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Torino Myeloma Conference
April 23, 2004

April 23, 2004

Session V—Prognosis

Dr. Kyle

Dr. R. A. Kyle opened the first morning session with a discussion of monoclonal gammopathies of undetermined significance (MGUS). Dr. Kyle reported results from the Mayo Clinic from 1956–1994, evaluating the time from recognition of MGUS until progression. He also assessed the prevalence of MGUS in a county in Minnesota , USA . Dr. Kyle indicated that actuarial risk of progression was 17% at 10 years; 34% at 20 years; and 39% at 25 years in the institution’s experience from 1956–1970. In the second analysis of patients, from 1960–1994, the risk of disease progression was10% at 10 years; and 21% at 20 years. He also concluded that MGUS is one of the most premalignant disorders found in the general population ≥50 years of age.

Dr. D. M. Weber presented on the prognostic features of asymptomatic multiple myeloma (MM), often called indolent or smouldering MM (about 20% of patients).
Dr. Weber identified 3 risk factors or variables to study: M protein; IgA protein type; and Bence Jones protein (BJP). Where available, MRI of the spine was included in the assessment. She concluded that although IgA and M protein are predictive of rapid time to progression, an abnormal MRI of the spine is the single most predictive indicator for time to progression in these patients. She warned that these conclusions need to be validated.

Dr. Façon

Dr. T. Façon evaluated the cytogenetic changes in the evolution of MGUS to MM. The origin of MGUS is largely unknown and use of conventional cytogenetics has proven unsuccessful. With this in mind, Dr. Façon reported on the use of the fluorescence in situ hybridization (FISH) assay to assess changes in MGUS to MM. In the end; however, this approach has failed to explicitly distinguish MGUS and MM, but these analyses continue and have been extended to SMM.

Dr. B.G.M. Durie presented next on the advances in the diagnosis and staging of MM. He considered techniques of imaging as they are essential for management of myeloma. Imaging establishes the (1) presence, (2) location, and (3) activity of myeloma lesions. Considered and discussed were: standard radiology; and other less standard techniques including MRI, CT-scanning, fluorodeoxyglucose/positron emission tomography (FDG/PET) and 99m Tc-MIBI. Overall, Dr. Durie suggested that having several complementary imaging techniques gives greater flexibility in evaluating patients with myeloma; and, that specifically, whole body FDG/PET imaging provides important staging and prognostic information that can reliably identify active myeloma vs. MGUS. FDG/PET also identifies poor risk patients pretreatment and potential for relapse. Dr. Durie closed with a description of how to incorporate imaging and non-image analyses.

Dr. M. Ladetto reported on the relevance of cyclooxygenase-2 (COX-2) in MM. COX-2 is a key enzyme in the prostaglandin pathway, especially in inflammation, and has been documented to play a role in a number of cancers. Few data are available of a role for COX-2 in MM. Dr. Ladetto presented data from patients with MM and concluded that COX-2 is frequently expressed in diseases of plasma cell dysfunction. More frequently, COX-2 is seen in advanced disease and at initial diagnosis; COX-2 expression seems to be related to a worse outcome. Whether COX-2 might be a useful clinical or prognostic marker, or as a therapeutic target, remains to be elucidated and is under study.

Dr. Morra

Dr. E. Morra evaluated predictive variables for malignant transformation in asymptomatic IgM monoclonal gammopathies (IgM-MG). Although the majority of IgM-MG patients will not develop symptoms, subsets have evolved to overt malignant disorders with a frequency ranging from 6% to 13% for IgM-MGUS to virtually 100% for smouldering Waldenstrom’s Macroglobulinemia (WM). Dr. Morra evaluated the natural history of 384 asymptomatic IgM-MG patients. She concluded that hemoglobin levels, peripheral lymphocytosis and para-protein size predict disease transformation. Combining these with Bence Jones protein and ESR identifies patients needing careful monitoring.

Dr. Corradini

Dr. P. Corradini reported on the role of molecular monitoring after allogeneic transplantation in MM. He discussed how molecular monitoring of minimal residual disease (MRD) after allo-hematopoietic stem cell transplant (allo-HSCT) has been proposed as a prognostic parameter helpful in making clinical decisions regarding immunosuppression taper or timing of donor lymphocyte infusions. Dr. Corradini provided information on a process called “TaqMan PCR” suggesting that use of this technique seems promising in assessing the kinetics of the graft vs. myeloma effect and possibly also developing “individualized” posttransplant immunotherapy in patients with MM following allo-HSCT. Prospective studies are required to validate this concept.

Dr. Greipp

Dr. P.R. Greipp presented a highly relevant presentation of the emerging Myeloma International Staging System (ISS). This presentation was an extension of data presented at the Salamanca conference in May 2003. The new staging system is remarkably simplified, having evaluated a number of clinical variables including Beta-2 microglobulin (B2M), platelets, albumin, calcium, and serum creatinine. In the end, B2M and serum albumin were found to be the most relevant markers. Patients are categorized depending on their level of B2M and albumin to either stage 1 or stage 3 disease; patients fitting neither stage are classified as stage 2 disease. Dr. Greipp then provided data validating the new ISS under actual trial conditions and further extended the value of the new ISS to include findings using the plasma cell labeling index. Publication of these data are expected shortly.

Session VI—Supportive Therapy

The second morning session was initiated by Dr. K. Anderson, on behalf of Dr. J. Berenson, who discussed the use of zoledronic acid in metastatic bone disease.

Dr. Anderson updated data comparing zoledronic acid with pamidronate with regard to effect on skeletal lesions in MM. These data reflected that zoledronic acid and pamidronate were equally effective and safe, although patients may prefer zoledronic acid because of its shorter administration time. More relevant may be the ability of zoledronic acid to decrease myeloma cell proliferation, increase apoptosis, decrease microvessel proliferation, and perhaps, as seen in a mouse model, increase survival in MM. Future directions include use of zoledronic acid as part of primary therapy for MM.

Dr. Ludwid

Dr. H. Ludwig presented on the pathogenesis and treatment of anemia in MM as anemia is a common complication. Anemia is more common in patients who are unresponsive and recurs in patients with relapsing disease and in patients with long-standing, highly-treated disease. Dr. Ludwig discussed the consequences of anemia and indications for treatment in patients with MM. He also discussed the use of blood transfusions and erythropoietic support. A major question addressed by Dr. Ludwig was how to select candidates for erythropoietin treatment. He lastly presented a compilation of randomized trials using erythropoietin in patients with MM, stressing tolerance of the treatment and its benefits. Dr. Ludwig continued the discussion of anemia in MM on behalf of Dr. F. Dammanco. He explained a number of pathogenetic events that have been postulated to account for defective erythrogenesis in MM. Dr. Ludwig also discussed the roles of interleukin-6 and tumor necrosis factor in anemia. Dr. Ludwig then presented findings on the ability of malignant plasma cells to exert a cytotoxic effect on erythroblasts and the role for treatment with erythropoietin. Dr. Ludwig finished with a discussion of interim data from an international open-label phase IIIb trial in anemic patients with MM, illustrating an improved quality of life for these patients.

Dr. J. Westin moved to a new topic, if not an old topic: Is there still a role for conventional chemotherapy in MM? The question is one that must be addressed since not all patients, especially the elderly, are suitable candidates for more intensive therapies. Case in point: in Scandinavian countries at least half of all myeloma patients are >70 years of age at diagnosis. Dr. Westin presented existing data demonstrating that in the absence of better alternates, oral intermittent melphalan/prednisone is still what we have to offer these patients. However, even elderly patients should be considered for enrollment into appropriate ongoing clinical trials or other established combined modality approaches if suitable candidates.

Dr. Dimopoulos

Dr. M.A. Dimopoulos presented treatment strategies for Waldenstrom’s macroglobulinemia (WM). Most patients diagnosed with WM present with symptoms, but a small proportion of patients are diagnosed by chance without signs or symptoms–termed as patients with asymptomatic WM. When systemic therapy is indicated in WM patients, treatments including alkylating agents, nucleoside analogues, and the monoclonal antibody, Rituximab, are appropriate. Dr. Dimopoulos then described the use of each of these agents in WM and the use of high dose therapy with autologous stem cell transplantation.

Dr. Merlini

Dr. G. Merlini closed the morning session, discussing AL amyloidosis, focusing on current progress and future challenges. Dr. Merlini discussed the common form of systemic amyloidosis in Western countries. The correct typing of amyloid deposits is essential as it dictates both prognosis and treatment. He went on to describe a number of independent predictors of survival, including natriuretic peptide type B and troponins. Treatment is a balancing act, balancing the toxicity of therapy with the need to eliminate the source of amyloid. Dr. Merlini suggested that treatment modalities used in MM may be very helpful in treating amyloidosis, especially some of the newer emerging approaches such as high dose dexamethasone and thalidomide. These directions await clinical testing.

Session VII—Round Table on Autologous Transplantation

Dr. Bladé

The afternoon sessions were in round table format and presented in most cases updates on ongoing global trials and studies. Dr. J. Bladé opened the session with the experience from Spain . Dr. Bladé discussed high dose therapy (HDT) intensification with autologous transplantation in patients with MM who responded to their initial chemotherapy. He indicated that HDT followed by autologous stem cell support is commonly part of front-line therapy for patients with MM <65 years of age, but that not all patients in whom HDT is feasible achieve significant benefit. Dr. Bladé went on to discuss his current results directed to identify factors that will predict which patients will achieve complete remission (CR), in order to limit application of HDT to those who will most benefit. In his experience, tumor burden at the time of transplant and percentage of bone marrow involved are the critical predictors of success.

Dr. J. A. Child provided the British experience with conventional chemotherapy dose vs. HDT. His presentation covered results from 1964. Overall, results of British and other trials tended to support that HDT is effective and should be considered as a standard component of first-line treatment for patients with MM. This needs to be viewed from the perspective of newly emergent data such as optimizing induction therapy and new maintenance therapies, as examples.

Next, Dr. M. Cavo presented the Bologna experience with single vs. tandem HDT. He reported that clinical benefits from double autologous transplantation was greatest among patients who failed to respond to first-line conventional chemotherapy and/or who did not achieve CR with autologous transplantation.

Dr. Fermand

Dr. J. P. Fermand presented the experience from France reporting results from single vs. tandem HDT supported with autologous blood stem cell transplantation (ABSC) using unselected or CD-34 enriched ABSC in patients with MM. The data provided did not show any significant benefit of single vs. tandem HDT; or of selection CD34+ autografts, which tended to increase the incidence of serious infections.

Dr. H. Goldschmidt presented the study from Germany . He provided the analysis of the GMMG-HD2 trial evaluating single vs. double HDT in MM. Findings presented indicated that sequential HDT with melphalan 200 mg/m2 and autologous peripheral blood stem cell transplant (PBSCT) results in superior event free survival compared to single HDT. He ended with discussion of the impact of Beta-2 microglobulin and albumin levels, and of deletion of 13q14 on survival.

Dr. Sonneveld

Dr. P. Sonneveld presented data from the updated analysis of the phase III study HOVON 24 MM: Intensive vs. durable intensive therapy in untreated MM (the Netherlands study). In this updated analysis, second intensification by myeloablative treatment with cyclophosphamide and total body irradiation when added to intensified chemotherapy alone resulted in superior event free survival, progression free survival, and time to disease progression, but not overall survival.

In the next presentation, Dr. M. Boccadoro presented 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, event free survival, and overall survival.

Dr. Harrouseau

Dr. J. L. Harousseau opened the discussion of his presentation on autologous stem cell transplantation by commenting on the emerging belief that multiple transplants are superior to one, or none. He discussed the correlation between ASCT and improvement in CR, and compared studies from France , UK , Spain , and Italy . He highlighted evidence supporting the use of repeat intensive treatments, moving onto evidence that shows that double transplants are feasible in younger patients with newly diagnosed MM; that they are safe and significantly superior to single ASCT when evaluating EFS and OS. However, more still needs to be done to increase long-term survival. The next steps are to identify markers of what patients will do well with multiple ASCTs and to include more novel therapies into the treatment regimen.

Dr. M. Attal then presented in more detail the findings from the IFM experience from France , which evaluated the impact of HDT in MM. Dr. Attal presented findings from a number of IFM trials and concluded that these studies identified a subgroup of poor-prognosis patients after single or double transplantation, notably Beta-2 microglobulin and deletion of chromosome 13. Dr. Attal ended with discussion of new results from the IFM 9902 trial.

Dr. Barlogie

Dr. B. Barlogie updated on total therapy 2 (TT 2) versus total therapy 1 (TT 1). He cautioned that the study is ongoing and that thalidomide data are still blinded. TT 2 has achieved its accrual goal; TT 3, a successor protocol including bortezomib, is in phase 2.

Round table discussions of all the presented data concluded session VII.

Session VIII—Round Table on Allogeneic Transplantation

The day’s final session followed the round table format and began with a presentation from Dr. P. Tosi. Dr. Tosi offered the Bologna experience for related and unrelated allografting after myeloablative conditioning. Myeloablative allogeneic bone marrow transplantation (BMT) in treating patients with MM was introduced in the early 1980s. Long-standing remissions were observed even in heavily treated patients, but transplant-related mortality (TRM) exceeded 40%. Also discussed today was application of allogeneic stem cell transplant and its capacity to eradicate the myeloma clone through the graft versus myeloma effect, and extension to include novel drugs.  

Dr. H. M. Lokhorst presented data on T-cells and its graft versus myeloma effect. The data came from an updated outcome of donor lymphocytic infusion (DLI) of 54 patients with relapsed myeloma following partially T-cell depleted allogeneic stem cell transplantation. Conclusions are that T-cell depleted myeloablative allogeneic stem cell transplant has no place in therapy for MM since TRM is not reduced. However, Dr. Lokhorst discussed the continued role of DLIs in relapsed MM disease.

Dr. Kroger

The next presentation from Dr. N. Kroger provided an update of autologous-allogeneic tandem stem cell transplantation with newly diagnosed MM, with emphasis on unrelated donors. Dr. Kroger added that reduced conditioning with melphalan and fludarabine with pretransplant ATG followed by related or unrelated transplantation provides rapid and  sustained engraftment with durable, complete chimerism and low 1-year transplant related mortality (TRM). Dr. Kroger closed with an exciting discussion of next steps. These include adoption of auto/allo transplant into a program to drive increased CRs with minimal residual disease. In the absence of minimal residual disease (or cure) or on relapse, this will be treated with donor lymphocyte infusions, possibly with addition of novel new drug agents.

Dr. G. Tricot followed and discussed allogeneic transplantation in MM. His findings suggested that nonmyeloablative allotransplants remain risky interventions and are capable of reducing only a limited tumor load. Patients should have an autologous transplant followed by a planned non-myeloablative allotransplant while in good partial or complete remission.

Dr. B. Bruno presented the Gruppo Italiano Trapianto di Modollo experience (GITMO) on nonmyeloablative conditioning. The GITMO experience was a multicenter trial that showed that low dose total body irradiation-based (TBI) nonmyeloablative allografting is feasible in patients with MM, including older patients. Dr. Bruno spent considerable time addressing the needs of nonmyeloablative conditioning efforts, namely ensuring engraftment; lowering day-20 transplant related mortality to <20%; and increasing the eligible age of the transplant patient. He addressed the clinical rationale of the GITMO studies and compared experiences of post-auto and post-allo transplant. He closed stressing the importance of the CR as the springboard to superior progression free survival in MM and indicated that longer follow up is needed for further assessment of chronic graft versus host disease (GVHD) on disease response, survival, and overall quality of life.

Dr. G. Garhton’s presentation focused on an analysis from the European Group for Blood and Marrow Transplantation (EBMT) registry concerning myeloablative allografting in MM. Findings indicated that the best offer for a younger patient with myeloma is to enter a trial of nonmyeloablative transplantation following an autologous transplant and to be prepared to later receive donor lymphocyte transfusions. Dr. Garhton finished his presentation by introducing a new direction, one seeking to take advantage of allo-NK cells and autologous transplant.

Dr. Storb

Dr. R. F. Storb concluded the day’s session and addressed myeloablative to nonmyeloablative conditioning regimens in MM (the Seattle experience). Dr. Storb presented data related to the use of CY/TBI or BU/CY and allo-HCT in MM. Overall event-free survival and overall survival were low, unrelated and related transplants were not significantly different, and transplant-related mortality was high. Dr. Storb then moved on to a new nonmyeloablative conditions program, allografting from HLA-matched siblings with a conditioning regimen comparing melphalan and fludarabine, both with TBI and an immunosuppressive regimen. Dr. Storb then discussed results from a number of studies and finished with an explanation of the BMT-CTN 0102 schema–an upcoming study that is pending FDA approval to proceed.

Round table discussions reviewed all of the data presented and concluded Session VIII.

For more information regarding these sessions, look for the complete proceedings from the Multiple Myeloma 2004 meeting to be published after the conclusion of this conference.

April 22, 2004

April 24, 2004

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