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Spring 2000 Volume 3, Issue 8:
Myeloma Today Profile: Raymond Comenzo, MD, Part I
03.01.00
This is Part one of a two part series. Part two of this interview can be read in Myeloma Today, Volume 3, Number 9

Myeloma Today: Please tell us a little about yourself.

Dr. Comenzo: I was an English literature major at Amherst College and spent much of my time there reading novels, literary criticism, plays and poetry. I also wrote a lot. I did study science, though, including biology and astronomy. Several years after graduating, having worked as a community organizer, I began to think seriously about going to medical school. I had to take organic chemistry and physics to fulfill the basic requirements for medical school. After graduating from medical school in the mid-80?s, I did a residency in medicine at the old Boston City Hospital. It was there in the old CRC (Clinical Research Center) that I first met patients with amyloidosis. One of the first patients that I ever took care of was a man who had secondary amyloidosis because of chronic lung infections. There was another gentleman whom I cared for at that time who fractured his spleen simply on being transferred from his transport gurney to the X-ray table. So my interest in amyloidosis was established many years ago. As house officers, we had the opportunity to interact with Dr. Alan Cohen, the amyloid specialist, because he gave a morning report every Monday. I seriously considered doing a rheumatology fellowship and, as a senior resident, spent a half day with Dr. Cohen receiving encouragement and direction (he could be very direct) about pursuing that path.

MT: At what point was an interest in hematology-oncology established?

Dr. Comenzo: Well, unfortunately for Dr. Cohen?s recruitment efforts, by that time I had fallen in love with the appearance of blood and bone marrow cells under the microscope and had a strong sense that great changes were going to occur in the world of hematology-oncology. So I decided to submit my application for fellowship to Dr. Robert Schwartz at New England Medical Center. He called me within several days, offered me a fellowship position and I did not hesitate for a minute to accept it. At the time, I was familiar with his work in identifying immunosuppressive drugs, in autoimmune diseases, B cell ontogeny and immunoglobulin genes. I thought it was somewhat ironic that Dr. Schwartz, who had trained in rheumatology and then had become a commanding presence in hematology, was going to be one of my mentors. My happiest professional years were at New England Medical Center. The 3 years I spent there training in hematology, oncology and blood banking were wonderful and invigorating. In addition to a talented staff of doctors and scientists, my mentor in transfusion medicine, Gene Berkman, provided a tremendously fertile and helpful environment for a young hematologist-oncologist cum stem cell transplanter.

MT: How did you become interested in myeloma and related conditions?

Dr. Comenzo: The first fellow?s conference that I gave in October of my first year was on the newly discovered B cell growth factor interleukin-6. In addition, the first patient that I cared for as a fellow was a young man in his 40?s who had multiple myeloma and had had an allogeneic bone marrow transplant seven months previously. One of the seminal experiences of my first year of fellowship was caring for both this young man and another patient with myeloma, a Roman Catholic priest, Fr. Joseph Greer, whose battle with myeloma was recounted in The New Yorker. Fr. Greer had had one of the first peripheral blood stem cell transplants in the United States for myeloma in the 80?s. When the young man died of relapsed myeloma that Christmas, Fr. Greer officiated at his funeral mass and ministered to his young widow and small children in their time of loss. It was an act of human courage the likes of which I have rarely seen.

MT: Your group in Boston was the first to regionally evaluate high dose melphalan with stem cell rescue in amyloidosis. How did that get started? How would you characterise that program?

Dr. Comenzo: With interests in amyloidosis and myeloma, after completing my hematology-oncology-blood banking fellowship, it was a real opportunity for me to return to Boston Medical Center and assume a leadership role in the formation of the stem cell transplant program there. There was no program there at the time and the hospital, under the leadership of Drs. Charlie Arkin, the Lab Chief and Doug Faller in the Cancer Center, provided about $150,000 to develop the necessary infrastructure to collect and cryopreserve stem cells. Charlie also gave me the job of overseeing the merger of the blood banks of Boston City Hospital (public) and Boston University Hospital (private), a unique situation in the annals of medicine. And Doug handed me the job of designing a protocol to transplant patients with primary amyloidosis. He was in touch with Dr. Rob Simms of Rheumatology, and Rob, an old friend from residency, wanted to pursue intensive therapy. The idea seemed perfectly plausible to me although I was somewhat skeptical given how sick these patients often were. Nevertheless, it took us a year and a half to get an IRB approved protocol ready for patient enrollment. Our first patient was enrolled on 1/12/94 but unfortunately died shortly after stem cell collection while at home in Connecticut and I became somewhat despondent for several months about ever enrolling another patient. Our second patient was enrolled in June 1994 and now 6 years post-transplant he remains in a complete remission with complete resolution of his amyloid related organ involvement. During that early period I had the chance to seek the advice of Dr. Ken Anderson who played a pivotal role in the development of transplant for amyloid patients. Several colleagues at BU wanted to fudge the diagnostic facts of amyloid cases in order to get insurance approval by saying the patients had myeloma. Ken was clear-minded on that point and insisted that the procedure, if it worked, would never gain currency unless one was up front with the insurers from the start. Amyloid patients to this day owe Dr. Anderson a debt for his characteristically excellent advice to a budding young clinical researcher. Then for several years I spent my working time either overseeing the merger of two blood banks, one in a private the other in a public hospital, or taking care of amyloid transplant patients. It was truly a struggle at times because no one had ever done either of these things before. There were no textbooks or guides available to me. Indeed, the chief of hematology frequently expressed his reluctance at having to care for amyloid-transplant patients in any manner, shape or form during that period, so I had to round every day and every weekend when I had patients in-house and did not get coverage from the Heme-Onc staff. It was not until it was obvious that the treatment worked that the chief and others became interested enough to participate. Then it was a simple matter of victory having 1,000 fathers ? which is quite good for patients, obviously. Because I am a blood banker I spent a good deal of effort creating standardized approaches to all aspects of transplant for amyloid patients. In the process of doing that, one develops procedures and practices that are independent of individual ego or personality. Therefore, suffice it to say, I am extremely proud of the fact that the program which I helped to start remains viable to this day and is indeed one of the major transplant programs for amyloidosis in the world. Currently, I would characterize the program in Boston as an excellent program devoted to the care and cure of patients with this disease, as is the program at Mayo Clinic. The major difference between the programs is that the clinical leaders at the Mayo ? all of whom are hematologists ? do the hands-on work themselves, do the data analysis in real time and write the manuscripts for publication. They do not solely depend on an occasional fellow to come along, read through charts and do the analytic work. Therefore, the group at the Mayo knows the data better as a rule, in my opinion, analyzes the data more thoroughly (and almost always on an intention-to-treat basis), and publishes more extensively. That defines them in my mind as a first-rate academic program.

MT: What is the current status of transplant for amyloidosis? Which patients should be recommenced for transplant?

Dr. Comenzo:
Currently, stem cell transplant for amyloidosis is a standard therapy for patients who have limited organ involvement, that is to say patients who have one or two systems involved with the disease and who do not have complicated cardiac involvement. By that I mean they do not have recurrent pleural effusions, a history of arrhythmias or cardiac syncope. For eligible patients, stem cell transplant reliably halts or reverses the progression of organ dysfunction associated with this disease. Hopefully, as new drugs are made available to reverse amyloid deposition, the need for stem cell transplant will disappear and we will be able to treat patients with oral chemotherapy and anti-amyloid drugs.

MT: What areas of research are you currently involved with?

Dr. Comenzo: My responsibilities as Director of the Stem Cell Laboratory at Memorial Sloan-Kettering Cancer Center are occupying much of my time although I am fortunate to have several collaborators who are quite active. Our major research interests involve immunoglobulin variable region genes and light-chain production by plasma cells. With our collaborators Jeremy Wally, a graduate student at Boston University, and Drs. Perfetti and Merlini in Pavia, Italy, Dr. Yana Zhang and I are working to determine the links between immuno-globulin variable region germline gene use and the organ-system tropism of AL amyloidosis. Dr. Zhang and I are also working at Memorial on developing immunoglobulin variable region genes as inserts in DNA-based vaccine therapies for AL amyloidosis. With respect to clinical research, we have a series of protocols that are in review employing intravenous melphalan for stem cell mobilization, thalidomide and steroids for the treatment of refractory myeloma and amyloidosis, and Phase I antiangiogenesis drugs to treat patients with myeloma, Waldenstrom?s and amyloidosis.

MT: Tell us about the priorities of the new program at Sloan-Kettering in New York?

Dr. Comenzo: The priorities of the program at Sloan-Kettering, which has recently received funding from the Graziano family, are to find a cure for multiple myeloma by pursuing excellence in scientific and clinical research. In myeloma this means that our myeloma research working group directed by Dr. Stephen Nimer meets regularly to review current work in immunotherapy and new drug development. Clinically under Dr. Nimer?s leadership we will participate in the Phase III Holmium-DOTMP study and, with our colleagues in Immunology and Gene Therapy, will also develop and apply novel approaches to post-transplant immunotherapy. These strategies will be designed to increase the complete remission rate and hopefully provide durable long-term remissions for some patients. In AL amyloidosis this means that we will work with our collaborators around the world to implement trials using inhibitors of amyloid formation both small molecule, vaccine-related and drug based. One of our collaborators, Dr. Guillermo Herrera, has shown in an in vitro model of amyloidosis that certain drugs can inhibit uptake of light chains by renal mesangial cells and thereby inhibit in vitro amyloid formation. We are excited to try and develop such approaches in Phase I trials.

MT: What areas of research do you view as having the greatest potential for understanding myeloma and developing better treatment?

Dr. Comenzo:
I believe that the use of gene array technology will enable us to understand myeloma more acutely. I do not believe that myeloma is a single disease entity. There clearly is a spectrum of plasma cell disorders from MGUS to rapidly progressive myeloma. In the part of the spectrum that includes myeloma, we have yet to account for the fact that non-secretory myeloma patients appear to live longer than those with aggressive disease and, as well, for the fact that patients with smouldering myeloma can go for years without needing treatment. I am hopeful that the study of gene expression arrays will help us to understand these variations. I do not believe that much of what we currently claim to understand about myeloma will turn out to be useful or valid. Many of the chromosomal abnormalities which we have begun to appreciate appear to be more relevant to immortalization of plasma cell clones than to understanding the spectrum of disease that we clinically appreciate as myeloma. I am constantly confronting three mysteries associated with myeloma. The first is that myeloma cells are very difficult to eradicate completely from within the marrow and circulation of a patient but that they are very difficult to culture outside of the body. What causes this dichotomy? The second is that we don?t completely appreciate the impact on the immune response of having a circulating monoclonal protein continuously present. Therefore, the complex immunologic interplay between the M protein, dendritic cells, T cells and plasma cells remains a mystery. The third involves the complex role that DNA repair activity appears to play in myeloma although there is much emphasis on proliferative signals suppressing programmed cell death. We know that, except in the most aggressive cases, tumor cell turnover is limited. My sense of the disease is that a great deal of genetic material is lost or jumbled as subclones evolve. Yet myeloma clones have a unique ability to lose genetic material and yet not respond to the losses, or to provide Rube Goldberg-like reparative measures, enabling remnant subclones to become drug resistant. B cells in general are one of the few cell types that happily lose DNA as they mature. There is probably a link here, I believe, between developmental factors and the malignant plasma cell phenotype. In amyloidosis, one of the key mysteries remains. What is the significance of lambda 6 germline gene use? I suspect it has something to do with clonal survival given the large stretch of chromosome 22 that separates the joining and constant region cassettes from the lambda 6 variable region germline gene. The elimination of that intervening stretch of DNA which is over 10 KB may be related to losses or exchanges on other chromosomes that we currently know nothing about. Also, I believe that the prospect of interfering with heat-shock protein and light chain interactions intracellularly in the Golgi to reduce or eliminate light chain secretion is a promising avenue of research to explore. Therefore, by understanding these areas of molecular biology, we may develop better treatments for myeloma and amyloidosis.

MT: What do you see as the role of the IMF in the myeloma community?

Dr. Comenzo: The establishment and growth of the IMF will no doubt be regarded as the major turning point in the global appreciation of myeloma and in defining the road to a cure. The role of the IMF in the myeloma community is to act as a source of information, direction, camaraderie and solace for patients and their families; to provide funding for novel research that may or may not always pan out; and to provide the necessary political advocacy required in the unending search for priority standing in the funding of medical research.

MT:
How important is patient advocacy?

Dr. Comenzo: I am a strong believer in patient advocacy and have been responsible for giving web sites information relevant to insurance approval for transplant and the latest information available on research. At Memorial we have a well developed system of patient representatives for any patient whose family becomes concerned about the direction of care. Individual patient representatives are available 24 hours a day to provide a bridge between the medical staff and the family when such a bridge is needed. In addition, the in-patient transplant service at Memorial has consulting services such as the Integrative Medicine Service. This service provides novel beneficial therapies that many patients advocate, ranging from music therapy to foot massage to aroma therapy for those undergoing stem cell transplant, an ordeal that can often be difficult to bear.

MT: There has been interest in "IDOX", developed by Merlini in Italy, as treatment for amyloidosis. Although there are concerns about cardiac toxicity, do you view this as a potentially important treatment?

Dr. Comenzo: I do not believe that IDOX will become an important treatment for patients with amyloid cardiac involvement. That said, I do believe that IDOX will play a useful role in the treatment of amyloidosis particularly before and after stem cell transplant. I look forward to developing clinical trials in which patients have stem cells collected and then are treated with IDOX prior to and just after high-dose therapy. It may be that the full benefit of IDOX will not be appreciated until the factory producing the amyloid protein is shut off acutely. In the current trials there are responses being seen and there can be little doubt that, once the data are aggregated, the drug is likely to be approved since there are so few medicines available to treat patients with amyloid. Furthermore, it is likely that IDOX may also play a more long-term role post-transplant accelerating the removal of amyloid from involved organs. Therefore on the whole I am optimistic about a role for IDOX as part of a combination chemotherapy regimen.

MT: What about the potential of ENBREL, proposed as a new treatment for amyloidosis?

Dr. Comenzo: I have only used ENBREL in a few patients. I have discussed the upcoming trial at length with Ann Hayes of Immunex and have had an opportunity to discuss the drug with Mo Hussein from Cleveland Clinic who pioneered its use in amyloid. I am hopeful that it will have a role in AL amyloidosis and possibly in myeloma as well since TNF likely contributes to the clinical picture in amyloidosis and possibly even functions as a growth-factor for myeloma plasma cells.

MT: How optimistic are you about new effective, even curative, treatments?

Dr. Comenzo: I am extremely optimistic about the potential for developing curative therapies for myeloma. I believe that the use of chelated radioisotopes such as Holmium-DOTMP with several cycles of high dose therapy or with additional agents will increase the complete response rate to stem cell transplant allowing a fraction of patients to be cured. I am also encouraged by the application of immunotherapy post transplant and believe that we will have useful vaccines available to us within several years. As you can tell, I have an equal enthusiasm about the potential for curative therapies in AL amyloidosis. Indeed, I believe some of the patients who have undergone stem cell transplant have likely been cured. Unfortunately, the chelated radioisotopes that hold promise for myeloma patients are not safe in amyloid patients because the amyloid organ deposits contain so much calcium. Hopefully, vaccine-based strategies that target the immunoglobulin light chain per se will be of value in preventing the disease from progressing or recurring. It may be that the cellular immune links I mentioned earlier are more intact in amyloid patients since they don?t usually have large serum M proteins. However, until we can stabilize and reverse the organ dysfunction associated with progressive multisystem amyloidosis we will be hard pressed to provide beneficial therapy to all patients.



Part two of this interview can be read in Myeloma Today, Volume 3, Number 9


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