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June 2001 Volume 4, Issue 5:
VIIIth International Myeloma Workshop:
By Brian G.M. Durie, MD
Meeting Report From Banff, Canada, May 4th-8th, 2001
06.01.01
The VIIIth International Myeloma Workshop brought together the top myeloma investigators to present and discuss the most recent research findings. The Meeting was hosted by IMF Scientific Advisor Dr. Linda Pilarski and colleague Dr. Andy Belch. Together with the organizing committee, they did an excellent job planning this event. The setting was beautiful ? the Banff Springs Hotel, nestled among pine trees surrounded by gorgeous snow covered mountain peaks. But the meeting was grueling ? satellite and corporate meetings started by 7:00 in the morning and the poster sessions ran until 11:00 in the evenings. So much for a stroll in the woods!


So what was new? What was accomplished? For five packed days, there was a tremendous exchange of information and ideas. Groups of myeloma doctors huddled to discuss results; researchers planned their next projects. Prior conclusions about both basic science and treatment results were updated and consolidated. Full summaries will be distributed as part of the Comprehensive Guide to Banff. (See page 12 for aditional information.)


The pre-workshop symposia focused on genomics, arsenic trioxide, bone treatment, signal transduction, prognostic factors and Waldenstrom?s macroglobulemia ? the spectrum of priorities was immediately evident. The broad hope is that understanding the DNA abnormalities will lead to better diagnosis and treatment. Phase II arsenic trioxide trials are underway and we?ll soon know if this therapy can be helpful in myeloma. There is new understanding of cell to cell interactions in the development of bone disease. New therapies will certainly follow. Signal transduction, the transmission of messages from the cell surface to trigger DNA expression and activity was a hot topic for discussion in part because of the dramatic recent success with STI-571 (Gleevec®) in the treatment of chronic myelogenous leukemia. Can this drug work in myeloma? It might. Certainly, more selective similar drugs can be developed to target myeloma cells. There was much discussion about which signals need to be blocked in myeloma cells.


The Prognostic Factor Workshop, sponsored by the IMF, brought together investigators to better classify myeloma, identify patients who can truly benefit from specific therapies (e.g. stem cell transplant, thalidomide) and clarify what?s necessary to document and monitor response. A series of publications will come from this working group. The separate symposium on Waldenstrom?s highlighted the need for a special focus on this disease since both testing and treatment are different than for myeloma. All this before the meeting even got started!


On Friday evening, IMF Scientific Advisor Prof. Håkan Mellstedt received the Waldenstrom?s Award for distinguished contributions to the field. An outstanding researcher, Prof. Mellstedt presented the lecture on the topic of immunotherapy in which he has a longstanding interest.
The Saturday morning meeting raised the question ?What is the cell (clone) of origin of myeloma?? Precursor B lymphocytes can be ?recruited? to join the myeloma clone triggering initial growth and relapse but the mechanisms still remain hazy at best. Genetic studies using DNA array technology combined with traditional genetic studies and fluorescent chromosome studies (FISH) are starting to provide clues. The surface is just being scratched to find increasingly complex layers of interacting chromosomes.


Loss of chromosome 13 is important since it is associated with more active disease. But why is the loss so important and what about all the other chromosome changes? Several large groups or consortia are now emerging to work on these problems, including Drs. Shaughnessy and Barlogie (Little Rock, AR); Dr. Lief Bergsagel and colleagues (Cornell group, NY); Dr. Fonseca and colleagues (Mayo Clinic, MN); Drs. Avet-Loiseau, Bataille and colleagues (IFM group, France); and Dr. Keith Stewart and colleagues (Candian group in Toronto) to name a few. From the list of names it is clear that this is a priority. Angiogenesis was also discussed but because of suspicions that thalidomide may work by a different mechanism, the clinical relevance of angiogenesis remains unclear presently.
Saturday afternoon was devoted to a review of results with transplants. Discussion was heated because, depending upon which statistician you choose to believe, the benefit was ?too close to call.? The French (IFM) study still does not show clear benefit of double autologous transplant versus single, although they will continue to evaluate double transplant in their next randomized study. A pointed question from the audience brought the gathering back to reality: ?We are discussing double transplant when we are still struggling to assess the benefit of a single transplant!? The role of transplantation is still unclear in part because poor risk patients (e.g. with chromosome 13 abnormalities) don?t necessarily do better with transplant and conversely good risk patients (e.g. with low SB2M) can often do well without transplant. There was a sense that good and/or intermediate risk patients may do well with single transplant but proof was hard to find. Results of the large US inter-group study will not be available until 2003.


Allotransplant met a similar fate at the hands of discussants. Although the EBMT data presented by IMF Scientific Advisor Prof. Gösta Gahrton showed evidence of reduced toxicity in the last 5-10 years, most investigators were still concerned that the up-front risks (20% or greater risk of death from complications) still outweigh a small and uncertain chance of potential cure. Attention turned to mini-allo transplants as a way to achieve graft versus myeloma benefit with lesser risks. However, the risks of graft versus host and related complications remain high and as yet the benefit is unclear. Nonetheless, many studies incorporating mini-allo transplant (plus additional immunotherapy with lymphocyte infusions or dendritic cells or vaccines) are underway or on the drawing board. Results should be clarified by 2003.


Saturday evening was the first opportunity to review some of the 231 posters presented at Banff ? molecular studies from Germany, Australia and the UK; the epidemiology of myeloma from Brazil; transplant results from Portugal and the Czech Republic; interesting follow-up studies from M.D. Anderson Cancer Center on the negative impact of age on myeloma outcome and the progressive decline (1965-1999) in referral of myeloma patients with advanced disease to centers such as the one in Houston. I was pleased to see so many new groups from around the world working on myeloma.


Sunday morning began with a concerted search for coffee to prepare for the day?s long discussions of new therapies as well as updates on standard approaches. There was excitement about the preliminary results with Millenium product PS-341 (a biologic agent ? proteasome inhibitor) which has produced remissions in patients with advanced disease. There was concern about platelet-related toxicity with NeoRx compound 166 Holmium-DOTMP which will require further safety testing before continuation of full scale trials. Preliminary results from the prognostic factor group were presented and a very important and interesting evaluation of ?quality of life and cost utility? from Norway was discussed. Finally, at 4:30p.m. it was time for a break! Thankfully, the organizers had set-up a wonderful dinner at Chateau Lake Louise, a 45 minute bus ride from the conference center. Speakers and listeners alike welcomed the beautiful walk along the lake and magnificent scenery. A wonderful evening.


Monday morning was off to a rapid start with more discussion of genes and cell-cell interactions ? new targets for therapy. In the afternoon, immunotherapy and vaccine strategies. Not much has changed since the 1999 International Myeloma Workshop in Stockholm ? immune approaches are promising but we still have not defined targets and results are preliminary in terms of efficacy. Maybe 2003 will see progress.


Another late evening of posters. Again an interesting mixture of new topics and investigators from around the world. Phase I results from London, Leeds and Japan (sponsored by Chugai Pharmaceuticals, Japan) evaluated a new humanized monoclonal antibody against HM1.24 antigen on myeloma cells. This HM1.24 antigen is a new promising target for immune therapy against myeloma.


Results with kyphoplasty (for the treatment of compression fractures of vertebrae) from the Cleveland Clinic and the use of FDG/PET scanning from Cedars-Sinai Cancer Center were presented. Laboratory data showed that macrolide antibodies such as Clarithromysin (Biaxin®) enhance the in vitro efficacy of steroids such as dexamethasone and thalidomide against myeloma cells. Remarkably, there were no reports about the HHV-8 virus at this meeting. However, there was an updated report on the finding of a new ?stealth virus? (related to cytomeglalovirus [CMV]) in myeloma patients.


On Tuesday, IMF Scientific Advisor Dr. Gregory Mundy chaired a wonderful session on bone disease in myeloma. The details of why and how bone damage in myeloma occurs were summarized along with details of how drugs such as the bisphosphonales actually work. New acronyms such as RANK, TRANCE and OPG (potential targets for bone disease treatment) have been added to the myeloma lexicon. There was a strong sense of excitement that osteoclast inhibitors and statins which trigger bone healing can soon make a difference for myeloma patients.


The final session was devoted to the role of thalidomide. This important topic kept investigators in their seats until the final moment. Details of single agent and combination studies were discussed. Even low doses (50-200 mg/day) work well and combinations with dexamethasone and/or Biaxin can be remarkably effective as discussed by groups from the Mayo Clinic and M.D. Anderson. Dr. Mort Coleman from New York discussed his excellent results with the BLT-D protocol.
The huddles in the hallways were now about what time the shuttles depart for the airport. Attention turned to the expectations for the 2003 meeting in Salamanca, Spain. Perhaps siesta can be incorporated into the program.

Banff Guide available in PDF format


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