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 Sloan-Kettering Cancer Center, 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 Sloan-Kettering 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.

The preceding was Part Two of the Myeloma Today interview with IMF Scientific Advisor Dr. Raymond Comenzo. Part One appeared in Myeloma Today Volume 3, Number 8.