title: Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study. Nordic Myeloma Study Group. Peripheral Blood Stem Cell and Bone Marrow Transplantation for Solid Tumors and Lymphomas: Hematologic Recovery and Costs: A Randomized, Controlled Trial Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Transplantation in patients with multiple myeloma: a multicenter comparative analysis of peripheral blood stem cell and allogeneic transplant. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. Comparison of interferon tolerance after autologous bone marrow or peripheral blood stem cell transplants for myeloma patients who have responded to induction therapy. A randomized trial of maintenance interferon following high‐dose chemotherapy in multiple myeloma: long‐term follow‐up results
abstract: High-dose therapy has become a common treatment for myeloma . The objectives of this study were to estimate in a prospect i ve , population -based setting the impact on survival of high-dose therapy in newly diagnosed , symptomatic patients less than 60 years old and to compare the results with those of conventionally treated historic controls . The prospect i ve population comprised 348 patients . Of these , 274 were treated according to a specified intensive-therapy protocol ( Nordic Myeloma Study Group [ NMSG ] # 5/94 ) and constituted the intensive-therapy group . The historic population consisted of 313 patients identified from 5 previous population -based Nordic studies . Of these , 274 fulfilled the eligibility criteria for high-dose therapy stated in NMSG # 5/94 and constituted the control group . The expected numbers of patients in the prospect i ve population and the historic population were 450 and 410 , respectively , estimated from previously established data on the incidence in this population and the population base for each study . Survival was prolonged in the intensive-therapy group compared with the control group ( risk ratio for the control group 1.62 ; 95 % confidence interval 1.22 - 2.15 ; P = .001 ) . These groups represented more than 60 % of the expected number of patients . When survival for all the registered patients in the 2 population s was compared , representing more than 75 % of the expected number of patients , the advantage for the prospect i ve population persisted ( risk ratio for the historic population 1.46 ; 95 % confidence interval 1.14 - 1.86 ; P = . 002 ) . These results indicate that the introduction of high-dose therapy for newly diagnosed myeloma has result ed in prolonged survival for the total patient population aged less than 60 years . ( Blood . 2000 ; 95:7 - 11 Peripheral blood stem cells ( PBCs ) have recently been used to reconstitute hemopoiesis after myeloablative therapy [ 1 , 2 ] . The cells can be collected in patients who are in steady state , but several leukaphereses are needed [ 3 ] . Mobilization of progenitor cells from the bone marrow to the peripheral blood can be achieved with chemotherapy , alone or in combination with hemopoietic growth factors [ 4 - 6 ] , or with hemopoietic growth factors alone administered to patients in hematologic steady state [ 7 - 12 ] . Most studies have shown that the duration of granulocytopenia after autograft is shorter if PBC transplantation is used instead of bone marrow transplantation [ 13 , 14 ] . In 1992 , Sheridan and associates [ 12 ] found a significant reduction in the duration of thrombocytopenia after PBC and bone marrow transplantation compared with bone marrow transplantation alone . However , their study was not prospect i ve and did not include a group that received PBC transplantation alone . Moreover , preliminary reports [ 15 - 17 ] suggest that autologous PBC transplantation is less costly than bone marrow transplantation . Given these encouraging findings , in 1993 the French Federation of Cancer Centers began a r and omized , controlled trial in patients who were receiving high-dose chemotherapy for a solid tumor or lymphoma . The trial compared PBC transplantation with bone marrow transplantation with respect to hematologic recovery and costs . The results of this trial are presented here . Methods Patients Persons of any age and sex who had a solid tumor or lymphoma and were c and i date s for a first course of high-dose chemotherapy and autologous hematopoietic progenitor cell transplantation were eligible for inclusion . No grafts were collected from patients whose condition was newly diagnosed . Patients with a contraindication to cytapheresis or filgrastim , patients with a severe invasive infection , and patients who required an ex vivo purged autograft were ineligible . Written informed consent was required from all eligible adults and from the parents of eligible children . This protocol was approved by the Kremlin-Bicetre ethical committee , France . Interventions When a graft was planned for an eligible patient , the attending physician contacted the trial 's data manager by telephone . The manager used a computer software program to r and omly assign the eligible patient to receive either a PBC graft mobilized by filgrastim or a bone marrow graft . R and omization was stratified by center and , because of the particular hematotoxicity of busulfan and total-body irradiation , by the type of programmed conditioning regimen ( total-body irradiation and high-dose chemotherapy with or without busulfan ) . Stem cells were collected within 1 month after r and omization . Collection of Peripheral Blood Stem Cells and Bone Marrow The initial protocol included bone marrow harvest for rescue for all patients in the PBC group . However , because rescue was not used for the first 30 patients in this group , it was decided that bone marrow be harvested for rescue only when the product of leukapheresis was insufficient . Patients had to be in hematologic steady state before mobilization . Mobilization was done with 10 g of filgrastim per kg of body weight per day , administered subcutaneously over 6 consecutive days . The PBC grafts were collected by three cytaphereses done on days 5 , 6 , and 7 of filgrastim administration . The minimum hemoglobin level required before collection was 10 g/L in adults and 12 g/L in children . Three cell separators were used in the different centers : Spectra ( Cobe Laboratories , Lakewood , Colorado ) , CS 3000 ( Baxter Health Care Corp. , Deerfield , Michigan ) , or AS104 ( Fresenius AG , Bad Homburg , Germany ) . Given the wide variations between laboratories , collection of colony-forming unit granulocyte macrophages ( CFU-GM ) was classified as rich or poor or normal . In the main laboratory , the PBC graft was considered rich if it contained more than 30 104 CFU-GM/kg ; this threshold was adapted for use in the other laboratories . Bone marrow was collected from the iliac crests while patients were under general anesthesia , as described elsewhere [ 18 ] . The graft was considered rich if it contained more than 15 104 CFU-GM/kg . Conditioning Regimen and Transplantation The conditioning regimen consisted of high-dose chemotherapy with or without total-body irradiation , in accordance with current protocol s developed by national tumor committees for each type of cancer ( Table 1 ) . Transplantation was to be done 1 to 2 days after the end of the conditioning regimen . Table 1 . Principal Conditioning Regimens according to Diagnosis Filgrastim ( 5 micro g/kg per day ) was administered intravenously to all patients in both groups from day 1 after transplantation until granulocyte recovery ( to a granulocyte count > 1 109/L ) ( controlled twice at 48-hour intervals ) . Use of all other hemopoietic growth factors was prohibited throughout the trial . Data on the side effects of filgrastim  were collected . Follow-up Daily surveillance began on the first day of hospitalization for high-dose chemotherapy and was continued throughout the hospital stay . All patients received right atrial catheters on admission and were isolated in laminar air-flow single rooms . They received parenteral nutrition and broad-spectrum antibiotics when indicated . Platelet infusions and erythrocyte concentrates were used to maintain a platelet count greater than 20 109/L and a hemoglobin level greater than 70 g/L. All blood products were irradiated with a dose of 25 Gy before transfusion . All extra hematologic complications were recorded [ 19 ] . After discharge , patients were checked monthly during the first 3 months and once every 3 months thereafter . Outcome Measures Clinical End Points The main clinical outcome measure was the duration of thrombocytopenia ( platelet count < 50 109/L ) . Other clinical measures were the time between transplantation and the last platelet transfusion , the duration of thrombocytopenia ( platelet count < 30 109/L and platelet count < 100 109/L ) , the duration of granulocytopenia ( granulocyte count < 0.5 109/L ) , the number of febrile episodes ( a febrile episode was defined as a 12-hour period during which the body temperature was > 38 C ) , the duration of febrile granulocytopenia , and the duration of hospitalization . Costs Direct medical costs were estimated by measuring the physical quantities of capital and labor consumed by each patient . Monetary values were assigned to these quantities on the basis of average 1995 prices in French francs [ 20 ] . Costs were estimated from the date on which patients were admitted to the transplantation unit until discharge and were based on patients ' medical records . These costs included the room cost , the cost of filgrastim after transplantation , the cost of collection ( including the costs of filgrastim priming and cell cryopreservation ) , and other treatment-related costs ( such as those for drugs , laboratory tests , and transfusions ) . Given the inherent differences between hospital charges and real costs ( especially in the context of a publicly funded health care system , such as that in France ) , hospital charges were not used to assess room costs associated with stays in the transplantation unit . Two per diem real costs were calculated on the basis of the Institut Paoli Calmettes transplantation unit ( for adults ) and the Institut Gustave Roussy pediatric transplantation unit ( for children ) . The annual expenditure for consumable supplies , cost for personnel in the unit , and depreciation of equipment were evaluated to calculate these per diem costs for each stay in the transplantation unit . The step-down method was used to add overhead costs to these per diem costs [ 21 , 22 ] . An additional study was done on the basis of detailed observations made during 42 leukapheresis procedures and 141 bone marrow harvest procedures done between January 1992 and May 1993 at the Institut Paoli Calmettes to determine the average cost of the two collection procedures . These average costs were ultimately applied to the study patients . Statistical Analysis It was estimated [ 23 ] that at least 70 patients per group would be needed to show a minimal reduction of 10 days in the duration of thrombocytopenia in the PBC group ( one-tailed test , = 0.05 , = 0.10 ; duration of thrombocytopenia in the bone marrow group SD , 33 20 days ) . Analyses were done using the intention-to-treat principle . Differences between groups were evaluated by the chi-square test or the Fisher exact test for categorical variables and by the Student t-test or nonparametric test for continuous variables ( two-sided tests ) . All analyses of clinical end points were adjusted for center and type of conditioning regimen . In the life-table analysis , actuarial probabilities were estimated using the Kaplan-Meier method [ 24 ] . The curves carry 95 % CIs calculated according to the method of Rothman [ 25 ] . Survival curves were compared using the log-rank test [ 26 ] . Values are the mean SD unless otherwise indicated . Industry Support Laboratoire AMGEN ( Neuilly , France ) provided support for this study with an agreement that the report would be su bmi tted for publication regardless of the findings . One of the authors participated in developing the protocol s and is a Laboratoire AMGEN employee . Results A total of 148 patients were r and omly assigned to treatment in nine transplantation units between April 1993 and December 1994 . Fourteen patients ( 7 in each group ) had relapse after r and omization and were no longer eligible for high-dose chemotherapy , 2 patients ( both in the PBC group ) refused treatment , and collection could not be done in 3 patients ( 1 in the PBC group and 2 in the bone marrow group ) . Thus , the analysis presented here includes the 129 patients who received high-dose chemotherapy ( 64 in the PBC group and 65 in the bone marrow group ) . Table 2 shows the baseline characteristics of the two groups . High-dose chemotherapy was Virtually no progress has been made during more than 2 decades of clinical trials for multiple myeloma ( MM ) involving st and ard therapy ( ST ) . Recent studies suggest that dose intensification requiring hematopoietic stem cell support results in higher complete response ( CR ) rates and extended disease control .  " Total Therapy " ( TT ) consisting of noncross-resistant induction regimens , followed by a double autotransplant ( AT ) procedure , was administered to 123 untreated patients with symptomatic MM . Upon hematologic recovery , interferon ( IFN ) maintenance ( 3 million units [MU]/m2 subcutaneously thrice weekly ) was given until disease recurrence/progression . Results were compared with the outcome of untreated patients receiving ST according to Southwest Oncology Group ( SWOG ) trials . One hundred sixteen pair mates were selected from both TT and among 1,123 patients to match for the major prognostic features . TT induced CR in 40 % of all 123 patients ( intent-to-treat ) . By 12 months , 7 % had died , including 4 % from treatment-related complications . With a median follow-up of 31 months , median duration s of event-free survival ( EFS ) and overall survival ( OS ) are 49 and 62 + months , respectively . Abnormalities of chromosomes 11q and 13 were associated with inferior outcome , whereas CR within 6 months after induction was a favorable prognostic feature for both EFS and OS . In comparison to ST , TT induced higher PR rates ( 85 % v 52 % , P < .0001 ) ( CR rates not available on SWOG trials ) and extended EFS ( 49 v 22 months , P = .0001 ) and OS ( 62 + v 48 months , P = .01 ) . Compared to ST , dose intensification with double AT markedly augments tumor cytoreduction , effecting not only higher CR rates but also significantly extending EFS and OS in previously untreated patients with MM Results to date indicate that high-dose therapy ( HDT ) with autologous stem cell support improves survival of patients with symptomatic multiple myeloma ( MM ) . We performed a multicenter , sequential , r and omized trial design ed to assess the optimal timing of HDT and autotransplantation . Among 202 enrolled patients who were up to 56 years old , 185 were r and omly assigned to receive HDT and peripheral blood stem cell ( PBSC ) autotransplantation ( early HDT group , n = 91 ) or a conventional-dose chemotherapy ( CCT ) regimen ( late HDT group , n = 94 ) . In the late HDT group , HDT and transplantation were performed as rescue treament , in case of primary resistance to CCT or at relapse in responders . PBSC were collected before r and omization , after mobilization by chemotherapy , and , in the two groups , HDT was preceded by three or four treatments with vincristine , doxorubicin , and methylprednisolone . Data were analyzed on an intent-to-treat basis using a sequential design . Within a median follow-up of 58 months , estimated median overall survival ( OS ) was 64.6 months in the early HDT group and 64 months in the late group . Survival curves were not different ( P = .92 , log-rank test ) . Median event-free survival ( EFS ) was 39 months in the early HDT group whereas median time between r and omization and CCT failure was 13 months in the late group . Average time without symptoms , treatment , and treatment toxicity ( TWiSTT ) were 27.8 months ( 95 % confidence interval [ CI ] ; range , 23.8 to 31.8 ) and 22.3 months ( range , 16.0 to 28.6 ) in the two groups , respectively . HDT with PBSC transplantation obtained a median OS exceeding 5 years in young patients with symptomatic MM , whether performed early , as first-line therapy , or late , as rescue treatment . Early HDT may be preferred because it is associated with a shorter period of chemotherapy We performed a multicenter comparative analysis of autologous peripheral blood stem cell transplantation ( PBSCT ) and allogeneic bone marrow transplantation ( alloBMT ) in multiple myeloma . Forty-eight consecutive patients received either PBSCT ( 24 patients ) or alloBMT ( 24 patients ) at one of three institutions in the study group . Preparatory regimens consisted of melphalan and total body irradiation ( TBI ) or melphalan alone in the PBSCT group . The alloBMT group received one of four regimens : cyclophosphamide and TBI ; cyclophosphamide , VP-16 and 1,3-bis(2-chloroethyl)-1-nitrosourea ( CVB ) ; busulfan and cyclophosphamide ( BU/CY ) and total marrow irradiation ( TMI ) ; or melphalan and TBI .  Procedure-related mortality was 12.5 % for the PBSCT group and 25 % for the alloBMT group . With a median follow-up for survivors in the PBSCT and alloBMT groups of 11 months ( range , 4 - 46 ) and 15 months ( range , 2 - 84 months ) , respectively , there was no significant difference in median overall survival ( 33.5 versus 38.6 months , p = 0.7637 ) or event-free survival ( 16.7 versus 31 months , p = 0.8450 ) . There was , however , a plateau in survival at 40 % in the alloBMT group . No plateau in survival was seen in the PBSCT group . Clinical relapses occurred as late as 39 months posttransplant . Patients have survived up to 28 months postrelapse BACKGROUND The median survival of patients with myeloma after conventional chemotherapy is three years or less . Promising results have been reported with high-dose therapy supported by autologous bone marrow transplantation . We conducted a r and omized study comparing conventional chemotherapy and high-dose therapy . METHODS Two hundred previously untreated patients under the age of 65 years who had myeloma were r and omly assigned at the time of diagnosis to receive either conventional chemotherapy or high-dose therapy and autologous bone marrow transplantation . RESULTS The response rate among the patients who received high-dose therapy was 81 percent ( including complete responses in 22 percent and very good partial responses in 16 percent ) , whereas it was 57 percent ( complete responses in 5 percent and very good partial responses in 9 percent ) in the group treated with conventional chemotherapy ( P < 0.001 ) . The probability of event-free survival for five years was 28 percent in the high-dose group and 10 percent in the conventional-dose group ( P = 0.01 ) ; the overall estimated rate of survival for five years was 52 percent in the high-dose group and 12 percent in the conventional-dose group ( P = 0.03 ) . Treatment-related mortality was similar in the two groups . CONCLUSIONS High-dose therapy combined with transplantation improves the response rate , eventfree survival , and overall survival in patients with myeloma Interferon ( INF ) has been incorporated as part of maintenance therapy after high dose treatment in order to make remissions more durable . In this study we have compared peripheral blood stem cell transplant ( PBSCT ) versus autologous bone marrow transplant ( ABMT ) with respect to INF tolerance . Thirty nine PBSCT patients have been compared to 37 ABMT patients for INF tolerance . This is followed by a comparison of 15 PBSCT patients versus 21 ABMT patients for engraftment details , response and survival . INF was started at a median of 61 days in the PBSCT and 58 days in the ABMT patients ( P = NS ) . It was well tolerated in both groups without a significant difference in toxicity in the two arms . Engraftment was more rapid in the PBSCT patients with platelet recovery being significantly faster . Response and survival showed a favourable trend for ABMT patients though statistical significance was not reached and the cost of PBSCT was 12 % cheaper . We were thus able to conclude that PBSCT grafts were as durable and could tolerate INF just as well as ABMT .  Engraftment was more rapid and the procedure of PBSCT was also cheaper . Further studies with a larger group of patients will be required before comments on the efficacy of treatment can be made High‐dose chemotherapy ( melphalan ) with autologous marrow stem cell support ( AMSCS ) results in high response rates in multiple myeloma ( MM ) , with up to 50 % of patients achieving complete remission . However , these remissions are generally not durable . As the cytokine interferon alpha has been shown to prolong partial response following conventional chemotherapy , this trial was conducted to evaluate its role following high‐dose chemotherapy . 85 patients were r and omly assigned to maintenance treatment with interferon alpha , 3 × 106 units/m2 subcutaneously three times weekly until relapse or no further treatment following recovery from high‐dose chemotherapy ( melphalan 140–200 mg/m2 or busulphan 16 mg/kg ) combined with AMSCS . At 5.8 years following the accrual of the last patient in this trial , 38 patients had died  , 17 in the interferon arm and 21 in the control arm . The median progression‐free survival ( PFS ) in the 42 patients r and omized to interferon alpha was 46 months versus 27 months in the controls . Both overall survival and PFS , which were highly significant at median follow‐up of 52 months , have now ceased to be significant , because most patients have ultimately succumbed to their disease . Interferon  was tolerated by the majority of patients with very good compliance . Toxicity consisted mainly of flu‐like symptoms and malaise which were usually self‐limiting . The results of such a pilot study should be carefully interpreted and the benefits of interferon should be confirmed in larger multi‐centre studies in the setting of minimal residual disease following autologous transplantation
target: The Hematology DSG noted that the use of transplantation for patients with myeloma varied among practice s across the province .
  In terms of survival , is  peripheral blood stem-cell  or  marrow transplantation better than conventional chemotherapy ?
  What is the relative efficacy of autologous versus allogeneic transplantation ?
  What specifics of the transplantation process can be recommended ?
  The addition of interferon is unlikely to influence outcomes in the control group .
  In Terms of Survival , Is Autologous Peripheral Blood Stem-Cell or Bone Marrow Transplantation Better than Conventional Chemotherapy ?
background: After more than three decades of clinical trials testing various st and ard-dose chemotherapy regimens , the disease course of patients with multiple myeloma has not changed appreciably .
  Conventional chemotherapy can provide effective palliation but is not curative ( 1 ) .
  Case series have described encouraging results in patients with myeloma undergoing allogeneic or autologous bone marrow or peripheral blood stem-cell transplantation ( 2 ) .
  Other studies of transplantation , including r and omized trials , have been reported in the past 6 years ( 3 , 4 ) .
  To facilitate decisions about treatment options , practice guidelines have been developed for use by health care providers and consumers .
  In Ontario , Canada , cancer treatments and policies are led by a state-funded organization , Cancer Care Ontario .
  To help derive treatment options , Cancer Care Ontario has developed the Program in Evidence -Based Care , which includes the Practice Guidelines Initiative .
  To approach this topic , the DSG addressed the following questions : What is optimal st and ard-dose chemotherapy for patients with myeloma ?
  When should transplantation be performed ?
  Who should ( or should not ) receive a transplant ?