The first morning's session was opened by Professor Douglas Joshua, chairman of the organizing committee. Professor Joshua remarked that this meeting was the largest gathering of the myeloma community, with over 1100 delegates in attendance. The new initiatives of this meeting include concurrent plenary and focus sessions due to the vast amount of material to be covered. Additionally, this meeting is planned to include a chairman's symposia, oral presentations for abstracts, poster sessions, industry exhibitions, and industry-sponsored symposia. Professor Joshua briefly discussed the history of the meeting as a series of workshops held globally beginning in 1987. The 10th International Workshop included a representation from 64 countries, with the largest representation from the USA, Australia, UK, Italy, and France . Professor Joshua credited the development of the intense and comprehensive scientific program to Dr. Joy Ho. The workshop's plenary and focus sessions were formatted as 15-minute presentations from renowned experts in the field, followed by questions and discussions from the participants.
Dr. Ian MacLennan opened the session on unconventional switched bone marrow plasma cells With Ig V-region mutations and provided a summary on multiple myeloma (MM), where tumor cells are found in the bone marrow. These tumor plasma cells produce antibodies via what may be classified as traditional or non-traditional (alternative) pathways. The presence of alternative antibody production pathways is supported by responses seen following rituximab treatment of patients with various autoimmune diseases. In these patients, rituximab sensitive and rituximab non-sensitive plasma cells are seen. Then the question arises as to which of these cells (rituximab sensitive or rituximab insensitive) may be involved in the origin of MM. Dr. MacLennan reviewed studies addressing traditional and alternative pathways for antibody production. Some studies show that cells producing antibodies (B-cell memory clones) respond to various triggers and that these cells can undergo mutations. Other studies show that there are alternate sources of tumor plasma cells and suggest that both traditional and non-traditional pathways for producing antibodies exist.
Dr. Selina Chen-Kiang followed with a discussion on cell cycle control in MM. Dr. Chen-Kiang identified MM as a disease of cell cycle dysregulation and loss of apoptotic control. Positive cell cycle regulators [cyclins and cyclin-dependent kinases (CDK)] and negative cell cycle regulators (CDK inhibitors) control cell cycle progression and myeloma pathogenesis. Chen-Kiang and colleagues proposed that an imbalance in positive and negative cell cycle regulators occurs as an early event in MM pathogenesis. They developed functional cell assays to examine cell cycle regulation and identified specific cyclins, CDKs, and CDKIs that are associated with tumor stages. Specifically, cyclin D is correlated with a more favorable clinical course of MM. The use of the functional cell assay along with other prognostic indicators may improve the ability to characterize the likelihood of disease progression and the aggressiveness of the disease. Use of the assay may also assist with the development of therapies targeted at cell cycle regulation.
Dr. Federico Caligaris-Cappio reviewed the role of hypoxia in the bone marrow microenvironment in his discussion of cross-talk between plasma cells and the microenvironment. Plasma cells from patients with MM express statistically significantly more hypoxic factor 1-alpha (HF1a) than do plasma cells from MGUS patients. Hypoxia also turns on an angiogenic switch; plasma cells in MM are hypoxic and so are producing angiogenic factors. Notably, hypoxia causes a large number of cells to proliferate. Strong interactions between MM cells and the bone marrow icroenvironment results in signals being delivered to developing tumor cells. These interactions may serve as a new target for developing therapies. Similarly, the potential for T cells to act in the bone marrow microenvironment of MM may lead to the potential to develop an immunotherapeutic therapy based on T-cells recognizing naïve tumor cells.
Dr. Jesus San Miguel reviewed the use of immunophenotypingusually restricted to research or to the diagnosis of unusual cases of MM and the potential this technique has in daily practice. Immunophenotyping identifies the abnormalities in plasma cells and thus distinguishes between normal and malignant plasma cells. Identification of such differences in antigen profiles provides a means to distinguish between monoclonal gammopathy of undetermined significance (MGUS) and MM; MGUS patients routinely have greater than 5% normal plasma cells while MM patients routinely have less than 5% normal plasma cells. When assessing minimal residual disease (MRD), immunophenotyping applies to the vast majority of patients and is highly predictive or the risk of relapse. Dr. San Miguel discussed the results of more than 700 of his patients who were treated using the GEM2000 protocol. Antigen panels were obtained before chemotherapy was initiated; more than 90% of cases of malignant plasma cells had abnormalities in antigen expression. All MM patients were positive for CD38 and CD138 antigens; B-cell antigens were present in 5% to 20% of cases. They observed a down regulation of CD56 and CD117 correlated with a poor prognosis and shorter survival. Similarly, CD19 and CD28 were correlated with poor prognosis while CD20 and CD 35 had no influence on prognosis. These results support the clinical benefits of immunophenotyping MM patients.
Dr. Michael Kuehl opened session 2 with his discussion on th integration of genetics in a comprehensive pathogenesis model for MM. He stated that MGUS and MM may be considered as a cluster of different diseases that have distinct characteristics through progression of the diseases. MM can be organized into 7 groups based on expression of at least 1 cyclin D gene. The 7 groups are quite distinct with variable degrees of bone disease, frequency of relapse, and progression of tumors. Kuehl and colleagues suggest that dysregulation of the cyclin D gene may be an early or initiating event in the development of MGUS and MM. The investigators suggest that characterizing tumor cells may assist with the selection of therapies most likely to be effective against a specific tumor cell for patients.
Dr. Leif Bergsagel and colleagues suggested that early pathogenic events determine MM biology and clinical course. Specific IgH gene translocations, while infrequent at diagnosis, increase in frequency with relapse and correlate with poor prognosis. By analyzing 6 specific genes, clinical features of individual's disease, prognosis, and response to therapy can be identified. Patients with a 4p16 immunoglobulin translocation have a poor survival regardless of the treatment regimen they receive and so new treatment options need to be developed. Bergsagel and associates are evaluating novel agents that would specifically influence pathways affected 4p16 translocation.
Dr. Rafael Fonseca provided an overview of the integration of genetics in a comprehensive pathogenesis model for MM. Different pathways of pathogenesis follow from MGUS to MM and the progression from MGUS to MM likely follow specific pathways dependent on the genetic composition of the MGUS cells. In rapidly progressing cases, long term bone destruction does not have time to develop. The susceptibility for individuals to develop MGUS and MM is not clear but may be related in part to racial differences linked to the ability to repair double stranded DNA. Fonseca and colleagues suggest that genetics must be incorporated into the development of targeted therapies. Such an approach would identify the treatment regimen most likely to succeed for individual patients.
Dr. Johannes Drach reviewed the epigenetic changes in the molecular pathology of MM. Methylation of specific regions of genes blocks tumor suppression genes in some cancers. By comparing the methylation profile of MGUS and MM genes, Drach and colleagues were able to identify genes that were associated with MM. They report that the development of MM is stimulated by multiple genetic abnormalities and that methylation may be a signal of an early event or of disease progression.
Dr. Linda Pilarski presented findings on alternative gene splicing in myeloma hyaloronan synthetase 1 (HAS1) synthesizes hyaluronan (HA), an extracellular matrix protein that is involved in cell signaling and in malignant progression. HAS1 is the first blood born prognostic marker for malignant cells and predicts poor outcomes in MM patients. Various forms of HAS1 may be produced in cells and these various forms have strong impact on clinical outcomes. Pilarski and associates report that abnormal forms of HAS1 may predispose patients to disease or to the development of progressive MM and short survival.
This focus session presented exciting new findings on standard and supportive therapies in MM. Dr. Donna Weber posed the question, “Is Thalidomide First-line Therapy?”. She presented an overview of several trials utilizing combination therapy of thalidomide in untreated MM. The results of these trials, at this time, showed a clear superiority for using thalidomide, but also the increased risk of thrombosis and neuropathy. Several more trials have ensued using combination thalidomide, but with the use of prophylactic anticoagulants. Dr. Weber indicated that further research will evaluate the use of newer agents and lower doses of thalidomide to provide a greater response with fewer effects.
Dr. Maurizio Zangari followed Dr. Weber and provided an overview of the early uses of thalidomide and its teratogenic effects. Dr. Zangari pointed out that the success of thalidomide with leprosy led to the initiation of clinical trials in oncology. Research in these areas demonstrated a possible association of thalidomide with thromboembolism. Because incidence was low, several trials with thalidomide in combination with existing agents have been investigated for the newly-diagnosed patient with MM. Incidence of thrombosis with thalidomide has been observed to occur in early treatment with thalidomide and there is a higher incidence with newly diagnosed patients compared with relapsing patients. Dr. Zangari reviewed studies that compared prophylactic low- weight-molecular heparin, warfarin, and aspirin with thalidomide-based therapies suggesting that there may be a reduction of thrombosis with prophylactic therapy. Another complication seen in trials with thalidomide is the observation of sinus bradycardia. Similar to the management of thromboembolism, prophylactic use of anticoagulants is recommended for cardiovascular complications.
Dr. James Berenson presented new advances in the management of myeloma bone disease. A clinical consequence of MM is bone disease in non-vertebral bones and vertebral bodies, ultimately leading to spinal compression and impacting the patient's quality of life and survival. A review of a 21-month period showed that more than half of patients with MM develop bone fracture requiring radiotherapy. Vertebral compression is the most common complication leading to bone pain. Kyphoplasty, a minimally invasive and simple procedure, expands the collapsed vertebral body thereby reducing pain and improving patient function. An important therapy in managing patients with MM includes the use of bisphosphonates. Most of the trials of the last decade have shown a marked reduction of bone fractures with the use of IV bisphosphonate (pamidronate). More recently, the introduction of zoledronic acid, a more potent treatment, has shown to be effective in managing patients with MM and breast cancer. Dr. Berenson reviewed a trial comparing this newer agent to the pamidronate. The results from this trial showed that zoledronic acid was as effective as pamidronate; however, the infusion rate of zoledronic acid was modified to reduce the risk of renal impairment. Dr. Berenson advised the supplemental use of oral vitamin D and calcium with the administration of bisphosphonates to optimize the patient's bone health. A possible risk of bisphosphonate use is osteonecrosis of the jaw. Several treatment options for osteonecrosis include good oral hygiene as prophylaxis and throughout the duration of treatment, as well as intermittent antibiotic use. He cautioned against surgical intervention. Dr. Berenson closed by comparing the benefit to risk ratio of bisphosphonate use. Benefits include reduced bone fractures, less radiotherapy, and decreased bone pain.
Dr. Graham Jackson discussed the common complication of renal impairment in patients with MM; 20-30% of patients suffer from renal impairment at diagnosis, 50% at some time during the course of their disease, while 2% require dialysis. Dr. Jackson reviewed major factors contributing to renal impairment such as dehydration and hypercalcemia with the major cause of renal impairment due to tubular damage. There has been conflicting evidence in the literature about the use of plasma exchange to improve renal function. Dr. Jackson presented a new study taking place in the UK (the MERIT study), which is currently enrolling patients to determine whether plasmapheresis affects overall survival and quality of life. Dr. Jackson encouraged collaborators from different countries to participate in this trial.
Dr. Heinz Ludwig closed the session with a discussion on the prevalence, pathogenesis, and treatment of anemia with erythropoietic agents. Anemia is a common complication with MM and has a higher prevalence in MM than in patients with solid tumors. He stated the main goal of the European Cancer Anemia Survey (EACS) is to analyze the prevalence of anemia, the incidence of anemia, the impact of age, identify predictors of anemia, and treatment options. Dr. Ludwig indicated that age is an important factor to consider with anemia and in a recent study with elderly patients, whose median age was 68 years, the prevalence of anemia was 72%. Dr. Ludwig recommended that treatment options should be based on the patient's individual symptoms and less on hemoglobin levels and symptomatology. Erythropoietic agents, transfusion, and iron supplements may be considered as treatment options. The benefits of erythropoietic treatment agents include an increased appetite, improved cognitive function, and improved quality of life, while reducing dependency on transfusions.
The third plenary session opened with Dr. Dalsu Baris, of the NCI, discussing the epidemiology of MM. The highest risk of MM in the United States is among Blacks, with the lowest risk, in both Asia and the United States, among Asians. Mortality is higher in Blacks versus Whites, and higher in males versus females. Dr. Baris presented SEER data showing an increased risk MM with increased age. Risk factors are unclear but are related to exposure to ionizing radiation, solvents, and agricultural and farming occupations. Studies also suggest an association of MM with low socioeconomic status (SES) and obesity. A recent study conducted among women in Connecticut ( United States ) examined the impact of environmental, lifestyle, and genetic factors with the risk of MM. This study showed the risk was higher for subjects with less than a high school education and those in the lowest economic bracket. There was no evidence of increased risk with smoking or use of alcohol; however, this study did find that risk was increased with an increased body mass index (BMI). Although it appears that environmental factors may have a part in the pathogenesis of MM, further, larger studies will need to be conducted to identify exact environmental agents and genetic factors.
Dr. Robert Kyle followed, presenting an update on smoldering MM (SMM). Dr. Kyle characterized SMM with a serum M-protein level of 3 g/dL or higher, or 10% or more plasma cells in the bone marrow. He stated that the definition of SMM is not standardized and it is not known whether both M-protein and bone marrow plasma cells are necessary for diagnosis. Dr. Kyle provided an update from his study at the Mayo Clinic ( Rochester, Minnesota, United States ). In this study, patients were categorized in three groups of SMM; patients had a median age of 65 years. At the 15-year follow up, 53% of patients had progressed to MM, 2% of the patients had progressed to primary amylodosis ( AL ). Dr. Kyle concluded that most patients with SMM have a much greater risk of progressing to symptomatic MM or AL .
Dr. Joan Blade supported Dr. Kyle's presentation with his discussion on the evolving versus non-evolving nature of asymptomatic monoclonal gammopathies. Monoclonal gammopathy of undetermined significance (MGUS) indicates a serum M-protein of less than 30 g/dL and less than 10% bone marrow plasma cells (BMPC). Dr. Blade commented that evolving SMM showed a progressive increase in M-protein size until symptomatic MM developed. Whereas, non-evolving SMM characterized a stable M-protein until symptomatic disease developed. In studies, the median time to progression to symptomatic MM was 3 years. However, the evolving SMM had a shorter median time to progression of 1.5 years. Studies also showed that evolving SMM has a pattern of genetic abnormalities and chromosomal losses, whereas chromosomal losses were less common in non-evolving SMM. Dr. Blade's preliminary analysis suggests that MGUS is a predictor of malignant transformation probability.
Dr. Philip Greipp provided an update on the International Staging System (ISS) for MM and indicated that an article on ISS is to be published in the May 20 issue of the Journal of Clinical Onoclogy. The staging system was developed after analyzing the data from 3 groups: Asia, Europe, and North America . The goal was to develop a validated and confirmed staging system for MM. Results from the study formed 3 stages based on ß2 microglobulin and albumin levels. A summary of survival outcomes based on these stages was presented: Stage 1 = 62 months, Stage 2 = 44 months, Stage 3 = 29 months. The ISS staging system may prove to be superior to the Durie Salmon staging system with more equal distribution across the 3 stages. Dr. Greipp suggested that the ISS system should be the only system used until another easily usable, validated, and confirmed system is developed.
Dr. Brian Durie next presented advances in diagnosis and imaging in MM. He focused on the importance of a precise diagnosis especially with the new understanding of disease biology made available from imaging. Dr. Durie discussed the critical role of new molecular pattern classifications such as circulating nucleotides RNA and DNA. In 2005, approximately 25% of patients are diagnosed with MM during their routine physical exam. In addition to standard methods, new techniques should be added to the patient work up, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. The use of these imaging agents provides a full spectrum view of the disease through a full body scan including extramedullary area. The prognostic and predictive value of circulating nucleic acids (RNA and DNA) provides a new understanding of MM and allow for better tracking and monitoring of the disease.
Dr. Surinder S Sahota reviewed normal plasma cell development and pathology of MGUS and MM. In order to understand MM, one must understand the origin of the plasma cells causing MM. Sahota and colleagues focused on analyzing the regions of immunoglobulin molecules present in MM and MGUS to answer some of these questions. Their research showed that normal plasma cells produce different forms of immunoglobulins G and A in response to signals from the bone marrow. In smoldering MM plasma cells, some immunoglobulins are produced consistently. In MGUS, these same immunoglobulins are produced in a variable manner and Sahota suggests that these variable immunoglobulins are linked to the development of MM.
Dr. Regis Bataille and colleagues suggest that an understanding of the different classes of plasma cells identified by the protein CD45 may lead to a better understanding of the development and progression of MM. Abnormally growing plasma cells are maintained by a very small fraction of plasma cells and these cells have a specific CD45 molecule on their surface. Identifying which CD45 molecule is on the surface of the plasma cells may help to distinguish different types of MM. For example, some CD45 molecules are associated with more proliferation of plasma cells, some are increased when MM progresses, and some are associated with poor prognosis. An understanding the correlations between the types of CD45 present on plasma cells and MM may assist with the development of therapies.
Dr. Bernard Klein presented on the identification of intracellular communication involved in MM with microarrays. MM cells must interact with the bone marrow to continue to grow and proliferate. Growth factors in the bone marrow influence the ability of plasma cells to grow and thus influence the progression of MM. Klein and associates suggest that identifying molecules that may inhibit these growth factors may impact myeloma cell growth. By identifying patients with specific genes, Klein and associates suggest that specific therapies may be able to be developed to meet the needs of those individual patients.
Dr. Michio Kawano discussed the function and movement of CD45 molecule in interleukin-6-induced myeloma cell proliferation. Myeloma cells vary in morphology and genetic composition. Normal myeloma cells have a variety of CD45 molecules on their surfaces. The stage of development of the plasma cell (immature, mature) and the presence or absence of CD45 on the cell surface determines whether the cell can respond to stimulants, such as interleukin-6 (IL-6). IL-6 is a growth promoting factor which causes CD45+ immature myeloma cells to proliferate in the bone marrow. The amount of IL-6 is limited so that CD45+ cells are converted to CD45- cells which are then more stable to environmental stress. Kawano and colleagues suggest that therapeutic strategies should focus on CD45.
Dr. Thomas Rasmussen presented on MM14q32 translocations. Researchers have not yet identified which cells are involved in the genetic events necessary for the development of MM. Rasmussen and colleagues looked at memory B cells to find out whether those cells contain the same genetic memory that is seen in MM plasma cells. Although B cells have some of the characteristics on MM plasma cells, B cells do not have the key characteristics of plasma cells that develop into malignant MM plasma clone cells.
Dr. Michel Attal opened the fourth plenary session with an update on the Intergroup Francophone Du Myelome (IFM) study on maintenance treatment with thalidomide and pamidronate after autologous transplantation. Dr. Attal reviewed the IFM's previous findings that high-dose therapy (HDT) significantly increased survival over use of conventional chemotherapy. More recently, studies have shown that double transplant significantly improves overall survival versus single transplant. This outcome has been seen in patients who do not achieve a very good partial response (VGPR) after first transplant. Today MM is the first indication for transplantation. The IFM designed a trial to evaluate the impact of maintenance treatment with thalidomide and pamidronate after HDT. Patients were treated with 3-4 cycles of vincristine, adriamycin, and dexamethasone (VAD), followed by a first autologous transplant with melphalan 140 mg/m2 and a second transplant of melphalan 200 mg/m2. Patients were then randomized to receive no maintenance, maintenance with pamidronate, or maintenance with pamidronate and thalidomide. Based on interim analysis, thalidomide was found to significantly decrease incidence of progression, improve progression-free survival (PFS), and significantly improve 3-year PFS. This benefit was mainly observed in patients with 1 adverse prognostic factor. Pamidronate was found to significantly decrease the 3-year risk of bone events. Dr. Attal indicated that a longer follow up is required to further assess patient outcomes.
Dr. Bo Bjorkstrand's presentation focused on the value of transplant registries. He provided an overview of the European Group for Blood and Marrow Transplantation (EBMT) and the history of data collected on allogeneic and autologous transplants since 1983. Recent studies are being conducted to determine the impact of donor gender and transplant, stem cell transplant (SCT) in plasma cell (PC) leukemia, SCT in rare MM type, and SCT in amyloidosis. From 1986 to 2005, a total of 19,562 patients have been registered. The data from this registry show that the majority of patients are male and younger than 60 years of age. Time from diagnosis to first transplant is less than 1 year. Overall survival (OS) at 10 years post-transplant is 40%; with PFS at 20% and complete response (CR) at 50%. An analysis of prognostic factors showed a slight significance of survival with females, and patients less than 60 years of age performed better with transplant. Dr. Bjorkstrand summarized retrospective study results of autologous SCT in PC leukemia and autologous SCT in rare MM. He lastly highlighted the registry's key benefit: continuous monitoring of transplant activity shows information on trends and changes in treatment methodology.
In the next presentation, Dr. Mario Boccadoro reviewed findings from the Italian study, which, by using intermediate-dose melphalan, showed superior to standard treatment in elderly patients with myeloma. Specifically, intermediate-dose melphalan (100 mg/m2) followed by ASCT constitutes a more effective first-line regimen than standard treatment of melphalan/prednisone in those aged >65 years, improving response rate, EFS, and overall survival (OS). Currently, a study is being conducted to evaluate intermediate-dose melphalan (100 mg/m2) with high-dose melphalan (200 mg/m2); results from this study are pending.
Dr. Bart Barlogie's presentation was an update on total therapy 2 (TT 2) versus total therapy 1 (TT 1). Dr. Barlogie reviewed data supporting the superiority of TT 2 over TT 1 with improved CR duration and doubled EFS. TT 3, a successor protocol including bortezomib with DT PACE, shortens the induction phase to 2 cycles to allow for completion of tandem transplants. Dr. Barlogie cautioned that the study is ongoing and that results will be discussed at future meetings in 2005.
Dr. Jean-Luc Harousseau's presentation was a focus on the benefits of double autologous stem cell transplantation (ASCT) versus single. He reviewed results from several studies that are showing a trend towards significant benefits in EFS and OS with double ASCT. He commented that longer follow up is needed before drawing conclusions; however, preliminary results are in favor of double ASCT. He stated that patients with adverse prognostic factors have a poorer outcome and the only factor that can predict the impact of a second transplant is the result of the first transplant. Preliminary results using fluorescent in-situ hybridization (FISH) analysis in the IFM 99 trial show that double ASCT improves results and poorer results could be related to cytogenetic abnormalities. Dr. Harrousseau discussed potential future trials with the use of novel agents instead of double ASCT, or in combination with double ASCT (before transplant to increase overall CR/VGPR or to decrease number of patients who will need a second transplant; or after transplant), or the use of novel agents as part of induction treatment regimen.
Dr. G. David Roodman presented on the pathogenesis of bone disease in MM. Bone lesions occur in up to 80% of MM patients; bone fractures occur in 60% of MM patients. MM patients also experience bone pain related to destruction of their bone tissue. Roodman and associates show that myeloma cells are involved in both the destruction of bone tissue and in the prevention of the repair of bone tissue. Patients with MM produce molecules that stimulate osteoclasts (cells that break down bone tissue) and inhibit osteoblasts (cells that build bone tissue). Combined, these effects result in the severe bone disease that MM patients experience.
Dr. Greg Mundy discussed osteoblast function in MM. Myeloma cells are found in bone marrow and through the course of MM myeloma cells influence bone destruction by inhibiting formation of bone and increasing resorption of bone. Velcade is successful in the treatment of myeloma, causing the myeloma cells to behave in a more normal manner. Mundy and associates suggest that Velcade may also be helpful in stimulating bone formation, thus possibly acting as a treatment for bone disease associated with myeloma. They are conducting experiments to clarify if Velcade can both limit tumor burden and repair bone destruction.
Dr. Peter Croucher outlined bisphosphonates and the bone marrow microenvironment. Managing bone disease is necessary for MM patients. To date, only bisphosphonates are used to treat bone disease in MM patients. Research in animal models of bone disease shows differences between the various bisphosphonate agents. Pamidronate and zoledronate improve survival in a myeloma model; ibandronate has no effect on survival in the same model. Croucher and colleagues suggest that treatment with bisphosphonates may have an anti-myeloma effect that may be mediated in part by inhibiting bone resorption.Dr. Joshua Epstein focused on the mouse model in tumor microenvironment. As a patient progresses from MGUS to symptomatic myeloma, the rate of their bone turnover changes. Epstein and associates looked at whether changes in the bone marrow were related to their disease (myeloma) and whether the changes were necessary for the survival of myeloma cells. Osteoclasts (cells that break down bone tissue) support myeloma cell survival and proliferation. Osteoblasts (cells that build bone tissue) have a more complex relationship with myeloma cells, supporting or killing the myeloma cells depending on conditions. Epstein and colleagues note a 20% to 30% decrease in tumor burden being associated with an increase in bone density. They continue to investigate the relationships between myeloma cells and bone tissue.
For more information regarding these sessions, look for the complete proceedings to be published after the conclusion of this workshop.