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Myeloma Today: Please tell us a little about your background.

Dr. Sighal: I graduated from Seth GS Medical College and KEM Hospital of Bombay University in India in February 1991, after doing post graduation in Internal Medicine.

In March 1991, just after the Gulf War, I began a one-year bone marrow transplant fellowship at the Hadassah hospital in Jerusalem, Israel.

Thereafter I was in London, UK from 1992 to June 1996, where I was senior registrar in the Leukemia and Myeloma units at the Royal Marsden Hospital. In July 1996, I took up a faculty position (Assistant Professor of Medicine) in the Myeloma program at the University of Arkansas for Medical Sciences at Little Rock, Arkansas.

After 3 years in Little Rock, I moved to the University of South Carolina in Columbia, S.C. to start up a Myeloma and Lymphoma program in a department that was already a well-known center for mismatched bone marrow transplants.

After a wonderful year in South Carolina, circumstances led me to move to Chicago, IL where I am now a Professor of Medicine and Director of the Myeloma Program at Northwestern University and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

My husband, Jayesh Mehta, is in the same field and we have been fortunate to have been given appointments together in all the places we have worked. He is currently Professor of Medicine and Director of the Hematopoietic Stem Cell Transplantation Program at Northwestern University and the Robert H. Lurie Comprehensive Cancer Center.

MT: You and your husband, Dr. Jayesh Mehta, worked as registrars with Prof. Ray Powles at the Marsden in the U.K. on the myeloma transplant unit. Is that how you got into the field of myeloma?

Dr. Sighal: Yes. My original focus was bone marrow transplantation, but when I moved to the Marsden, I worked with Prof. Powles who is chief of both the leukemia and the myeloma programs there. In that position, my area of interest expanded from one aspect of therapy (transplantation) to management of the entire course of the illness- from diagnosis to salvage therapy.

MT: You also worked with Dr. Barlogie in Little Rock, Arkansas. What are your insights into the differences between U.K. and U.S. transplant practice/philosophy?

Dr. Sighal: The Arkansas experience was unique for me in that it was an intense sharpening of focus to one disease.
The contrast between the U.K. (Marsden) and the U.S. (Arkansas) ?style? is mainly in the degree of aggressiveness of the approach to myeloma, both in regard to diagnosis and therapy.

For example, MR scanning of the bone marrow of all patients, CT guided biopsies of MRI ?hot spots? to obtain material for cytogenetic studies are tests that were routine in Arkansas but almost never performed in UK.

The major difference in the therapeutic approach is the single vs. double transplant strategy. The Marsden was the center that first used high dose therapy (IV Melphalan was developed there) in myeloma. After pioneering that first move towards intensification of chemotherapy, the Marsden program has chosen to stick with planned single transplants followed by maintenance therapy (they conducted a trial of post transplant maintenance interferon in myeloma). Further transplants are only done for salvage therapy, if suitable. Their results in terms of survival are comparable to the Little Rock results.

The Little Rock program, on the other hand, is well known for the planned double or tandem transplants (3-6 months apart) for all patients, irrespective of the response to the first transplant. Therefore even a patient achieving a complete response before a first transplant will go on to receive a planned second transplant.

I have now an ?aggressive? approach towards diagnosis and documentation of information about prognostic factors before starting therapy and a ?moderate? approach towards therapy with induction followed by single transplants and maintenance therapy, leaving the second transplant as a salvage option. Thus, I seem to have been influenced by both the places in my past!

MT: Is Bone Marrow Transplantation your area of special interest?

Dr. Sighal: Bone Marrow Transplantation was what I received my initial training in, and I continue to be fascinated by the biology of both autologous and allogeneic transplantation. In my current position, I am also one of six members of the bone marrow transplant program at Northwestern University.

However, my area of special interest is now various aspects of therapy of multiple myeloma with transplantation being one of several possible modalities of treatment. The single vs. tandem transplant strategy is a dilemma that plagues the myeloma community today and the data currently available is unable to give a clear indication.

Having had the privilege of working at both the Marsden and Little Rock, I have come away with my own (somewhat uncertain!) opinion about double transplants! Although double transplants are well tolerated and may result in better degrees of response, this strategy has not been conclusively shown to prolong the duration of responses and survival in comparison with single transplants.

Even after double transplants, patients do eventually relapse and need salvage treatment. At that time a prior second transplant may leave patients with diminished reserve capacity to withstand extensive further therapy.

In these days when we have a plethora of exciting new drugs in trials for myeloma, patients have so many salvage options that a better strategy than planned double transplants may be a single transplant with enough stem cells harvested before that transplant so that the subject has cells in store for a future salvage second transplant if needed. The second transplant can then be one of many salvage therapy options for the patient when faced with relapsed disease.

Information that would be helpful in this area is one, an analysis of the available data, or further clinical trials, to show if a planned second transplant is better than a salvage second transplant and two, an analysis of data to see if there are sub-categories of patient groups that clearly benefit from the double transplant strategy in terms of prolongation of life after diagnosis.

MT: How did you become involved in the thalidomide trial for which you were the primary author on NEJM paper? What is your current perspective on thalidomide/ImiDs?

Dr. Sighal: I was part of the Little Rock myeloma team when Beth Wolmer, the wife of one of our patients, first brought thalidomide as a drug for therapy of myeloma to our attention. Her husband had relapsed myeloma and was running out of treatment options. In her determined search for new therapies, she heard about Dr. Judah Folkman in Boston and his work in anti-angiogenesis therapy for tumours. Dr. Folkman studied the patient?s bone marrow slide for the presence of neo-vascularity, confirmed that anti-angiogenesis therapy was a reasonable approach in this case and suggested thalidomide as a good potential anti-angiogenesis agent. This and the fact that increased bone marrow angiogenesis in myeloma patients had been reported by Dr. Angelo Vacca in Italy led to the setting up of a clnical trial of thalidomide for relapsed myeloma.

Unfortunately, this drug did not work in the case of Beth?s husband but the second patient who was placed on this trial (a day after the first), went on to have a dramatic response. This was a patient I was closely following and so I was privileged to be the first person to actually look at the serial test results clearly pointing to the success of this agent. I then was the person who tracked, charted and analyzed all the laboratory results of the subsequent patients on this trial and went on to write the developing story that was finally published in the NEJM.

My current perspective on thalidomide is that this drug has revolutionized the way we treat cancer patients. There is no doubt regarding its activity. It is being rapidly promoted to front line therapy with good initial response rates (although much remains to be learned about the response durations evoked by this agent specially in comparison with transplantation). The synergism between thalidomide and other agents opens up a prospect of continuing advances in response rates and durations. Also, the surge in research activity in trying to determine the mechanism of action of thalidomide in myeloma (still unclear) has lead to greater understanding of the disease biology.

The Imids are hovering on the horizon and should be available for Phase II trials early next year, I hope. I have experience with one patient (more closely followed by my husband) who has followed us around from the Little Rock days and who could not tolerate thalidomide. He started compound CC5013 (Imid) in March 2000 (before it was available in phase I trials in USA) by way of U.K. where he registered as a private patient. His tolerance is good and the disease is stable. His is the longest duration of therapy on this drug.

MT: What do you think are the most promising areas of myeloma research?

Dr. Sighal: The most promising areas of myeloma research are the newer agents in clinical trials and the insights in disease biology gained from the study of the mechanism of action of these agents. This research will result in development of therapies that can be applied sequentially or together so that, at the very least, patients can be given long continuous (or discontinuous) periods of remission and, dare we hope, finally a cure.

MT: What is the greatest need currently in the myeloma clinical research arena?

Dr. Sighal: The greatest need currently in the myeloma clinical research arena is a co-ordination of efforts in the various centers so that there is no wasteful duplication of work. Festering issues such as single vs. double transplants, post transplant maintenance therapy do not appear to be heading towards resolution with the current clinical trials. Better trial design and perhaps review of trials by a general forum for opinion prior to patient accrual may allow for more rapid advancement in collective knowledge.

MT: What are the research priorities now at the Robert H. Lurie Comprehensive Cancer Center in Chicago?

Dr. Sighal: The current myeloma program at the Robert H. Lurie Comprehensive Cancer Center is newly established under my direction, (I started here January 2001), and happily undergoing rapid growth in terms of patient numbers. The research priority on the clinical side is exploration of newer agents such as Proteosome inhibitors; neovastat (shark cartilage anti-angiogenesis agent) and Bcl-2 antisense oligonucleotide therapy. Also immunotherapy and development of suitable vaccination strategies.

Another important area of clinical research is the development of mini-allogeneic transplants in myeloma. The strategy we employ was created by my husband while he was director of allogeneic transplantation at Little Rock. It involves the adminstration of a very low dose of melphalan (100mg/m2) followed by planned infusions of donor stem cells at various times post transplant to ensure continued engraftment and chimerism and graft versus myeloma effect. The results have been spectacular in terms of a very low mortality and durable engraftments. The Arkansas group has continued this approach and the results were recently published in Blood journal. This approach has radically broadened the population of patients eligible for allogeneic transplantation and improved results with this procedure.

On the basic research front, Dr. Steven Rosen?s (who is also the Robert H. Lurie Comprehensive Cancer Center Director) laboratory has focused on mechanisms of stimulating apoptosis in glucocorticoid resistant myeloma cell lines (that they have developed) by manipulating signal transduction pathways and in the development of newer agents (such as 8-chloro-adenosine) in myeloma. Drs. Ron Gartenhaus and Leo Gordon (who is the Division Chief of Hematology/Oncology) are developing strategies to enhance the activity of arsenic trioxide in myeloma and I hope to bring these approaches to the clinical arena.

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

Dr. Sighal: The IMF is doing a great job of keeping the community together. In fact, I believe there was really no ?myeloma community? before the IMF. This sense of belonging to a group that cares most about what goes on in this medical area is very comforting to both patients and physicians.

The patient seminars are a forum where information is received but more importantly the patients connect with each other and my patients tell me that the shared experiences and comradeship goes a long way in helping them cope with the diagnosis, the consequent physical and emotional challenges and the flood of technical information that comes their way. Another significant interaction is that between the physicians participating in these meetings. The personal contact results in sharing of ideas and development of collaborative efforts.

Thus the IMF plays the role of a facilitator of the community, a sort of ?guide? that patients can turn to for information about all aspects of being a myeloma patient.

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