Aproximately one year ago, the leadership of New York Presbyterian Hospital-Weill Cornell Medical Center decided to develop a center for myeloma and lymphoma. The recruitment of two notable pathologists, Drs. Dan Knowles and Glauco Frazzera, laid the foundation for the establishment of the Center together with Drs Morton Coleman, Lief Bergsagel and his group, John Leonard, and Elaine Schattner. At the same time, my group had started to work closely with Dr. Bergsagel’s group as well as with Dr. Ethel Cesarman. The frequent interactions between these groups led to the decision to join forces in working towards our mutual goal: finding the cure for myeloma. When the hospital leadership extended an offer for me to join the Department of Medicine as Chief of Myeloma Service and Director of Research, I accepted with enthusiasm.
Currently, Dr. Selina Vhen-Kiang and her team are working on plasma cell proliferation and differentiation. Dr. Leif Bergsagel’s lab is known for its contributions regarding the molecular pathogenesis of myeloma, particularly the role of translocations involving the immunoglobulin heavy chain rearrangement region. My lab, under Dr. Andrew Bush, is focusing on the molecular and biochemical events which are sufficient and/or necessary for myeloma cells’ commitment to cell death. Also, we are exploring the role of C-MYC and P-27, as well as the role of Fibroblast Growth Factor (FGF). We have recently found that a substantial proportion of myeloma patients have very high FGF levels. Dr. Roger Pearse, recipient of the IMF research grant in both 1999 and 2000, has now joined the lab. Dr. Pearse delineated the role of two novel cytokines, TRANCE and OPG, in mediating bone destruction in myeloma. Since OPG, which seems to be essential for bone integrity and is deficient in myeloma patients, is available for treatment, the new model proposed by us may open a new avenue in the treatment of bone disease.
Another exciting collaboration has been initiated between our Center and Dr. Michel Nussenzweig from Rockefeller University. Dr. Nussenzweiger has made major contributions to the understanding of normal B-cell and plasma cell development. In addition, we are continuing our close collaboration with Drs. Lucio Luzzatto and Raymond Thertulien from Memorial Sloan-Kettering Cancer Center to identify genes which are preferentially expressed (or silenced) in patients with MGUS, Stage I myeloma, and advanced myeloma. In order to approach this enourmous project, we had to find a way to isolate DNA from normal plasma cells as a baseline reference. After many attempts, we were able to come up with a selection procedure that now allows us to enrich the plasma cell population from normal bone marrows up to 96% purity. Thus we were able to construct CDNA libraries from normal plasma cells and from patients with various stages of myeloma. Furthermore, using sophisticated DNA array techniques we hope to identify genes that may play an essential role in the transition from normal to abnormal plasma cells and in keeping malignant plasma cells in check (such as MGUS and Stage I myeloma). In collaboration with Dr. Shahin Rafii’s lab at New York Hospital, we are exploring the role of endothelial cells and fibroblasts in promoting the growth of myeloma cells in vitro and in vivo.
Drs. Leonard and Coleman have recently reported that a combination of low-dose Thalidomide, Dexamethasone and Biaxin (BLTD) was effective in all 29 patients studied with many patients having significant responses despite being relatively resistant to Dexamethasone or Thalidomide when given alone. To prove this potentially important finding, our study for newly diagnosed patients randomizes them to receive BLTD versus high-dose Dexamethasone. Likewise, patients relapsing after first line chemotherapy are randomized to BLTD versus one of two standard salvage therapies. Those who relapse after Melphalan and Prednisone are randomized to BLTD versus VAD, and those relapsing after a Decadron-containing regimen are randomized to BLTD versus ABCM (Adriamycin, BCNU, Cytoxan, and Melphalan). Patients in first remission will be offered high dose chemo-therapy and stem cell support. We will randomize transplant eligible patients to receive high dose Cytoxan or combination chemo-therapy called CDEP to see which of these yields better stem cell mobilization. It is also possible that one of these approaches may have a better impact on the myeloma itself. We are also offering a transplant regimen that is different from the standard high dose Melphalan as a single agent. We believe that a combination of Melphalan and BCNU might be additive, and we will use it for newly diagnosed patients for their first transplant.
We are also initiating a series of Phase II studies for patients relapsing after high dose chemotherapy or after two courses of standard chemotherapy (second line salvage therapy). These include Thalidomide and GMCSF, Thalidomide and Arsenic Trioxide (ATO), and a monoclonal antibody against an antigen expressed by myeloma cell lines (MUC-1). The rationale for the combination of Thalidomide and GMCSF stems from the observations made by Dr. G. Kaplan of Rockefeller University suggesting that Thalidomide enhances the immune response against myeloma cells, a property shared by GMCSF. In collaboration with her group, we hope to prove that the use of these two agents in combination will result in an additive or synergistic enhancement of the immune recognition of the myeloma clone. Similarly, if the main effect of Thalidomide is mediated through antiangiogenic properties, its combination with ATO makes sense in view of the recent findings reported by Drs. Roboz and Rafii of the center, indicating that ATO is a potent antiangiogenic agent. Since the use of Thalidomide is increasing rapidly, it is prudent to understand its side effects. We were one of the first groups to note the occurence of thromboembolic phenomena such as deep vein thrombosis, pulmonary embolism, and transient ischemic attack (TIA) in several of our patients. We will initiate a detailed search for the underlying cause of Thalidomide-induced thrombogenesis, taking advantage of the expertise that New York Hospital provides regarding coagulation disorders and vascular biology.
The IMF has done a terrific job in educating patients and focusing the public’s attention on this disease. The IMF also assures myeloma patients that they are not alone in their battle with this disease. This sense of camaraderie, I believe, has an important impact on the patients’ ability to cope with myeloma.