International Waldenstrom's Macroglobulinemia Foundation Research

The IWMF encourages and promotes the development of information leading to a better understanding of the disease, Waldenstrom’s macroglobulinemia (WM). This goal is accomplished by providing grants for basic medical and scientific research into the causes, treatments and potential cures for Waldenstrom’s macroglobulinemia. We do so in a number of ways. Since we are a small organization with limited resources, we always try to leverage our investments into programs and institutions which are supportive, will contribute to the research, and will promote the cause. The Foundation research strategy supports the following areas:

2. Translational research to discover if drugs used for other cancers are effective with WM cells;

3. Exploratory research on promising new ways to target destruction of WM cells;

6. Meetings and conferences for researchers to encourage coordinated ongoing research.

Most of our research funds have been dedicated to basic research grants as described below. We have a rigorous process of application, evaluation by appropriate scientists selected by the Scientific Advisory Committee, and approval by an IWMF Research Committee and finally, the Board of Trustees. We are constantly looking for new applications for new research projects. (See listings below)

In 2000, the IWMF in cooperation with the NCI, sponsored the first Workshop on WM and invited the 21 prominent researchers in the US and several other countries for a 2-day intensive exploration of treatments for WM.

A follow up Conference was held in Athens Greece in September of 2002 which greatly increased the number of researchers, expanded the international exposure, and focused on diagnosis, prognosis, treatment, and the search for a cure.

IWMF was a Silver Sponsor of the fourth Waldenstrom’s Workshop held in June 2007 on the island of Kos, Greece. This site was significant in that it was the birthplace of Hipocrates.

In 2005 IWMF helped in sponsoring a Myeloma Workshop in Sydney, Australia where a number of papers on WM were presented. IWMF also provided funds and participated in a conference on Malignant Lymphomas in Lugano, Switzerland.

In October 2008 IWMF along with other foundations and pharmaceutical companies provided funds for the fifth Waldenstrom's Macroglobulinemia workshop in Stockholm, Sweden. During the workshop tribute was paid to the late Dr. Jan Waldenstrom who discovered the disease. Discussions were held concerning the previous consensus recommendations for treatment regimes. At the conclusion of the workshop, a seminar featuring doctors who treated Waldenstrom’s was held for European Waldenstrom's patients.

All of the members of the IWMF Scientific Advisory Committee are professional medical scientists and researchers and are attached to major institutions with which the IWMF seeks to develop long-term relationships of mutual support.

At the present time, the IWMF is not funding clinical trials, although this policy is always subject to change. Such trials are extremely expensive and are usually supported by the pharmaceutical companies. The funds raised by IWMF are concentrated on basic research.

Fellowships have been provided to young scientists and medical doctors to encourage them to work in the field of WM research.

Ansell, Stephen M., MD – Mayo Clinic, Rochester, MN. (Project Period 11/01/06-10/31/09) $515,683. TITLE: “Factors Regulating Immunoglobulin Producing B-cells in Patients with Waldenstrom’s Macroglobulinemia”

[A study to help identify genetic predisposition, growth factors and prognostic indications of IgM production by WM cells. Specifically BlyS and various cytokines (small proteins) will be studied for their effect on IgM growth.]

Treon, Steven P., MD, MA, PhD – Bing Center for Waldenstrom’s Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA. (Project Period 01/01/07-12/31/10) $1,038,942. TITLE: “Comprehensive Studies Into the Genetic Basis and Pathogenesis of Waldenstrom’s Macroglobulinemia”

[A three part study including: 1.The determination of genetic factors which predispose a person to have WM; 2. Investigation of the genetic causes of low IgA and IgG in patients with WM; 3. An analysis of molecular mechanisms which enable the multiplication of lymphoplasmacytic cells in the bone marrow of WM patients.]

Tsingotjidou, Anastasia S., DVM, PhD – Aristotle University, Thessaloniki, Greece, (Project Period 1/15/2007-1/14/2008 extended to 1/12009). $45,900. TITLE: “Study of the Neuropathy Associated With Waldenstrom’s Macroglobulinemia Using a SCID-hu Bone Animal Model”

[Peripheral neuropathy (PN) often accompanies Waldenstrom’s macroglobulinemia (WM) and causes painful suffering. Dr. Tsingotjidou showed that mice could be caused to develop WM in a previous IWMF supported project. In this project one of the main goals is to produce PN in WM infected mice, so that different treatments can be developed before testing on humans.]

Ghobrial, Irene M., MD-Dana-Farber Cancer Institute, Boston MA. (Project Period 12/01/2006-11/30/2008). $216,000. TITLE: “Molecular and Functional Sequelae of the P13K Pathway in Waldenstrom Macroglobulinemia”

[There are numerous reactions occurring in the body which affect the generation, growth and death of cancer cells like WM. Dr. Ghobrial has tested a chemical, perifosine in mice with WM and in cell lines in “test tubes” and has shown that it inhibits the growth of WM cells. Her previous work has indicated that it interrupts a development pathway that causes WM cells to seek shelter in the bone marrow. It also appears to cause WM cells that are already “sheltered” in the bone marrow to be released into the peripheral blood where they can be destroyed by other reagents. This project will enable Dr. Ghobrial to test the blood of patients before and after they are treated with perifosine to determine if the same effects occur in humans.]

Braggio, Esteban in the laboratory of Dr. Fonseca, Mayo Clinic, AZ. (Project Period 10/01/2007-09/30/2008). $74,234. TITLE: "Genome-Wide Characterization of DNA Copy Number Changes Using Array-based Comparative Genomic Hybridization in Waldenstrom Macroglobulinemia and Delineation of the Minimal Region of 6Q Deletion"

[This project is a continuation of the work started by Dr. Fonseca on the genetic changes which occur with patients who have Waldenstrom's Macroglobulinemia.]

Pilarski, Linda M.,-Cross Cancer Institute, University of Alberta, Edmonton, Canada. (Project Period 5/1/05-4/30/08) $307,152 CAD. TITLE: “Genetic Characteristics of Waldenstrom’s Macroglobulinemia”

[A study of the mutations occurring in cells of patients with Waldenstrom’s macroglobulinemia. Specifically the project showed that the HAS1 gene in WM patients generates abnormal proteins. The work identified targets for developing new and possibly more effective therapies.]

Ansell, Stephen M., MD – Mayo Clinic, Rochester, MN, (Project Period 7/1/04-6/30/06) $269,273. TITLE: “BlyS Inhibition in Immunoglobulin Producing B-cells”

[The research program has demonstrated that the BlyS protein stimulates the generation of IgM and increases the survival and proliferation of malignant cells (Waldenstrom’s cell). The studies have also shown the sites on B cells which interact with BlyS. Agents have been identified which interfere with the actions of BlyS and future work will determine if these agents can be made in a form that will enter the body’s blood stream and reduce the effect of BlyS on the B cell life and its ability to produce IgM.]

Mitsiades, Constantine S., MD – Dana-Farber Cancer Institute, Boston, MA, (Project Period 01/01/04-12/31/05) $60,000. TITLE: “In Vitro and in Vivo Molecular Profiling of WM as a Framework for the Design of Novel Combination Therapies for the Disease”

[Dr. Mitsiades determined that WM cells have different sub-types. This finding may be indicative of why various patients with WM react differently to the same treatment. He also identified a number of proteins which regulate the activity of the WM cells. The proteasome inhibitor bortezomid (Velcade™, PS-341) can turn off expression in certain genes which in turn reduces the activity of proteins which prevent the death of WM cells and also affects the behavior of proteins which try to repair damage to the WM cells. Another compound called heat shock protein-90 was found to play a part in the proliferation of WM cells. By inhibiting the action of this protein death could be more easily induced in WM cells. A third category of proteins called histone deacetylases (HDACs) was determined to interact with DNA in such a manner as to assist in regulating the growth, survival and drug-resistance of WM cells. By identifying compounds which inhibit (HDACs) cell death could be increased.]

Tsingotjidou, Anastasia S., DVM, PhD – Aristotle University of Thessaloniki, Thessaloniki, Greece, (Project Period 7/01/04-6/30/05). $50,000. TITLE: “Establishment of a Waldenstrom’s Macroglobulinemia Animal Model”

[There has only been limited success in creating WM in mice, so that the pathology of the disease can be studied and also new therapies can be tested prior to their use with humans. Dr. Tsingotjidou has successfully developed such a mouse for use in the studies of diseases such as multiple myeloma and prostate cancer. In this project the researcher has actually grafted human bone fragments from patients with WM to the bones of mice and determined that high concentrations of IgM are produced in an infected mouse. Studies are currently underway to determine the progression of the disease in the animals. Future work would involve using the mice to test promising agents identified by other IWMF studies.]

Bredeson, Christopher, MD, MSc, FRCPCA/ Parameswaren, Hari, MD – International Bone Marrow Transplant Registry, Medical College of Wisconsin, Milwaukee, WI. (Project Period 7/01/04-6/30/05). $28,674. TITLE: “High Dose Chemotherapy Followed by Autologous or Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Waldenstrom’s Macroglobulinemia”

[Introduction: The role of stem cell transplantation (SCT) in Waldenstrom's macroglobulinemia (WM) has not been extensively studied. The authors performed a retrospective analysis of 36 patients with WM who received autologous (N=10) or allogeneic (N=26) SCT and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Methods: Diagnostic and response criteria for WM were based on the Second International Workshop on WM definitions. The following outcomes were analyzed: non-relapse mortality (NRM), relapse, progression-free survival (PFS) and overall survival (OS).

Results: Median age at the time of SCT was 51 years and median time from initial treatment to SCT was 29 months. 78% of the patients had>2 prior chemo regimens and 52% had resistant disease to salvage chemotherapy. 58% of patients in the allogeneic SCT group received myeloablative conditioning regimens (agents that changed the bone marrow). Only 5/26 allogeneic SCT cases received non-myeloablative/reduced intensity conditioning. After a median follow-up of 65 months, 21/36 (58.3%) patients have died. Primary disease accounted for 29% and 25% of the deaths in the allogeneic and autologous SCT groups respectively. Relapse rate at 3 years was 29% and 24% for the allogeneic and autologous SCT group respectively. PFS at 3 years was 31% and 65% and OS was 46% and 70% respectively for the allogeneic and autologous SCT group.

Conclusion: The role of stem cell transplantation (SCT) in Waldenstrom’s macroglobulinemia (WM) has not been extensively studied. A retrospective analysis of patients with WM who received autologous or allogeneic SCT and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) was performed. The major conclusions as presented at the IWMF meeting in Tampa by Dr. Parameswaran Hari were that autologous SCT is a safe (1 yr nonrelapse mortality [NRM] of 11%) and feasible treatment option for patients with WM especially for those who present with adverse prognostic factors. Nucleoside analogues and alkylators that may affect stem cell mobilization should therefore be avoided before stem cell collection in patients who may be candidates for ASCT. Allogeneic SCT carries a much higher (40%) NRM risk and should not be considered outside the context of a clinical trial.]

Al-Katib, Ayad, MD-Wayne State University, Cleveland, OH. January 2000, TITLE: “A study of the Response of WM to Treatments with Bryostatin l and 2-CdA”.

[Dr. Al-Katib had previously established what was believed to be an immortal WM cell line from a patient. This line could be grown in mice and cultured in vitro for research purposes. At the time it was one of the few known WM cell lines. The study used bryostatin 1, a natural product derived from a marine animal and 2CdA to determine the optimum dosage and schedule for treating the cell line in mice and in vitro WM cells. Results of the in vitro culture showed that WM cells are relatively sensitive to 2CdA, but not to bryostatin 1 when each agent is used alone for treatment. When the cells were pre-exposed to bryostatin 1 and then treated with 2CdA significant growth inhibition was observed. A similar interaction was observed in a chronic lymphocytic leukemia model (CLL). When WM cells were treated with both agents after nine days, tumor weight was reduced. The preliminary results suggest a useful interaction between the agents which could lead to enhanced therapeutic action against WM.]

Treon, Steven P., MD, MA, PhD, Harvard University, Dana Farber Cancer Institute, Boston, MA— January 2000

TITLE: “Treatment of Waldenstrom’s Macroglobulinemia by antibody mediated immunotherapy and induction of tumor selective antigens”.

[Description: To develop an antibody-mediated immunotherapy for treating WM by identifying novel tumor selective antigens to target WM plasma cells, as well as identifying agents which could be used clinically to induce such plasma cell selective antigens. The study sought to (1) identify how Rituxin, a monoclonal antibody (MoAb) works in WM patients; (2) to develop strategies to overcome the body’s resistance to Rituxin; (3) to identify how protein markers on the surface of WM tumor cells block the immune system activity and (4) to identify new therapies for use in WM. Resistant proteins were located on the WM cells, but they did not interfere with the Rituxin reaction. Other immune mechanisms appeared to be more important in determining the response to Rituxin. During the project another suitable antigen target labeled CD52 was identified on WM cells and an FDA approved monoclonal antibody (Campath-1H) has been shown to have activity against that site].

Rajkumar, Vincent, MD, Mayo Clinic; Rochester, MN -January 2000 TITLE: “Blood vessel development and cell division and growth in Waldenstrom’s macroglobulinemia.”

[Description: Sought to determine the degree of blood vessel development and its prognostic value in WM. Dr.Rajkumar had previously shown that multiple myeloma tumors had excessive new blood vessels feeding the tumor and were predictive of the disease progression. In this study it was demonstrated that WM tumors do not develop an increased network of blood vessels, as is the case with myeloma. This study predicted that a chemical such as thalidomide would probably not be as effective in treating WM as it was in myeloma.]

Fonseca, Rafael, MD-Mayo Clinic; Scottsdale, AZ, (Project Period 11/01/01-10/31/03); $109,834; TITLE: “Waldenstrom’s Macroglobulinemia Genomics”

[This study followed a previous one of Dr. Fonseca in which he studied the chromosomal and molecular abnormalities of the diseased cells of Waldenstrom’s patients. In the first study it was shown that about 50% of WM patients had a deletion of the long arm of chromosome 6(6q). In this project the 6q arm of the chromosomes of patients with monoclonal gammopathy of undetermined significance (MGUS) was compared with that of WM patients. No 6q deletions were found in patients with MGUS, whereas 55% of the WM patients showed the deletion. This result could be useful in separating WM patients from those with MGUS.]

The International Waldenstrom’s Macroglobulinemia Foundation (IWMF) is a non-profit organization which offers support for basic scientific research that will further knowledge of the cause, diagnosis, treatment and cure for the disease Waldenstrom’s macroglobulinemia. Research proposals may be submitted at any time. Each proposal will receive consideration from the IWMF Research Committee, the Scientific Advisory Committee and the IWMF Board of Trustees.

Scientific researchers interested in applying for a grant may receive an application packet by contacting:

1. Project Title_______________________________________________________________________

2. Applicant ____________________________________________ Degrees:______________________

Institution:____________________________________________________________________

Department:___________________________________________________________________

Address:______________________________________________________________________

Telephone:_________________________________

Institution’s Financial Officer for Grants Research:

Name: ___________________________________________________________________

Address: ___________________________________________________________________

___________________________________________________________________

Telephone:_______________________________

Email:___________________________________

Have you cleared your proposal with your institution? Yes________ No _________

APPLICATION OUTLINE: Please provide the following information in your proposal:

Your application for IWMF research funds should be mailed to: Tom Myers, 23 State Park Road, Swanton, MD 21561. We would appreciate receiving two copies. In addition, we ask that you provide your proposal electronically by email to: tom@mountaineerlog.com

PURPOSE: The IWMF Research Grant Program is pledged to promote and support research leading to improved understanding of the cause, diagnosis, treatment, and cure for the disease Waldenstrom’s macroglobulinemia.

Submissions: Research proposals may be submitted at any time. Following a review process that may take as long as three months, awards will be made to successful applicants.

Review Process: Research proposals are reviewed by scientists and/or doctors selected by members of the IWMF Scientific Advisory Committee. Their comments and recommendations are considered by the IWMF Research Committee which in turn forwards the comments on to the applicant for a response. Once the application is approved by the reviewers it goes to the IWMF Board of Trustees for funding decisions. Authors of proposals will be notified by the IWMF Research Committee as soon as a decision is made. The Grant Award Agreement is signed by the IWMF President and Treasurer then sent to the research institute for signature by the appropriate, authorized financial officer prior to funds being awarded. A Project Liaison Officer will be appointed by the IWMF Research Committee. This person is the IWMF point of contact for the Principal Investigator for technical questions. The Project Liaison Officer is responsible for keeping the IWMF members informed about the progress of the project.

Range of Grant Awards: IWMF anticipates funding grants in the range of $50,000 to $100,000, depending on complexity and goals, and on the funds available for research projects. However, grants in excess of $200,000 have been awarded for certain projects.

Project length: IWMF anticipates research projects will have a 12 to 24 month project period.

Payment policy: IWMF payments are made on a six-month basis. The IWMF Treasurer will pay a pro rata amount for six months at the start of the project. Future payments will be made every six months after receipt of a six-month progress report. Five per cent of the last payment will be withheld until a final report is approved by the IWMF Research Committee. An addition of 8% of the actual costs is the maximum amount permitted for indirect costs.

Reporting requirements: Six-month progress reports in non-scientific language shall be submitted to the IWMF Project Liaison Officer by the Principal Investigator at the end of a period, but no later than 30 days after the period ends. Such progress reports will describe the activities and findings of the previous six-months and provide a plan for the next six-month period. A draft final report is required no later than two months after the project ending date which shall describe the results and findings as they relate to the stated goals of the project for the full term of the project.

The following is the list of review criteria used by the IWMF Scientific Advisory Committee to evaluate research proposals:

What is your analysis of the proposed project’s overall applicability to furthering scientific knowledge of the cause, diagnosis, treatment, or cure for the disease Waldenstrom’s macroglobulinemia?

Are key personnel sufficient in number, and qualifications, to undertake this project?

Are you aware of any similar studies recently completed or ongoing that parallel this proposal, or which would complement this proposal?

Is the budget reasonable and appropriate to costs for the proposed research activities to be performed?

                                    For more information please contact:

                                    Tom Myers, IWMF Vice President of Research

International Waldenstrom’s Macroglobulinemia Foundation, 3932D Swift Road, Sarasota FL 34231, (941) 927-4963

Address:______________________________________________________________________

Telephone:_________________________________