This is a summary of the events of September 3, 1999 at the VII International Workshop. Topics covered on Sept. 3 included:
Various drug therapies for multiple myeloma and factors that influence the outcome of treatment were discussed in this session. It should be noted that on many of these topics, there are conflicting points of view among the presenters that will be evident
- Dr. M. Boccadoro of the University of Turin provided an overview of the present status of chemotherapy for multiple myeloma. Conventional therapy refers to standard dose regimens of melphalan and prednisone or other drug combinations (e.g., VMCP, VBAP, VAD) that produce comparable results. In recent years, high dose therapy (HDT) with melphalan alone, supported by peripheral blood stem cell transfusion, has been shown to be superior to these regimens in producing complete remission and increasing survival. Originally recommended for patients under 65, HDT is now considered appropriate for those up to 70. Standard combination regimens are recommended primarily for older patients, and HDT should be considered the "conventional" therapy for most patients with multiple myeloma.
- Dr. Alberto Orfao of the University of Salamanca identified chromosomal abnormalities with prognostic implications in multiple myeloma. Over 70% of patients display such abnormalities, including gains of chromosomes 9, 15, 1, 3, 11, 7, 6, 18 and 17, and loss of chromosome 13 and chromosome X in women. An extra copy of chromosomes 6, 9 and 17 is associated with longer survival, while the absence of chromosome 13, indicates a poor prognosis Chromosome analysis at the time of diagnosis is a useful tool in evaluating prognosis and determining the therapeutic approach.
- Laboratory data that serve as prognostic indicators in multiple myeloma were presented by Dr. Philip Greipp of the Mayo Clinic. The most important negative factors are the presence of plasmablastic myeloma cells, a high plasma cell labeling index and high levels of beta-2 microglobulin The average survival time in patients with a combination of these factors is less than 2 years, compared with more than 5 years for patients in whom these factors are absent. For this reason, a novel therapeutic approach is warranted for high risk patients who do not achieve complete remission with traditional therapy.
- Dr. Joan Blade of the University of Barcelona discussed the treatment of patients with relapsing and refractory multiple myeloma. For patients who do not respond to initial therapy, a combination of high dose therapy and autotransplantation appears to be the treatment of choice. Alternatives are VAD or dexamethasone alone. However, no additional treatment is indicated for refractory patients with nonprogressive disease until progression occurs. For patients who are initially responsive but are refractory to therapy at relapse, VAD or the more convenient VBAD produces the highest response rate. A number of different combinations of established drugs have provided short-term responses, and a variety of newer agents and the resistance-reversing agent PSC 833 are currently being studied. Thalidomide has been found effective in refractory myeloma. A palliative regimen is recommended for refractory patients in whom more aggressive treatment is ineffective or inappropriate, such as older patients with other health issues or those with heart disease. The option of entering a clinical trial of new treatment strategies should be offered to patients with refractory myeloma.
- Results with thalidomide in patients with advanced or refractory multiple myeloma were presented by Dr. Bart Barlogie of the University of Arkansas Medical School. The study included many high-risk patients, including two-thirds with chromosome 13 deletions. At doses ranging from 200mg to 800mg per day, one-third of the patients had an objective biological effect, including more than one-fourth with a 75% response or better. Constipation was the most common side effect. Other side effects included somnolence (feeling sleepy) and neuropathy (numbness, particularly in the fingers and toes). It was noted that, unlike cytotoxic agents, thalidomide was not marrow surpressive (i.e., it did not reduce patients' blood counts.) Based on these results, thalidomide is now being studied as a component of various combination regimens as induction therapy for newly diagnosed patients, in patients who have responded to previous treatment, in patients with relapse and in those with smoldering myeloma or solitary plasmacytoma.
Autologous transplants use the patient?s own bone marrow (BM) or peripheral blood stem cells (PBSC). This procedure has a very low risk of transplant-related mortality ? that is, death occurring shortly after the graft ? as opposed to transplants using BM or PBSC from a donor, or allogeneic transplant, which still have much higher risk levels. However, relapses are more frequent with autologous transplants because some myeloma cells inevitably persist in the graft material and there is no "graft vs. myeloma" effect in autologous transplants. It should be noted that while there are a small number of durable long-term remissions observed, neither procedure can be considered curative. Results currently achieved with different types of autologous transplantation and various approaches to improving these results were the focus of this session.
- Dr. Bo Bjorkstrand of the Huddinge Hospital (Sweden) presented the results of autologous BM and PBSC transplantation performed in more than 5,000 patients with multiple myeloma at 287 medical centers that constitute the European Bone Marrow Transplant (EBMT) registry. The best results in terms of complete remission and overall and progression-free survival occurred when the transplant was carried out early in the course of the disease in younger patients who had previously responded well to chemotherapy. The use of total body irradiation (TBI) as part of the conditioning regimen prior to transplantation reduced survival, while the use of double transplants and maintenance therapy with alpha-interferon seemed to improve survival. A few of the patients are still alive 9-10 years after diagnosis, and Dr. Bjorkstrand raised the possibility that they could be considered cured.
- Dr. Bart Barlogie discussed the use of two courses of high-dose therapy (HDT) with melphalan in myeloma patients who had previously received standard therapy. Complete remission was achieved in 40% and was most likely to occur in patients without chromosome 13 deletions or other adverse prognostic factors (e.g., high levels of beta-2 microglobulin.) Event-free and overall survival were also longer in these patients. Dr. Barlogie concluded that achieving and sustaining complete remission by early treatment with available therapy such as tandem HDT with melphalan is a step in the direction of curing multiple myeloma.
- Strategies to improve the results of autologous transplantation in patients with multiple myeloma were discussed by Dr. Jean-Luc Harousseau of the Nantes University Hospital Center (France). One approach is to use PBSC grafts with a high proportion of cells carrying the CD34 antigen. In a non-randomized study, the outcome in terms of overall and event-free survival over a three-year period was the same whether or not CD34+-enriched PBSC was used. Another approach is to improve the conditioning regimen. This approach was tested by comparing the combination of melphalan and TBI with a higher dose of melphalan alone. Response and survival rates were somewhat higher with melphalan alone, although the difference fell just short of statstical significance. However, the melphalan alone produced significantly less toxicity. Preliminary results of a follow-up study suggest that even higher melphalan doses can be used without serious toxicity.
- Dr. M. Attal of the Toulouse University Hospital Center discussed the use of double autologous transplants performed at an average interval of three to seven months. After a relatively short follow-up of only three years, no significant differences in outcome have emerged, although there is a trend in favor of double transplantation.
- Autologous transplants using isolated CD34+ cells are associated with fewer post-transplant infections in patients with multiple myeloma. Dr. R.Vescio of the Veterans Administration Hospital, Los Angeles identified those who receive this benefit as low risk patients who achieve complete remission on the conditioning regimen. Although CD34+ selection reduces the tumor burden, it also increases the cost of therapy substantially and has not been shown to improve survival.
- Dr. Hans E. Johnson discussed a standard for counting CD34+ cells in PBSC transplant material and a technique for purging the potentially malignant CD19+ and CD34+ cells that emerge during CD34+ enrichment procedures. Although grafting of the purged/enriched PBSCs was successful, contamination with myeloma cells remains a serious problem with autologous transplants.
More abstracts on autologous transplants were presented on the following day.
- The use of a technique for analyzing the aberrant antigenic characteristics of plasma cells in multiple myeloma patients was described by Dr. Jesus San Miguel of Salamanca University Hospital. Changes in the populations of these cells were studied in patients who received autologous PBSC transplants at the time of diagnosis, before transplantation, and at three and 12 months post-transplantation. The average number of malignant plasma cells (myeloma cells) decreased from 13% at diagnosis to 0.1% one year after transplant. Longer follow-up is required to determine whether this technique can be used to assess remission status and predict relapse.
Longer remissions occur with allogeneic than autologous transplants, but transplant-related mortality is significantly higher as a result of graft versus host disease (GVHD), a generalized reaction of the immune system against the foreign tissue. Even when it is not fatal, GVHD can sometimes cause painful and disfiguring side effects. Another cause of tranplant-related mortality (TRM) is uncontrollable infection that results from suppression of the immune system to prevent GVHD. The same phenomenon which causes GVHD is responsible for "graft vs. myeloma effect", which is thought to be one of the factors responsible for the more durable remissions observed in allogeneic transplants. This effect describes the activity of the grafted marrow attacking residual myeloma cells not killed by the induction chemotherapy. Clinical results with different types of allogeneic transplants were presented in this session.
- Dr. Gosta Gahrton of the Huddinge Hospital (Sweden) reviewed data on allogeneic transplants in myeloma patients from the EBMT registry. Overall survival after allogeneic BM graft is worse than after autologous grafts due to the higher TRM rate. However, syngeneic (identical twin) transplants offer the best of both worlds, with lower TRM than with allogeneic grafts and lower relapse rates than autologous transplants. Improvements in TRM with BM transplants in the last five years have eliminated the advantage of PBSC transplants compared with BM transplants in terms of survival.
- Dr. Michele Cavo of the University of Bologna reviewed the results of allogeneic transplants involving groups of multiple myeloma patients who received different conditioning regimens and either BM or PBSC grafts in each of three different time periods. The TRM rate dropped from almost 40% to less than 20% in patients treated in the final period, who received PBSC grafts; whether this decrease is a function of a faster recovery due to the use of PBSC or simply reflects improvement over time could not be determined. Ten years after transplantation, four patients remain in complete remission according to stringently defined criteria; although these patients are thought to be at limited risk of relapse, they cannot yet be considered cured. However, the improvement in TRM after allogeneic transplant and the potential ability of this procedure to eradicate myeloma cells in some patients suggests that allogeneic transplant be considered in younger patients for whom an appropriate donor can be found.
- A modified conditioning regimen prior to allogeneic transplant in myeloma patients was described by Dr. Nigel Russel of the University of Nottingham. This regimen uses a relatively low dose of melphalan combined with total body irradiation. The overall five-year survival among patients who received either BM or PBSC transplants is 70%, with higher rates achieved in younger patients with less advanced disease. Outcomes were the same in patients with BM and PBSC grafts.
- Dr. Henk Lockhorst of the Utrecht University Medical Center discussed the effect of donor lymphocyte (B cell precursors) infusion (DLI) in patients with multiple myeloma who relapse after allogeneic transplantation. DLI stimulates a beneficial graft-versus-myeloma effect. Complete remission was achieved in 52% of patients, one of whom has remained in molecular as well as clinical CR for five years. A study of early allogeneic PBSC transplant followed by DLI is currently underway.
More abstracts on allogeneic transplants were presented on the following day.
A roundtable discussion followed, with the aim of identifying some consensus on application of the different transplant modalities. It was clear from the discussion that this remains an area of some controversy and that doctors and patients need to look carefully at the specifics of each case and keep informed on new developments.
This symposium was sponsored by Schering-Plough and was chaired by Dr. Jan Westin of Lund University Hospital (Sweden).
- Dr. Stefan Einhorn of the Karolinska Hospital (Sweden) discussed the possible mechanisms of antitumor activity of alpha-interferon (a -INF). One hypothesis is that it exerts a direct effect on malignant cells, perhaps by inducing apoptosis. Alternatively, it may act indirectly by stimulating the immune system or by inhibiting new blood vessel formation. Both the precise mechanism of action of a -INF in myeloma and its lack of effect in the majority of myeloma patients have yet to be explained.
- The results of British studies of a -INF in multiple myeloma were summarized by Dr. Keith Wheatley of the University of Birmingham. When used for induction or maintenance therapy, a -INF has produced small increases in average survival times and in complete and partial response rates. The most significant effect was improvement in relapse-free survival. The benefits of a -INF therapy must be weighed against its cost and its effect on the patient?s quality of life.
- Dr. G Avvisati of Italy reviewed published studies of a -INF as maintenance therapy in multiple myeloma. The data suggest that there is no effect on survival times, but that a -INF has a definite role in improving relapse-free survival, alone or in combination with prednisone.
- Results with a -INF maintenance therapy after autologous PBSC transplantation from the EBMT registry were analyzed by Dr. Bo Bjorkstrand of Huddinge Hospital (Sweden). In contrast to the previously presented data, this analysis indicates that overall survival as well as progression-free survival were significantly better with a -INF. The effect on overall survival was greater in patients who were in partial remission after transplant than in those who were in complete remission. The increase in average survival was as long as 3-and-a-half years, which may justify the adverse quality of life effects of a -INF.
- Data on the quality of life effects of a -INF were presented by Dr. Finn Wisloff of Ulleval Hospital (Norway). In one study, patients who received a -INF as part of a melphalan-prednisone regimen reported an increase in the following symptoms: chills, fever, pain, fatigue, nausea and vomiting, appetite loss and dry skin. After one year, however, there was no difference in quality of life between these patients and the control group This was attributed to the fact that some symptoms tend to diminish after the first few months, and that 60% of the patients with the most severe side effects stopped taking a -INF by the end of the second year. In contrast, the effects on quality-of-life reported by newly diagnosed patients who received a -INF as part of a high-dose regimen with stem cell support in. a later study were comparable to those reported by the control group in the previous study.
- Dr, Heinz Ludwig of the Wilhelm Hospital (Austria) discussed the clinical implications of results with interferon therapy. The available data suggest that the addition of a -INF to a chemotherapeutic regimen for multiple myeloma prolongs disease-free survival. The effect may be most pronounced in younger patients with less advanced disease who achieve complete remission. The $20,000 cost of the drug versus one year?s survival gain is considered reasonable. Therefore, the decision about the use of a -INF should be left to patients who should be well informed about its pros and cons.