We thank Celgene for providing an unrestricted educational grant which made possible these updates from Stockholm.
This is a partial summary of the events of September 4, 1999 at the VII International Workshop.
- Dr. Martine Amiot of the Institut de Biologie, Nantes, France presented work looking at the role of IL-6 in the disease process. Evidence was presented showing that sIL-6R (soluble IL-6 receptor) is released in unusually high quantities from myeloma cells. Metalloproteinase inhibitors appear to be capable of reducing the release of sIL6-R. It was also found that c-reactive protein, which is overproduced in myeloma patients, is a stimulator of sIL-6R. The presence of sIL6-R was also found to increase bone resorption, suggesting that treatment strategies aimed at reducing the levels of sIL-6R could prove valuable.
- The role of IL-1beta in myeloma bone disease and the
development of the disease was reviewed by Dr. John. Lust of the Mayo Clinic. Investigation of IL-1beta showed that increased levels of IL-1beta seemed to correlate with the transition from MGUS (monoclonal gammopathy of undetermined significance) to myeloma. Patients testing positive for IL-1beta also seemed to have a correlation with osteoclast activating factor (OAF), which plays a role in the process of bone resorption (destruction). It is felt that the initiation of production of IL-1beta by plasma cells in MGUS patients is a critical genetic event in the progression to myeloma. It was suggested that IL-1beta inhibitors could play a valuable role in control of the disease and of bone destruction. Work done in other diseases suggest that bisphosphonates may have some anti-IL-1beta activity.
- Dr. Melestios Dimopoulos of the University of Athens School Of Medicine discussed diagnostic procedures for myeloma bone disease. Skeletal x-rays will be abnormal in 80% of patients. (70% lytic lesions in specific locations, 10% diffuse osteoporosis.) Bone healing is rare after chemotherapy. Nuclear scans, using radioisotopes have proven useful in tracking progress. Magnetic resonance imaging (MRI) are useful in identifying sites of active disease. It was observed that diffuse disease can generate patterns on the MRI which can easily be missed by an inexperienced radiologist. A study at MD Anderson found that patients followed with MRI in addition to x-rays had less bone disease progression than those followed by x-rays alone (presumably because they were able to detect activity and receive treatment earlier. Dr. Dimopoulos found that the MRI pattern can also be a prognostic factor and can be used to assess response to treatment.
- Dr. Peter Croucher of the University of Sheffield Medical School presented work on the potential mechanisms for bisphosphonates in the control of multiple myeloma. Bisphosphonates like clodronate can be metabolized by cells to a cytotoxic level. By contrast, nitrogen-containing bisphosphonates (e.g., pamidronate) act by blocking signaling pathways that allow the transformation of Ras and Rho proteins. Both processes induce apoptosis (cell death) of osteoclasts (cells which resorb bone). Inhibiting bone resorption could alter the micro-environment in the bone marrow, reducing the level of some growth factors which could have a positive impact in controlling disease activity. It is also possible that there could be a direct anti-myeloma cell effects, particularly with the more powerful bisphosphonates. Experiments were performed in two different institutions on animals with high dose bisphosphonates showed no clear anti-myeloma effect vs. controls. These two studies were performed with ibandronate. Similar studies with pamidronate showed similar results—that the bisphosphonates had a significant impact in controlling bone lesions and reducing bone destruction but had demonstrated no significant impact on myeloma tumor cells
- Dr. Roger Pearse of Memorial Sloan-Kettering Cancer Center discussed the role TRANCE in myeloma-associated bone destruction. TRANCE is required for normal bone metabolism and are a key trigger for the activation of osteoclasts. It can be produced by osteoblasts (which cause bone to grow) to stimulate the growth of osteoclasts. TRANCE is a member of the TNF family. A compound called OPG can bind to TRANCE and prevent the stimulation of osteoclasts. OPG is a TNRF2 homologue. Dr. Pearse found increased production of TRANCE in patients with active myeloma. Myeloma cells seem to be able to block OPG, which would normally act to counteract the effect of TRANCE. Dr. Pearse's work is supported by a grant from the International Myeloma Foundation.
- Dr. Reiner Bartl of the University Hospital, Grosshadern, Munich discussed the use of bisphosphonates earlier in the disease process as a strategy for preventing bone lesions and slowing disease progression. 160 patients were treated, in a retrospective, non-randomized study with pamidronate and ibandronate immediately after being diagnosed with myeloma. After three months of treatment, there is dramatic reduction in osteoclast activity in the bone marrow and, in some patients, reduction in the apparent aggressiveness in the disease, as evidenced by images of bone marrow cells. The work suggested use of bisphosphonates in low doses for smoldering myeloma and escalating doses in active disease.
- Dr. James Berenson reviewed progress in use of
intravenous bisphosphonates for myeloma. These drugs
have a major effect on osteoclasts and also reduce the
levels of key cytokines (cell growth factors) like
IL-6. They are poorly absorbed orally. Dr.
Berenson reviewed the progress in developing safe and more
powerful bisphosphonates. Pamidronate (Aredia®) was established as a safe, effective agent during a key Phase III trial. A Phase II trial looked at higher doses of pamidronate for relapsed myeloma, treated at 90mg every two weeks and 180mg every two weeks. In those receiving 90mg, there was no significant reduction in tumor mass, although there was some effect observed at the higher dose. With the availability of zolderonate, this more potent agent is being substituted for pamidronate as this trial proceeds. Zoledronate has been shown to be effective at very low doses in controlling hypercalcemia. Doses of up to 8mg were well tolerated in a Phase I trial and significantly reduced markers for bone resorption. A Phase II trial showed that at 4 mg had at lease as powerful impact in preventing bone resorption than a 90mg dose of pamidronate. A Phase I trial is looking at doses of zoledronate up to 16mg. Side effects were not severe and included bone pain and conjunctivitis. It was felt that further trials are needed to establish the relative effectiveness of zoledronate vs. pamidronate. Dr. Berenson observed that the nephrotoxicity (kidney effects) of bisphosphonates was related to the backbone of the drug molecule rather than the active part of the molecule. As a result of this, the more powerful agents, which use the same backbone, more powerful doses because less off the drug needs to be administered to get the same effect. Ibandronate was studied in the same setting (relapsed myeloma) and found to have no significant anti-tumor effect.
- Findings regarding use of oral bisphosphonates were
presented by Dr. E.V. McCloskey of the University of Sheffield Medical School. A randomized trial of 549 patients looking at oral clodronate vs. placebo. The clodronate arm of the study had a significantly lower number of skeletal events (fractures or lesions requiring irradiation or other treatment). Dr. McCloskey also reported a modest increase in event free survival in the patients receiving clodronate. Those on clodronate had a significantly less number of height loss caused by vertebral collapse/compression). The average height loss for the placebo group was 3 cm whereas the height loss in the clodronate group was only 1cm. Dr. McCloskey expressed the view that clodronate properly administered can be as effective as intravenous pamidronate. He also stated that they should be given indefinitely and that further trials need to be done to determine the appropriate role of bisphosphonates in MGUS. There was a considerable amount of controversy in the question period about the need for an objective comparison of oral and intravenous bisphosphonates as no head to head trials have been performed.
- Dr. S. Yaccoby of the Arkansas Cancer Research Center presented work looking into the anti-myeloma effect of bisphosphonates using mouse models using zoledronate and pamidronate. In 6 of 7 experiments done with pamidronate and 3 of 4 done with zoledronate, there was some inhibition of tumor growth activity. Pamidronate appeared to reduce the size of osteoclasts and leave them detached from the wall of the bone but not reduce the number of osteoclasts. Zoledronate appeared to significantly reduce the number of osteoclasts present in the marrow.
A roundtable discussion about the use of bisphosphonates in myeloma followed the presentations. The investigators agreed that while there was no hard evidence to suggest that use of bisphosphonates in phase I and phase II patients with no overt bone lesions would have a benefit, they felt that the drugs should be used for all patients diagnosed with myeloma. There would be difficulties in conducting trials for MGUS patients as it would take a very long time to reach any conclusions. There was also agreement that no trials had been done comparing oral and intravenous bisphosphonates. Both clearly had benefit in preventing bone destruction but it was a matter of speculation and some controversy as to whether one was better than the other.
- Dr. B Bogen of the University of Oslo presented basic scientific research looking at plasmacytomas in mouse models to understand how APC's (antigen presenting cells, dendritic cells) can be primed to stimulate production of CD4+ t-cells that are specific to the idiotype (protein fingerprint) of the malignant myeloma cell.
- Natural idotypic immunity in multiple myeloma was
discussed by Dr. Håken Mellstedt of the Karolinska Hospital. It was observed that T lymphocytes are present in myeloma which recognize the idotypic region of the myeloma protein.. This suggests that these natural idotypic tumor antigens (immune system triggers) may be appropriate components of a vaccine approach.
- Dr. Larry Kwak of the National Cancer Institute discussed myeloma cells as potential targets for CD8 t-cells for recognition and lysis (destruction). Like Dr. Mellstedt's presentation, the suggestion here is that the proteins secreted by the myeloma cells could represent a tumor-specific antigen (something that would allow the immune system to uniquely identify the tumor.) The study confirmed that these proteins could, in fact, trigger a t-cell response specific to the tumor's idotype.
- Dr. Neal Kay of the Virginia Piper Cancer Institute presented work looking at the overall behavior of the immune system during the course of myeloma. It was noted that while the number of malignant myeloma cells increased as the disease progressed, the number of normal immune system cells tended to fall. This effect is exacerbated by the effects of chemotherapy on the immune system, which tends to further reduce the number of these cells. It is thought that the level of immune function may be a determinant of survival and that the degradation of immune system function may be a major negative factor in the course of the disease.
- Dr. Massimo Massaia of the University of Torino reviewed research performed into idiotypic vaccinations, post transplant. The trials were able to generate an immune response specific to the tumor idiotype. There was no tumor eradication observed, as the patients were in remission before vaccination. There was a wide range of remission duration in the patients. There is no conclusive evidence of benefit, despite the evidence of immune reaction, so further follow-up and further studies are required. One of the open questions is the immune competence of myeloma patients, which would speak to whether or not their immune systems are capable of responding properly to a vaccine. This suggests that it may be appropriate to test patients for immune system repertoire before moving forward with a vaccine program.
- Dr. Munshi presented a three arm trial looking at vaccination combined with two stem cell transplants utilizing melphalan. The trial compares a double transplant with a double tranplant with vaccination after each transplant and with vaccination only after the second transplant. Thus far, eighteen patients have been enrolled so this presentation represents a progress report. Again, there was an anti-idotype reaction observed, although most responses were in t-cells, not b-cells. The clinical implications are as yet unclear and will await further further progress on the trial.
- Dr. Seah Lim of the Arkansas Cancer Research Center discussed an approach to dendritc cell vaccine using monocyte-derived dendritic cells rather than from the peripheral blood. The approach was tried with a patient who had advanced disease and was refractory (not responsive) to other treatments. Six patients were treated using this protocol. Three patients were previously untreated. Each of the patients, with the exception of one post-transplant patient developed t-cell immune responses specific to the myeloma protein. Some reduction in blood protein levels were observed. However, the reductions seen were modest and it is felt that more powerful responses will be required to have real clinical benefit and that this will require further research into vaccination strategies.
- Dr. Freda Stevenson of the Tenovus Lab presented her approach for using DNA vaccines. These DNA vaccines target the DNA (genetic material) of the malignant cell versus the idiotypic proteins secreted by those cells. The DNA vaccine approach mimics a viral infection and generally invokes an immune response that incudes antibodies, CD4+ t cells and CD8+ t-cells One of the cautions is to make sure that the vaccine doesn't spur auto-immune responses, where the immune system would attack healthy cells. It is felt that this approach could be useful in myeloma as well as other malignancies. Immune responses were demonstrated in an early trial conducted for lymphoma in humans. A clinical trial is now starting for lymphoma and will be undertaken in the future for myeloma. To date, work in myeloma has only been performed in mouse models. It is thought that the MUC-1 protein could be used as a second antigen (immune system trigger) when this approach is applied to myeloma.
- Dr. Bernard Klein of INSERUM, France, discussed issues in cell-based immunotherapy approaches for multiple myeloma. The work focused on the different ways in which dendritic cells and myeloma cells can be used to generate immune responses to the myeloma. It was found that induction of Bt-1+ myeloma cells can induce CD8 t-cell production. The CD8 cells were able to kill tumor cells without killing normal blast cells.
- Dr. Kris Thielemans of Belgium discussed using MAGE-type genes as targets for vaccination in myeloma.
A roundtable followed the individual presentations. The discussions suggest that progress is being made on the mechanics of vaccination approaches and we are getting to the point where we can safely develop patient-specific vaccines that can induce an immune system response, these approaches are not yet generating responses powerful enough to have significant tumor control effects. There are also open questions as to whether or not the immune systems of myeloma patients, particular those with advanced disease or those who have been heavily pretreated, are powerful enough to respond to the vaccine at a level sufficient for tumor control. The consensus was that more work is needed both on vaccine strategies as well as on understanding the immune status of myeloma patients. There was also a feeling that there needs to be thought given to the appropriate antigen to be used in these approaches. One answer may be to use multiple antigens simultaneously to increase the response. It was noted, though, that if too many antigens are used, the response to any one antigen may be reduced as there could be competition for t-cell recruitment.
(Additional presentations on transplants were made on the prior day)
- Dr. Jean-Paul Fernand of the St. Louis Hospital (France) reported that overall and event-free survival were better with high-dose therapy combined with ABSC transplantation than with conventional chemotherapy, but differences were not statistically significant.
- Dr. Martha Lacy of the Mayo Clinic reported that delaying stem cell transplant has no apparent effect on survival time compared with early transplantation and the duration of frozen stem cell storage did not affect the success of the graft.
- Dr. Friedrich W. Cremer of Heidelberg University reported that the addition of total body irradiation to high-dose melphalan prior to PBSC transplant increases toxicity but has no effect on survival. Further, two cycles of melphalan prior to transplant did not eliminate myeloma cells from the circulation.
- Dr, Sergio Giralt of the M.D. Anderson Cancer Center reported that 166 Holmium, a radioactive pharmaceutical agent that is absorbed selectively by bone, can be added safely to a regimen of high dose melphalan alone or combined with total body irradiation prior to autologous PBSC transplantation.
- Dr. Christian Straka of the Innernstadt Medical Clinic (Germany) reported that purging of B cells before autologous PBSC transplant improved overall and event-free survival but the comparison with unpurged grafts was not statistically significant.
- Dr. Gary Schiller of the University of California/Los Angeles reported that CD34+ selection reduced tumor cell contamination of PBSC autografts compared with nonselected grafts. However, there were no differences in overall or event free survival, indicating that the system used for this study does not completely eliminate tumor cells from graft material.
- Dr. Hans E. Johnson of the University of Copenhagen reported on a system for selecting CD34+
cells and purging CD19+ cells prior to PBSC
transplantation in five patients. CD19+ cells were substantially reduced in four cases and eliminated in one.
- Dr. G. Martinelli (Italy) reported on a comparison of molecular remission (MR) rates – a reflection of the absence of residual myeloma cells – in selected patients who achieved clinical remission after allogeneic or autologous PBSC transplants. Among the allograft patients, half of those studied achieved MR. Among patients who received either one or two selected or unselected autografts, only 10% of those studied achieved MR.
- Dr. Paolo Corradini of San Raffaele Hospital (Italy) reported that 11/22 patients who achieved clinical CR after allogeneic transplantation also achieved molecular CR, although 1/11 suffered a relapse
- Dr. Henk Lockhorst of the University Medical Center (The Netherlands) reported that early allogeneic transplant following a relatively mild conditioning regimen was not associated with excessive transplant-related mortality.
- Dr. Ann Traynor of Northwestern University
reported that there was no transplant-related mortality
and only case each of grade III GVHD following allogeneic
transplants using a combination of bone marrow and CD34+-selected PBSCs and a mild conditioning regimen.
- Dr. Ignazio Majolino of the Cervello Hospital (Italy) reported that allogeneic PBSC transplants produced overall and progression-free survival rates of 70% and 45%, respectively, after almost four years; transplant-related mortality was 14%.
- Dr. Arthur Molina of the Fred Hutchinson Cancer Research Center reported that preliminary results of nonmyeloablative (i.e., without BM eradication) allografts of PBSCs following PBSC autografts in five patients indicate that this approach results in successful engraftment with minimal toxicity.
- Dr. Frederic Garban of Grenoble University Hospital Center reported that nonmyeloablative PBSC allogeneic transplantation can produce a beneficial graft-versus-myeloma effect in high-risk patients.
Summarizing this session, Dr. Gosta Gharton of the Huddinge Hospital, (Sweden) expressed the hope that these new approaches that reduce transplant related mortality with allografts and relapse associated with autografts will be more widely adopted.
This symposium was chaired by Dr. Gosta Gharton of
the Huddinge Hospital, (Sweden) and sponsored by Amgen
- The number of CD34+ cells in graft material
reflects the progenitor cell content and predicts the rate
of engraftment. Dr. Gilles Salles of the Lyon-South
Hospital Center presented the results of a study comparing
three CD34+ doses in autologous PBSC
transplants in patients with a variety of hematologic
malignancies. . (The CD34+ dose is usually
expressed as a multiple of 106 – that is
1,000,000.) The low dose was less than 2.5x106;
the high dose, more than 15x106; the
intermediate dose, more than 2.5x106 but less
than 15x106. Following transfusion, the time to
successful engraftment was significantly shorter for
patients in the high-dose group, who also required fewer
platelet transfusions, had a shorter hospital stay and
received antibiotics for a shorter period. Given the cost
of these these interventions, the findings suggest that
high CD34+ doses may be cost-effective as well as clinically beneficial.
- Dr. Gilles Salles of Centre Hospitalier Lyon-Sud reviewed work looking at hematological
reconstitution after transplant focusing on the number of
CD34+ cells reinfused in 168 patients with
lymphoproliferative diseases (including multiple
myeloma). It was found that a low dose of CD34+
cells (2.5x106) had delayed neutrophil and
platelet recovery. This given a high dose (>15
x106) had accelerated neutrophil and platelet recovery. Those with accelerated platelet recovery required fewer platelet transfusions, less antibiotics and shorter hospital stays. It was suggested that these data imply that techniques to enrich the CD34+ population in the allo- or autograft could be cost effective and improve patient quality of life.
- The challenges of achieving engraftment in disease that
involve the bone marrow microenvironment, such as multiple