the storage and distribution of newly developed cell lines.

  • Specific Aim 2: To maintain a comprehensive, prospective, interactive database with detailed clinical and pathologic data for patients with plasma cell dyscrasias.

  • Specific Aim 3: To facilitate inter- and intra-SPORE collaborations, and collaborations with non-SPORE investigators, through acquisition and distribution of clinical sample resources to and from SPORE investigators and others within the M. D. Anderson Cancer Center, as well as with other national or international sources. This includes developing and sharing the informatics systems with other SPORE sites.

  • Specific Aim 4: To provide stock and customized reverse phase protein arrays to SPORE investigators.

CORE C: ANIMAL MODELS CORE

Core Director:
Qing Yi, M.D., Ph.D.

Core Co-Director:
Jing Yang, Ph.D.

The main goal of this Myeloma SPORE program is to develop novel targeted therapies to more effectively treat patients with multiple myeloma (MM). Clinically relevant animal models are crucial for examining the in vivo efficacy of novel agents. The dedicated personnel and facilities of the Animal Models Core (Core C) provide the program with clinically relevant animal models and expertise in animal studies essential to achieving the aims of the Projects. Core personnel work closely with SPORE investigators to plan animal studies and to develop optimal and clinically relevant mouse models of myeloma. During the past 5 years, the Department of Lymphoma and Myeloma and M.D. Anderson Cancer Center have provided excellent conditions in terms of access to primary myeloma samples, myeloma tissue bank, interaction between clinical and translational research programs, and animal facilities for providing unique, clinically relevant samples to establish myeloma SCID and SCID-hu mouse models, which allow reproducibly engraftment of established human myeloma cell lines or primary myeloma cells freshly isolated from patients with MM, respectively. Establishment of myeloma in SCID-hu mice induces typical human MM manifestations including disease heterogeneity commonly seen in the clinic. The Animal Models Core is well suited to provide expertise and mouse models for the SPORE given that the Animal Models Core Personnel, animal facilities, and tissue banks are all located within the South Campus Research Buildings of our institution where our laboratories are concentrated. This provides a level of integration for the Core that will maximize uniformity and use of available animal models and patients' materials by SPORE investigators.

CORE D: CLINICAL TRIAS CORE

Core Director:
Donna M. Weber, M.D.

Core Co-Directors:
Edward A. Stadtmauer, M.D.
Peter W. Mclaughlin, M.D.

The Clinical Trials Core Facility of The M. D. Anderson Cancer Center SPORE in Multiple Myeloma will translate highly promising findings with potential application to the prevention, early detection, diagnosis, prognosis, and/or treatment of multiple myeloma from the laboratory to the clinic. Clinical trials coordinated by this Core will also promote the flow of information from the clinic back to the laboratory, with the goal of helping to inform and optimize the design of future clinical interventions. In order to accomplish these objectives, the Core will have the following specific aims: 1. To coordinate the development, submission, and regulatory approval of the SPORE clinical trials, in collaboration with the Administrative Core Facility (Core A) and the Biostatistics and Bioinformatics Core Facility (Core E); 2. To assist SPORE investigators in rapidly and efficiently accruing patients to translational clinical trials emerging from SPORE Projects; 3. To report adverse events to the Institutional Review Board and appropriate agencies, and assure compliance with all applicable regulatory guidelines, in collaboration with Core A; 4. To provide quality control of the SPORE clinical trial data; 5. To analyze clinical trials data from SPORE studies in collaboration with Core E; and 6. To facilitate and coordinate correlative specimen collection from patients enrolled on SPORE trials along with the Myeloma Tissue Core Facility (Core B). Taken together, therefore, this Core will provide the crucial link between the bench and the bedside that will allow this SPORE in Multiple Myeloma to meet its translational goals, and improve the outcomes of patients with multiple myeloma.

CORE E: BIOSTATISTICS AND BIOINFORMATICS CORE

Core Director:
Donald Berry, Ph.D.

Core Co-Directors:
Veera Baladandayuthapani, Ph.D.
Jonas Almeida, Ph.D.

The Biostatistics and Bioinformatics Core for the M.D Anderson Specialized Programs of Research Excellence in multiple myeloma will serve multiple needs with respect to the planning and conduct of the SPORE research. This resource will be used for hypothesis refinement, experimental design, data management, quality control, and informative presentation of results, and will be available for all projects of the SPORE. From a biostatistical perspective, design and analysis of laboratory and clinical projects will be performed in collaboration with Dr. Donald A. Berry, Dr. Veerabhadran Baladandayuthapani, and Dr. Heather Y. Lin. Data from the SPORE clinical trials, laboratory projects and high-throughput genomics studies will be entered into a customized integrative database infrastructure developed by Dr. Jonas Almeida. Thus, from inception to reporting, translational experiments will benefit from the Biostatistics and Bioinformatics Core that will be used to augment existing M. D. Anderson biostatistics resources and to align these considerable resources with SPORE research objectives.

The Specific Aims of the Biostatistics and Bioinformatics Core are:

  • Specific Aim 1: To provide the statistical design, sample size and power calculations for each project.

  • Specific Aim 2: To facilitate prospective collection, entry, quality control, and integration of data for the basic science experiments and clinical trials arising from the ongoing research of the SPORE.

  • Specific Aim 3: To provide innovative statistical modeling, simulation techniques, and data analyses needed by the projects and other Cores to achieve their Specific Aims.

  • Specific Aim 4: To ensure that the results of all projects are based on well-designed experiments and are appropriately interpreted.