The Role of High-Dose Chemotherapy and Stem-Cell Transplantation in Patients with Multiple Myeloma: A Practice Guideline of the Cancer Care Ontario Practice Guidelines Initiative Bortezomib in multiple myeloma and lymphoma: a systematic review and clinical practice guideline Effects of exercise in combination with epoetin alfa during high-dose chemotherapy and autologous peripheral blood stem cell transplantation for multiple myeloma. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. Efficient mobilization of peripheral blood stem cells following CAD chemotherapy and a single dose of pegylated G-CSF in patients with multiple myeloma Addition of lenalidomide to melphalan in the treatment of newly diagnosed multiple myeloma: the National Cancer Institute of Canada Clinical Trials Group MY.11 trial Facilitating exercise adherence for patients with multiple myeloma. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Systemic Sclerosis as an Indication for Autologous Hematopoietic Cell Transplantation: Position Statement from the American Society for Blood and Marrow Transplantation. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. Use of granulocyte colony-stimulating factor (G-CSF) in patients receiving myelosuppressive chemotherapy for the treatment of cancer. Provincial Systemic Treatment Disease Site Group. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. Continuous infusion of ceftazidime for patients with breast cancer and multiple myeloma receiving high-dose chemotherapy and peripheral blood stem cell transplantation Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for 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. Cost-effectiveness of a Transplantation Strategy Compared to Melphalan and Prednisone in Younger Patients with Multiple Myeloma Peripheral Blood Stem Cell and Bone Marrow Transplantation for Solid Tumors and Lymphomas: Hematologic Recovery and Costs: A Randomized, Controlled Trial Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. Single versus double autologous stem-cell transplantation for multiple myeloma. Feasibility of Exercise During Treatment for Multiple Myeloma Changes in quality-of-life and psychosocial adjustment among multiple myeloma patients treated with high-dose melphalan and autologous stem cell transplantation. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial High-Dose Melphalan and Autologous Stem-Cell Transplantation in Patients with AL Amyloidosis: An 8-Year Study
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 . Disease Site Groups ( DSGs ) , which comprise physicians , epidemiologists , and consumers , develop guidelines through a systematic process that involves assessment of evidence , consensus , and a validation process involving practitioners from across the province . Guideline topics are chosen through a prioritization process that includes the burden of illness , availability of evidence , perceived variation in practice , the potential to affect treatment decisions , and re source utilization . The Hematology DSG noted that the use of transplantation for patients with myeloma varied among practice s across the province . Variability in practice and emerging evidence of higher quality made this a priority topic for guideline development . To approach this topic , the DSG addressed the following questions : What is optimal st and ard-dose chemotherapy for patients with myeloma ? 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 ? When should transplantation be performed ? Who should ( or should not ) receive a transplant ? Methods Overview of Guideline Development This guideline was developed by the Cancer Care Ontario Practice Guidelines Initiative ( CCOPGI ) using the methods of the Practice Guidelines Development Cycle ( 5 ) . Members of the CCOPGI 's Hematology DSG selected , review ed , and interpreted the evidence . This DSG comprises 25 members , including hematologists , medical and radiation oncologists , an epidemiologist , and 2 lay representatives . Several of the physician members have background training in epidemiology ; 8 hematologists regularly perform stem-cell transplantation in clinical practice . The DSG 's draft recommendations were circulated through a mailed survey to hematologists and medical or radiation oncologists in Ontario for feedback and involvement in a consensus process . Responses were used to guide the reformatting of the draft into the final guideline recommendations . The Practice Guidelines Co-ordinating Committee ( PGCC ) , which ensures consistency of guideline development across the DSGs of various tumor sites , approved the guideline . The CCOPGI has a st and ardized process to up date each guideline report ; the current guideline was up date d and review ed by the PGCC in October 2000 . Literature Search Strategy We search ed the MEDLINE , CANCERLIT , and Cochrane Library data bases for literature published from 1992 to December 1997 and subsequently up date d the search in October 1998 , June 1999 , and April 2000 . For the search es , we combined multiple myeloma ( as a Medical Subject Heading [ MeSH ] and text word ) with bone marrow transplantation ( MeSH and text word ) and drug therapy ( MeSH ) . Then , we combined these terms with the search terms for the following study design s : practice guidelines ; systematic review s or meta-analyses ; review s ; r and omized , controlled trials ; controlled clinical trials ; and comparative studies . In addition , we search ed the PubMed and Physician Data Query ( PDQ ) ( www.cancer.gov/ search / clinical _ trials/ ) data bases and review ed relevant conference proceedings ( American Society of Hematology , 1997 to 1999 , and American Society of Clinical Oncology , 1999 to 2000 ) , article bibliographies , and personal files . To address the issue of optimal chemotherapy , we performed an additional search of the same data bases using the term multiple myeloma ( MeSH ) combined with r and omized , controlled trials ( MeSH ) and the text word r and om in the title . Inclusion Criteria We selected study reports meeting one of the three following criteria : r and omized trial or meta- analysis of therapy for patients with myeloma that reported survival or quality -of-life outcomes ; nonr and omized comparative trial that addressed transplantation strategy , including a contemporaneous control group , and that reported survival or quality -of-life outcomes ; or economic evaluation that addressed transplantation strategy . Because of insufficient data on the specifics of the transplantation process and the patients who would be most likely to benefit from transplantation , we performed a second search , which identified data from noncomparative case-series studies . Data Extraction and Interpretative Summary Three members of the DSG , including an epidemiologist , determined eligibility of the articles and abstract s obtained from the literature search . The lead DSG member for this guideline extracted and summarized relevant data according to the guideline question addressed . The DSG members then review ed the summarized data and key articles . The DSG met formally three to four times annually ; at these meetings , the members method ologically assessed the articles , interpreted the data , and debated specific points in an attempt to reach a consensus . Synthesizing the Evidence Because all of the nine r and omized trials on transplantation addressed different questions , we did not statistically pool the data . DSG Consensus Process Through an iterative process that included debate at formal meetings and circulation of draft recommendations , we considered the implication s of the appraised data for each guideline question . With this process , attempts were made to reach consensus ; when this was impossible , minority opinions were recorded . Approval by each member of the DSG was required before circulation of the draft version for practitioner feedback and su bmi ssion of the final guideline to the PGCC . Practitioner Feedback To obtain practitioner feedback , we mailed a survey to 211 practitioners in Ontario ( 94 hematologists , 93 medical oncologists , and 24 radiation oncologists ) . The survey consisted of st and ardized items asking the practitioner to rate the quality of each draft guideline and to judge whether the draft recommendations should serve as a practice guideline . Written comments were invited . Follow-up reminders were sent at 2 weeks ( by postcard ) and 4 weeks ( entire package ) . After exclusion of 18 retired practitioners , 137 of 193 practitioners ( 71 % ) responded ; 90 of 137 respondents ( 66 % ) indicated that the guideline was relevant to their practice . Approval of the draft guideline was strong among these 90 practitioners : 91 % agreed or strongly agreed that the summary of the evidence was acceptable , 87 % agreed with the draft recommendations , and 81 % approved of the recommendations as a practice guideline . Thirty-nine respondents provided written comments ; these comments were , like the other responses , incorporated in the final guideline . Results Sixty-six reports met the criteria for inclusion and are categorized in Table 1 . In each section below , we describe the studies , summarize results , and describe the guideline development . Table 1 . Evidence Included in This Practice Guideline Report What Is Optimal St and ard-Dose Chemotherapy  for Patients with Multiple Myeloma ? To properly compare transplantation with conventional chemotherapy , we must define optimal conventional chemotherapy . We identified 30 r and omized trials comparing therapies in previously untreated patients . Four meta-analyses ( 6 - 9 ) evaluated these data . The Myeloma Trialists ' Collaborative Group ( 7 ) compared combination chemotherapy with melphalan plus prednisone in a meta- analysis of 27 trials . Twenty of these trials supplied individual-patient data . No difference in survival was detected . The proportional reduction in the annual odds of death was 1.5 % in favor of combination chemotherapy ( 95 % CI , 8 % to 5 % ; P > 0.2 ) , with an odds ratio ( OR ) of 0.99 ( CI , 0.93 to 1.05 ) . An earlier literature -based meta- analysis ( 6 ) of 18 trials also failed to detect a survival difference between groups ( OR , 1.04 [ CI , 0.90 to 1.19 ] ; P > 0.2 ) . Two meta-analyses evaluated interferon for multiple myeloma . An overview of 24 r and omized trials published in abstract form ( 8) demonstrated that interferon improved recurrence-free survival by 6 months and improved 3-year overall survival by 4 % . Another meta- analysis ( 9 ) measured survival by a unique measure called the mean lifetime survival . This meta- analysis found no difference in survival rate between the group receiving interferon and the group not receiving interferon ( 3.9 vs. 3.4 years , respectively ; P = 0.095 ) . Guideline Recommendation Multiagent chemotherapy or melphalan plus prednisone is appropriate therapy for a control group in a comparison of transplantation versus st and ard-dose therapy . 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 ? We review ed two r and omized and three nonr and omized comparisons ( Table 2 ) . Attal and colleagues ( 3 ) r and omly assigned 200 previously untreated patients younger than 65 years of age with stage II or III ( 40 ) myeloma to conventional chemotherapy or to a strategy that included autologous bone marrow transplantation . Patients were r and omly Questions In patients with multiple myeloma , Waldenström macroglobulinemia , or lymphoma , what is the efficacy of bortezomib alone or in combination as measured by survival , quality of life , disease control ( for example , time to progression ) , response duration , or response rate ? What is the toxicity associated with the use of bortezomib ? Which patients are more or less likely to benefit from treatment with bortezomib ? Perspectives Evidence was selected and review ed by two members of the Hematology Disease Site Group and by method ologists from the Program in Evidence -based Care ( pebc ) at Cancer Care Ontario . The practice guideline report was review ed and approved by the Hematology Disease Site Group , which comprises hematologists , medical and radiation oncologists , and a patient representative . As part of an external review process , the report was disseminated to practitioners throughout Ontario to obtain their feedback . Outcomes Outcomes of interest were overall survival , quality of life , response rates and duration , and rates of adverse events . Methodology A systematic search was conducted of the medline , embase , HealthStar , cinahl , and Cochrane Library data bases for primary articles and practice guidelines . The result ing evidence informed the development of clinical practice recommendations . Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received . The systematic review and modified recommendations were approved by a review body w theithin pebc . Results The literature review found one r and omized controlled trial ( rct ) —the only published rct of bortezomib in relapsed myeloma . A number of phase ii studies were also retrieved , including a r and omized phase ii study . No r and omized trials were retrieved for lymphoma . The rct found bortezomib to be superior to high-dose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma , although grade 3 adverse events were more common in the bortezomib arm . Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment ; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation . Practice Guideline This evidence -based series applies to adult patients with myeloma , Waldenström macroglobulinemia , or lymphoma of any type , stage , histology , or performance status . Recommendations Based on the results of a large well-conducted rct , which represents the only published r and omized study in relapsed myeloma , the Hematology Disease Site Group ( dsg ) offers the following recommendations : For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments , including autologous stem-cell transplantation , and who are c and i date s for further chemotherapy , bortezomib is recommended as the preferred treatment option . Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation . The dsg is aware that thalidomide , alkylating agents , or repeat transplantation may also be options for these patients . However , evaluation of these other options is beyond the scope of this practice guideline . For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent – based chemotherapy who are c and i date s for further chemotherapy , further treatment with alkylating agent – based chemotherapy is recommended . Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials . Qualifying Statements Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease . The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg . For specific details related to the administration of bortezomib therapy , the dsg suggests that clinicians refer to the protocol s used in major trials . Some of those details are provided here for informational purpose s. Dosage Bortezomib 1.3,g/m2 is given as a rapid intravenous bolus over 3–5 seconds on days 1 , 4 , 8 , and 11 of a 21-day cycle ; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function . Vital signs should be checked before and after each dose . A complete blood count is recommended before each dose , with blood chemistries ( including electrolyte and creatinine levels ) monitored at a minimum on days 1 and 8 of each cycle . The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy , as described in the product monograph ; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities . Most toxicities are reversible if dose modification guidelines are followed . Response to Treatment Responses are usually apparent by 6 weeks ( 2 cycles ) . For patients achieving complete remission ( determined by negative electrophoresis and immunofixation ) , bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission . In patients with progressive disease after 2 cycles or stable disease after 4 cycles , dexamethasone added to the bortezomib regimen ( 20 mg by mouth the day of and the day after each bortezomib dose ) may produce an objective response .  Bortezomib ( with or without dexamethasone ) should be continued in patients showing benefit from therapy ( excluding those in complete remission ) unless disease progression or significant toxicity is observed . Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone . The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent – based chemotherapy . To date , no reported rcts have evaluated thalidomide in this role , and specifically , no trials have compared thalidomide with bortezomib . Given these limitations , the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone PURPOSE / OBJECTIVES To determine the effect of aerobic and strength resistance training and epoetin alfa ( EPO ) therapy on transfusions , stem cell collection s , transplantation recovery , and multiple myeloma treatment response . DESIGN R and omized clinical trial . SETTING A myeloma research and therapy center in the south central United States . SAMPLE 135 patients with multiple myeloma , 120 evaluable . METHODS R and om assignment to exercise or usual care groups . All patients received EPO based on an algorithm . Aerobic capacity , using the six-minute walk test , was assessed prior to induction chemotherapy , prior to stem cell mobilization , and following stem cell collection for all patients and before and after transplantation for patients continuing in the study . Data analysis included analysis of variance to compare other outcome variables by groups . MAIN RESEARCH VARIABLES Number of red blood cell and platelet transfusions during transplantation , number of attempts at and total number of days of stem cell collection , time to recovery after transplantation , and response to intensive therapy for multiple myeloma . FINDINGS Recovery and treatment response were not significantly different between groups after transplantation . The exercise group had significantly fewer red blood cell transfusions and fewer attempts at stem cell collection . Serious adverse events were similar in each group . CONCLUSIONS Exercise with prophylactic EPO therapy reduces the number of RBC transfusions and attempts at stem cell collection for patients receiving intensive treatment for multiple myeloma . IMPLICATION S FOR NURSING Exercise is safe and has many physiologic benefits for patients receiving multiple myeloma treatment BACKGROUND High-dose therapy with supporting autologous stem-cell transplantation remains a controversial treatment for cancer . In multiple myeloma , first-line regimens incorporating high-dose therapy yield higher remission rates than do conventional-dose treatments , but evidence that this translates into improved survival is limited . METHODS In this multicenter study , the Medical Research Council Myeloma VII Trial , we r and omly assigned 407 patients with previously untreated multiple myeloma who were younger than 65 years of age to receive either st and ard conventional-dose combination chemotherapy or high-dose therapy and an autologous stem-cell transplant . RESULTS Among the 401 patients who could be evaluated , the rates of complete response were higher in the intensive-therapy group than in the st and ard-therapy group ( 44 percent vs. 8 percent , P<0.001 ) . The rates of partial response were similar ( 42 percent and 40 percent , respectively ; P=0.72 ) , and the rates of minimal response were lower in the intensive-therapy group than in the st and ard-therapy group ( 3 percent vs. 18 percent , P<0.001 ) . Intention-to-treat analysis showed a higher rate of overall survival ( P=0.04 by the log-rank test ) and progression-free survival ( P<0.001 ) in the intensive-therapy group than in the st and ard-therapy group . As compared with st and ard therapy , intensive treatment increased median survival by almost 1 year ( 54.1 months [ 95 percent confidence interval , 44.9 to 65.2 ] vs. 42.3 months [ 95 percent confidence interval , 33.1 to 51.6 ] ) . There was a trend toward a greater survival benefit in the group of patients with a poor prognosis , as defined by a high beta2-microglobulin level ( more than 8 mg per liter ) . CONCLUSIONS High-dose therapy with autologous stem-cell rescue is an effective first-line treatment for patients with multiple myeloma who are younger than 65 years of age High-dose chemotherapy followed by autologous blood stem cell transplantation is the st and ard treatment for myeloma patients . In this study , CAD ( cyclophosphamide , adriamycin , dexamethasone ) chemotherapy and a single dose of pegfilgrastim ( 12 mg ) was highly effective in mobilizing peripheral blood stem cells ( PBSCs ) for subsequent transplantation , with 88 % of patients ( n=26 ) achieving the CD34 + cell harvest target of ⩾7.50 × 106 CD34 + cells/kg body weight , following a median of two apheresis procedures ( range 1–4 ) and with first apheresis performed at a median day 13 after CAD application ( range 10–20 ) . Patients treated with pegfilgrastim showed a reduced time to first apheresis procedure from mobilization compared with filgrastim-mobilized historical matched controls ( n=52 , P=0.015 ) . The pegfilgrastim mobilization regimen allowed for transplantation of a median of 3.58 × 106 CD34 + cells/kg body weight while leaving sufficient stored cells for a second high-dose regimen and back-ups in most patients . Engraftment following transplantation was comparable to filgrastim , with a median time of 14 days to leucocyte ⩾1.0 × 109/l ( range 10–21 ) and 11 days to platelets ⩾20 × 109/l ( range 0–15 ) . The results of this study thus provide further support for the clinical utility of pegfilgrastim for the mobilization of PBSC following chemotherapy in cancer patients scheduled for transplantation Oral melphalan and prednisone remain an effective and tolerable treatment for patients with multiple myeloma . For approximately 40 years , this combination has been the st and ard of care for patients not proceeding to stem cell transplant . Within the last 10 years , new agents have been found to be efficacious in the relapsed/refractory setting . Within the last year , two trials of added thalidomide in the newly diagnosed setting have demonstrated outcomes superior to those achieved with melphalan and prednisone alone . This improved outcome comes at the cost of increased toxicity . The National Cancer Institute of Canada Clinical Trials Group ( ncic ctg ) has recently developed a r and omized phase ii trial ( MY.11 ) that uses a combination of lenalidomide with melphalan for patients with newly diagnosed multiple myeloma .  Lenalidomide is a thalidomide analogue and , like thalidomide , is thought to work through immunomodulatory effects . It was shown to have activity in patients with relapsed or refractory disease and , in combination with dexamethasone , is superior to dexamethasone alone . Lenalidomide holds promise as a more effective and potentially less toxic derivative of thalidomide . Experience with lenalidomide in combination with chemotherapy is very limited , and the purpose of MY.11 is to establish tolerability and to gain knowledge about efficacy . The information gained from MY.11 is expected to help inform dosing levels and schedules for a large phase iii trial being developed by the Eastern Cooperative Oncology Group that will include participation by the ncic ctg Physical exercise is becoming an accepted part of therapy for many patients with cancer .  Exercise may alleviate patients ' fatigue and improve physical performance and psychological outlook . Much of the research is limited to women with breast cancer and excludes patients with bone metastases . This article reports on the authors ' work in facilitating exercise adherence for patients with multiple myeloma ( MM ) and bone lesions while they were enrolled in a feasibility/pilot exercise study as they were receiving treatment for their disease in an outpatient treatment program . The exercise program for these patients receiving high-dose chemotherapy and stem cell transplantation consisted of aerobic and strength-building components . The program was home based , and patients performed exercises without direct supervision . On average , the patients completed the six-month exercise prescription 75 % of the time . Overall trends showed that all 14 patients in the exercise group  improved in several areas of testing , and the test results of all 10 patients in the usual-care group declined . Flexibility and simplicity are essential when design ing exercise programs for patients , and encouragement and support also are needed to help patients adhere to prescribed exercise BACKGROUND Autologous haemopoietic stem-cell transplantation ( HSCT ) improves survival in patients with multiple myeloma , but disease progression remains an issue . Allogeneic HSCT might reduce disease progression , but can be associated with high treatment-related mortality . Thus , we aim ed to assess effectiveness of allogeneic HSCT with non-myeloablative conditioning after autologous HSCT compared with t and em autologous HSCT . METHODS In our phase 3 biological assignment trial , we enrolled patients with multiple myeloma attending 37 transplant centres in the USA . Patients ( < 70 years old ) with adequate organ function who had completed at least three cycles of systemic antimyeloma therapy within the past 10 months were eligible for inclusion . We assigned patients to receive an autologous HSCT followed by an allogeneic HSCT ( auto-allo group ) or t and em autologous HSCTs ( auto-auto group ) on the basis of the availability of an HLA-matched sibling donor . Patients in the auto-auto group subsequently underwent a r and om allocation ( 1:1 ) to maintenance therapy ( thalidomide plus dexamethasone ) or observation . To avoid enrolment bias , we classified patients as st and ard risk or high risk on the basis of cytogenetics and β2-microglobulin concentrations . We used the Kaplan-Meier method to estimate differences in 3-year progression-free survival ( PFS ; primary endpoint ) between patients with st and ard-risk disease in the auto-allo group and the best results from the auto-auto group ( maintenance , observation , or pooled ) . This study is registered with Clinical Trials.gov , number NCT00075829 . FINDINGS Between Dec 17 , 2003 , and March 30 , 2007 , we enrolled 710 patients , of whom 625 had st and ard-risk disease and received an autologous HSCT . 156 ( 83 % ) of 189 patients with st and ard-risk disease in the auto-allo group and 366 ( 84 % ) of 436 in the auto-auto group received a second transplant . 219 patients in the auto-auto group were r and omly assigned to observation and 217 to receive maintenance treatment , of whom 168 ( 77 % ) completed this treatment . PFS and overall survival did not differ between maintenance and observation groups and pooled data were used . Kaplan-Meier estimates of 3-year PFS were 43 % ( 95 % CI 36 - 51 ) in the auto-allo group and 46 % ( 42 - 51 ) in the auto-auto group ( p=0·671 ) ; overall survival also did not differ at 3 years ( 77 % [ 95 % CI 72 - 84 ] vs 80 % [ 77 - 84 ] ; p=0·191 ) . Within 3 years , 87 ( 46 % ) of 189 patients in the auto-allo group had grade 3 - 5 adverse events as did 185 ( 42 % ) of 436 patients in the auto-auto group . The adverse events that differed most between groups were hyperbilirubinaemia ( 21 [ 11 % ] patients in the auto-allo group vs 14 [ 3 % ] in the auto-auto group ) and peripheral neuropathy ( 11 [ 6 % ] in the auto-allo group vs 52 [ 12 % ] in the auto-auto group ) . INTERPRETATION Non-myeloablative allogeneic HSCT after autologous HSCT is not more effective than t and em autologous HSCT for patients with st and ard-risk multiple myeloma . Further enhancement of the graft versus myeloma effect and reduction in transplant-related mortality are needed to improve the allogeneic HSCT approach . FUNDING US National Heart , Lung , and Blood Institute and the National Cancer Institute Systemic sclerosis is a progressive inflammatory disease that is frequently fatal and has limited treatment options . High-dose chemotherapy with autologous hematopoietic cell transplantation ( AHCT ) has been evaluated as treatment for this disease in observational studies , multicenter r and omized controlled clinical trials , and meta-analyses . On behalf of the American Society for Blood and Marrow Transplantation ( ASBMT ) , a panel of experts in transplantation and rheumatology was convened to review available evidence and make a recommendation on AHCT as an indication for systemic sclerosis . Three r and omized trials have compared the efficacy of AHCT with cyclophosphamide only , and all demonstrated benefit for the AHCT arm for their primary endpoint ( improvement in the American Scleroderma Stem Cell versus Immune Suppression Trial , event-free survival in Autologous Stem Cell Transplantation International Scleroderma trial , and change in global rank composite score in Scleroderma : Cyclophosphamide or Transplantation trial )  . AHCT recipients also had better overall survival and a lower rate of disease progression . These findings have been confirmed in subsequent meta-analyses . Based on this high- quality evidence , the ASBMT recommends systemic sclerosis should be considered as a " st and ard of care " indication for AHCT . Close collaboration between rheumatologists and transplant clinicians is critical for optimizing patient selection and patient outcomes . Transplant centers in the United States are strongly encouraged to report patient and outcomes data to the Center for International Blood and Marrow Transplant Research on their patients receiving AHCT for this indication BACKGROUND High-dose chemotherapy with autologous stem-cell transplantation is a st and ard treatment for young patients with multiple myeloma . Residual disease is almost always present after transplantation and is responsible for relapse . This phase 3 , placebo-controlled trial investigated the efficacy of lenalidomide maintenance therapy after transplantation . METHODS We r and omly assigned 614 patients younger than 65 years of age who had nonprogressive disease after first-line transplantation to maintenance treatment with either lenalidomide ( 10 mg per day for the first 3 months , increased to 15 mg if tolerated ) or placebo until relapse . The primary end point was progression-free survival . RESULTS Lenalidomide maintenance therapy improved median progression-free survival ( 41 months , vs. 23 months with placebo ; hazard ratio , 0.50 ; P<0.001 ) . This benefit was observed across all patient subgroups , including those based on the β(2)-microglobulin level , cytogenetic profile , and response after transplantation . With a median follow-up period of 45 months , more than 70 % of patients in both groups were alive at 4 years . The rates of grade 3 or 4 peripheral neuropathy were similar in the two groups . The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patient-years in the placebo group ( P=0.002 ) . Median event-free survival ( with events that included second primary cancers ) was significantly improved with lenalidomide ( 40 months , vs. 23 months with placebo ; P<0.001 ) . CONCLUSIONS Lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival among patients with multiple myeloma . Four years after r and omization , overall survival was similar in the two study groups . ( Funded by the Programme Hospitalier de Recherche Clinique and others ; Clinical Trials.gov number , NCT00430365 . ) GUIDELINE QUESTIONS 1 ) Does G-CSF reduce the incidence of important adverse clinical outcomes due to infections in patients with cancer treated with myelosuppressive therapy ? 2 ) Does G-CSF allow maintenance of the chemotherapy dose with the goal of improving survival ? OBJECTIVE To evaluate the evidence for the role of G-CSF in patients receiving myelosuppressive chemotherapy for the treatment of cancer . OUTCOMES Clinical outcomes reflecting events that may affect quality of life and /or re source utilization ( e.g. , rates and duration of hospitalization , antibiotic use ) ; outcomes reflecting the effect of treatment on infection rates , tumour response and survival and those related to the biological effect of G-CSF . PERSPECTIVE ( VALUES ) Evidence was selected , review ed and synthesized by members of the Provincial Systemic Treatment Disease Site Group ( DSG ) of the Cancer Care Ontario Practice Guidelines Initiative . Drafts of this document have been circulated and review ed by members of the Systemic Treatment DSG . The DSG comprises medical oncologists , pharmacists , supportive care personnel and administrators . Evaluation by clinicians was considered in the final practice guideline . Community representatives did not participate in the development of this report but will in future reports . Guidelines approval does require participation by community representatives . QUALITY OF EVIDENCE Two published guidelines and an up date of one guideline were identified . Ten eligible r and omized controlled trials published in English were included . BENEFITS A meta- analysis of data from 8 trials showed that the odds of experiencing febrile neutropenia with G-CSF were significantly reduced ( odds ratio 0.38 ; 95 % confidence interval [ CI ] 0.27 to 0.52 ; p < 0.00001 ) . G-CSF reduced the risk of febrile neutropenia by 34 % ( risk ratio 0.66 ; 95 % CI 0.51 to 0.86 ; p = 0.0015 ) . The use of G-CSF was associated with a significant reduction in antibiotic usage and days spent in hospital in 2 trials and had no effect in the other 4 in which it was measured . Five trials reported no difference in overall median survival , with 2 small trials detecting a significant increase related to G-CSF . However , further research is necessary to confirm these results . HARMS The toxic effects of G-CSF are relatively mild . The most consistent clinical symptom attributed to G-CSF is bone pain , reported in incidence rates ranging from 20 % to 50 % in 3 trials . Except for one case , reported bone pain was mild . PRACTICE GUIDELINE In cancer patients receiving myelosuppressive chemotherapy , granulocyte colony-stimulating factor ( G-CSF ) may be beneficial for some patients . If a reduction in the number of febrile neutropenic episodes , or in the duration of such episodes , is expected to improve quality of life , then G-CSF is a reasonable treatment option for selected patients . A clear justification for the use of G-CSF should be stated . If the objective of using G-CSF is to maintain dose intensity of antitumour agents , then G-CSF can be recommended where reduction in dose intensity has been shown in r and omized controlled trials to reduce survival or disease-free survival . Although the evidence is weaker , the Systemic Treatment DSG would support the practice endorsed by other guidelines ( American Society of Clinical Oncology , Ontario Drug Benefit Plan ) and would recommend G-CSF for patients receiving potentially curative chemotherapy : i ) as primary prophylaxis ; that is , where dose reductions below a specified level are required because of a known high risk of febrile neutropenia , or ii ) as secondary prophylaxis in patients receiving chemotherapy of established efficacy who have suffered a prior serious episode of febrile neutropenia due to the same chemotherapy regimen . The exact cut-off for dose reductions is unknown at this time and ought to be left to the judgement of the clinician . In general , the use of  G-CSF  for dose reductions lower than 20 % is not recommended . ( ABSTRACT TRUNCATED 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 This prospect i ve study was performed to examine the safety and efficacy of a continuous infusion of ceftazidime in patients who developed febrile neutropenia after high-dose chemotherapy ( HDCT ) and autologous peripheral blood stem cell transplantation ( PBSCT ) and to determine if the underlying disease represents a risk factor for infectious complications . From September 1995 to May 2000 , 55 patients with breast cancer ( BC , group I , 54 females , one male ) and 32 patients with multiple myeloma ( MM , group II , 10 female , 22 male ) were included in this study . The febrile patients received a 2 g intravenous bolus of ceftazidime , followed by a 4 g continuous infusion over 24 h using a portable infusion pump . If the fever persisted for 72 h a glycopeptide antibiotic was added . The median age was 42 years ( range 22–59 ) in group I and 52 years ( range 35–63 ) in group II . Thirty-five BC patients ( 64 % ) and 20 MM patients ( 63 % ) responded to the monotherapy with ceftazidime . After addition of a glycopeptide antibiotic , an additional 11 BC patients vs 10 MM patients became afebrile . The causes of fever in group I were fever of unknown origin ( FUO ) in 49 patients , microbiologically documented infection ( MDI ) in five patients , and clinical ly documented infection ( CDI ) in one patient . The causes of fever in group II were FUO in 22 patients , MDI in eight patients and CDI in two patients . Forty-one febrile episodes in BC patients ( 75 % ) and 22 episodes in the MM patients ( 69 % ) were successfully managed by out-patient treatment , result ing in a saving of an average of 20 days of inpatient care . Significantly more episodes of MDI and CDI occurred in patients with MM ( P = 0.05 ) . The results indicate that BC and MM patients with febrile neutropenia after HDCT and PBSCT can be treated as out patients with close monitoring to ensure safety . This approach represents a better use of health care re sources Background High‐dose chemotherapy plus autologous stem‐cell transplantation has been the st and ard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age . However , promising data on the use of combination therapy with lenalidomide , bortezomib , and dexamethasone ( RVD ) in this population have raised questions about the role and timing of transplantation . Methods We r and omly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD ( 350 patients ) or high‐dose melphalan plus stem‐cell transplantation followed by two additional cycles of RVD ( 350 patients ) . Patients in both groups received maintenance therapy with lenalidomide for 1 year . The primary end point was progression‐free survival . Results Median progression‐free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone ( 50 months vs. 36 months ; adjusted hazard ratio for disease progression or death , 0.65 ; P<0.001 ) . This benefit was observed across all patient subgroups , including those stratified according to International Staging System stage and cytogenetic risk . The percentage of patients with a complete response was higher in the transplantation group than in the RVD‐alone group ( 59 % vs. 48 % , P=0.03 ) , as was the percentage of patients in whom minimal residual disease was not detected ( 79 % vs. 65 % , P<0.001 ) . Overall survival at 4 years did not differ significantly between the transplantation group and the RVD‐alone group ( 81 % and 82 % , respectively ) . The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD‐alone group ( 92 % vs. 47 % ) , as were the rates of grade 3 or 4 gastrointestinal disorders ( 28 % vs. 7 % ) and infections ( 20 % vs. 9 % ) . No significant between‐group differences were observed in the rates of treatment‐related deaths , second primary cancers , thromboembolic events , and peripheral neuropathy . Conclusions Among adults with multiple myeloma  , RVD therapy plus transplantation was associated with significantly longer progression‐free survival  than RVD therapy alone , but overall survival did not differ significantly between the two approaches . ( Supported by Celgene and others ; IFM 2009 Study Clinical Trials.gov number , NCT01191060 . 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 High dose chemotherapy with autologous stem cell transplantation ( ASCT ) improves outcomes in patients 65 years of age or less with multiple myeloma .  Survival and costs in a cohort of 16 patients who received melphalan and prednisone as part of a clinical trial were compared with those of 36 patients referred to our centre for consideration of ASCT . In the transplant group , survival and costs were extrapolated to match the period of observation in the melphalan and prednisone group . Patient-specific and average costs were calculated from the perspective of the Ontario Ministry of Health . Costs and survival were varied by 50 % in the sensitivity analysis . Transplantation improved life expectancy by 19.3 months with a cost difference of $ 30,517 Canadian . The incremental cost-effectiveness of transplantation compared with melphalan and prednisone was $ 25,710 Canadian per life-year gained when additional pamidronate and follow-up costs were considered . Discounting costs and survival at 3 and 5 % did not result in important differences . The sensitivity analysis result ed in best and worse case scenarios for transplantation compared with melphalan and prednisone of $ 13,049 and $ 63,954 per life-year gained respectively . In comparison with melphalan and prednisone , ASCT appears to be cost-effective in patients 65 years old or younger with myeloma 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 BACKGROUND Allogeneic or autologous bone marrow transplantation and intensive consolidation chemotherapy are used to treat acute myelogenous leukemia in a first complete remission . METHODS After induction treatment with daunorubicin and cytarabine , patients who had a complete remission received a first course of intensive consolidation chemotherapy , combining intermediate-dose cytarabine and amsacrine .  Patients with an HLA-identical sibling were assigned to undergo allogeneic bone marrow transplantation ; the others were r and omly assigned to undergo autologous bone marrow transplantation ( with unpurged bone marrow ) or a second course of intensive chemotherapy , combining high-dose cytarabine and daunorubicin . Comparisons were made on the basis of the intention to treat . RESULTS A total of 623 patients had a complete remission ; 168 were assigned to undergo allogeneic bone marrow transplantation , and 254 were r and omly assigned to one of the other two groups . Of these patients , 343 completed the treatment assignment : 144 in the allogeneic-transplantation group , 95 in the autologous-transplantation group , and 104 in the intensive-chemotherapy group . The relapse rate was highest in the intensive-chemotherapy group and lowest in the allogeneic-transplantation group , whereas the mortality rate was highest after allogeneic transplantation and lowest after intensive chemotherapy . The projected rate of disease-free survival at four years was 55 percent for allogeneic transplantation , 48 percent for autologous transplantation , and 30 percent for intensive chemotherapy . However , the overall survival after complete remission was similar in the three groups , since more patients who relapsed after a second course of intensive chemotherapy had a response to subsequent autologous bone marrow transplantation . Other differences were also observed , especially with regard to hematopoietic recovery ( it occurred later after autologous transplantation ) and the duration of hospitalization ( it was longer with bone marrow transplantation ) . CONCLUSIONS Autologous as well as allogeneic bone marrow transplantation results in better disease-free survival than intensive consolidation chemotherapy with high-dose cytarabine and daunorubicin . Transplantation soon after a relapse or during a second complete remission might also be appropriate BACKGROUND We conducted a r and omized trial of the treatment of multiple myeloma with high-dose chemotherapy followed by either one or two successive autologous stem-cell transplantations . METHODS At the time of diagnosis , 399 previously untreated patients under the age of 60 years were r and omly assigned to receive a single or double transplant . RESULTS A complete or a very good partial response was achieved by 42 percent of patients in the single-transplant group and 50 percent of patients in the double-transplant group ( P=0.10 ) . The probability of surviving event-free for seven years after the diagnosis was 10 percent in the single-transplant group and 20 percent in the double-transplant group ( P=0.03 ) . The estimated overall seven-year survival rate was 21 percent in the single-transplant group and 42 percent in the double-transplant group ( P=0.01 ) . Among patients who did not have a very good partial response within three months after one transplantation , the probability of surviving seven years was 11 percent in the single-transplant group and 43 percent in the double-transplant group ( P<0.001 ) . Four factors were significantly related to survival : base-line serum levels of beta2-microglobulin ( P<0.01 ) and lactate dehydrogenase ( P<0.01 ) , age ( P<0.05 ) , and treatment group ( P<0.01 ) . CONCLUSIONS As compared with a single autologous stem-cell transplantation after high-dose chemotherapy , double transplantation improves overall survival among patients with myeloma , especially those who do not have a very good partial response after undergoing one transplantation Fatigue and insomnia are problems for patients with cancer . Research findings show that aerobic exercise decreases cancer-related fatigue . Because patients with cancer who have skeletal muscle wasting may not obtain maximum benefit from aerobic exercise training , exercise programs may need to include resistance training . Thus far , testing exercise as an intervention for fatigue has focused on patients with breast cancer and excluded patients with bone metastasis . There is a need to test the feasibility and effectiveness of exercise for patients with other types of cancer and with bone involvement . The effect of aerobic and strength resistance training on the sleep of patients with cancer has not been tested . A pilot/feasibility study with a r and omized controlled design was conducted to investigate homebased exercise therapy for 24 patients receiving high-dose chemotherapy and autologous peripheral blood stem cell transplantation as treatment for multiple myeloma . None of the patients injured themselves . Because of the small sample size in the feasibility study , the effect of exercise on lean body weight was the only end point that obtained statistical significance . However , the results suggest that an individualized exercise program for patients receiving aggressive treatment for multiple myeloma is feasible and may be effective for decreasing fatigue and mood disturbance , and for improving sleep High-dose melphalan and autologous hematopoietic stem cell transplantation ( HSCT ) is a st and ard treatment for myeloma , but very little is known about the psychosocial or quality -of-life difficulties that these patients encounter during treatment . Data regarding older patients is particularly scarce . Using a prospect i ve design , this investigation evaluated 94 patients at stem cell collection and again after high-dose therapy and transplantation .  Outcomes included quality -of-life ( FACT-BMT ) and psychosocial adjustment ( ie , Brief Symptom Inventory , Impact of Events Scale , and Satisfaction with Life Scale ) . Findings were compared with age- and sex-adjusted population norms and with transplantation patient norms . At stem cell collection , physical deficits were common , with most patients scoring 1 st and ard deviation below population norms for physical well-being ( 70.2 % ) and functional well-being ( 57.5 % ) , and many reporting at least moderate fatigue ( 94.7 % ) and pain ( 39.4 % ) . Clinical ly meaningful levels of anxiety ( 39.4 % ) , depression ( 40.4 % ) , and cancer-related distress ( 37.0 % ) were evident in a notable proportion of patients . After transplantation , there was a worsening of transplant-related concerns ( P < .05 ) , depression ( P < .05 ) , and life-satisfaction ( P < .001 ) ; however , pain improved ( P < .01 ) , and social functioning was well preserved . Overall , the declines in functioning after transplantation were less pronounced than anticipated . Older patients were not more compromised than younger ones ; in multivariate analyses , they reported better overall quality of life ( P < .01 ) and less depression ( P < .05 ) before transplantation . Our findings emphasize the importance of early screening and intervention BACKGROUND In multiple myeloma , combination chemotherapy with melphalan plus prednisone is still regarded as the st and ard of care in elderly patients . We assessed whether the addition of thalidomide to this combination , or reduced-intensity stem cell transplantation , would improve survival . METHODS Between May 22 , 2000 , and Aug 8 , 2005 , 447 previously untreated patients with multiple myeloma , who were aged between 65 and 75 years , were r and omly assigned to receive either melphalan and prednisone ( MP ; n=196 ) , melphalan and prednisone plus thalidomide ( MPT ; n=125 ) , or reduced-intensity stem cell transplantation using melphalan 100 mg/m2 ( MEL100 ; n=126 ) . The primary endpoint was overall survival . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00367185 . FINDINGS After a median follow-up of 51.5 months ( IQR 34.4 - 63.2 ) , median overall survival times were 33.2 months ( 13.8 - 54.8 ) for MP , 51.6 months ( 26.6-not reached ) for MPT , and 38.3 months ( 13.0 - 61.6 ) for MEL100 . The MPT regimen was associated with a significantly better overall survival than was the MP regimen ( hazard ratio 0.59 , 95 % CI 0.46 - 0.81 , p=0.0006 ) or MEL100 regimen ( 0.69 , 0.49 - 0.96 , p=0.027 ) . No difference was seen for MEL100 versus MP ( 0.86 , 0.65 - 1.15 , p=0.32 ) . INTERPRETATION The results of our trial provide strong evidence to indicate that the use of thalidomide in combination with melphalan and prednisone should , at present , be the reference treatment for previously untreated elderly patients with multiple myeloma Context AL amyloidosis responds poorly to oral chemotherapy and rarely leads to elimination of plasma cell dyscrasia . Amyloid cardiomyopathy is a particularly fatal complication of the disease . Contribution Analysis of consecutive patients with AL amyloidosis from 6 separate trials over 8 years shows that high-dose intravenous melphalan therapy combined with autologous stem-cell transplantation greatly improves duration of survival and ameliorates organ dysfunction . Implication s Intravenous melphalan therapy combined with stem-cell transplantation represents a clinical ly significant improvement in treating AL amyloidosis and shows promise in reversing amyloid cardiomyopathy . The Editors The most common form of systemic amyloidosis in the United States is AL ( or primary ) amyloidosis . In this disease , amyloid fibrils are derived from monoclonal immunoglobulin light chains that are produced by an underlying clonal plasma cell dyscrasia . Although the burden of plasma cells is generally low , accumulation of amyloid deposits in vital organs leads to progressive disability and death . The median survival of untreated patients after diagnosis is 12 months and less than 5 months for those with cardiomyopathy ( 1 - 5 ) . AL amyloidosis is reported to occur in 5 to 12 persons per million per year in the United States ; however , death records and autopsy results suggest that the incidence may be higher ( 6 , 7 ) . Treatment with oral melphalan results in a modest increase in median survival but rarely eliminates the plasma cell dyscrasia and is not effective for rapidly progressive disease ( 8 - 10 ) . Alternative chemotherapy regimens have not improved survival further ( 11 - 15 ) . Promising treatment outcomes observed with high-dose intravenous melphalan and autologous stem-cell transplantation in multiple myeloma ( 16 - 19 ) provided a rationale for testing the hypothesis that this treatment would improve survival for patients with AL amyloidosis . Favorable responses to high-dose melphalan and stem-cell transplantation in patients with AL amyloidosis have been reported in case reports and in small series ; however , treatment-related mortality was high in multicenter trials ( 20 - 28 ) . Our initial experience with treatment in AL amyloidosis indicated that selected patients can tolerate treatment and that hematologic responses and reversal of amyloid-related organ dysfunction can be achieved ( 29 - 32 ) . Since 1994 , we have evaluated 701 patients with AL amyloidosis , 312 of whom initiated high-dose melphalan treatment and stem-cell transplantation .  This longitudinal study examines survival , hematologic response , and improvement of amyloid-related organ disease in patients who were treated with high-dose melphalan and stem-cell transplantation .  We contrast these data with features and survival of a simultaneous cohort of patients who were not eligible for treatment . Methods Patients Between July 1994 and June 2002 , 701 consecutive patients with AL amyloidosis were evaluated and clinical data were collected with the approval of the Institutional Review Board of Boston University Medical Center . All patients had biopsy-proven amyloid disease and a documented plasma cell dyscrasia , which was diagnosed by the presence of clonal plasma cells in the bone marrow or a monoclonal gammopathy detected by immunofixation electrophoresis of serum or urine proteins ( Figure 1 ) . To exclude another type of systemic amyloidosis and a monoclonal gammopathy of unknown significance , all patients with findings compatible with familial or secondary ( AA ) amyloidosis were tested by DNA analysis for gene mutations in transthyretin , apolipoprotein A1 , fibrinogen , and lysozyme known to be associated with amyloidosis and by immunohistochemistry of the biopsy tissue for AA amyloid fibril deposits ( 33 ) . Patients with multiple myeloma ( bone marrow plasmacytosis 30 % or lytic bone lesions ) were excluded . In patients older than 70 years of age with cardiomyopathy only , a diagnosis of senile cardiac amyloidosis ( caused by wild-type transthyretin ) was excluded by immunohistochemical examination of a tissue biopsy specimen using antiserum to transthyretin . All patients were evaluated for degree of organ involvement by physical examination , st and ardized blood tests , electrocardiography , echocardiography , chest radiography , pulmonary function tests , and a 24-hour urine collection . All patients were evaluated by a hematologist and cardiologist and , when appropriate , by nephrology , pulmonology , gastroenterology , and neurology specialists . Figure 1 . Algorithm for patient selection and treatment with high-dose melphalan and stem-cell transplantation . High-Dose Melphalan and Stem-Cell Transplantation Eligibility and Protocol s Patients were enrolled in several sequential institutional review boardapproved protocol s during the 8-year study period . Eligibility criteria for all protocol s required biopsy-proven amyloid disease ; evidence of a plasma cell dyscrasia ; at least 1 major organ affected by amyloid disease ; and minimum measures of cardiac , pulmonary , and performance status ( Figure 1 ) . Functional measures included cardiac ejection fraction 0.4 or greater , absence of symptomatic pleural effusions , absence of heart failure or arrhythmia resistant to medical management , oxygen saturation of 95 % or greater on room air , lung diffusing capacity of 50 % or more of predicted , supine systolic blood pressure of 90 mm Hg or greater , and Southwest Oncology Group performance status score of 2 or less unless limited by neuropathy ( on a scale of 0 to 4 , reflecting percentage of the day [ 0 % , 25 % , 50 % , 75 % , or 100 % ] spent in bed or in a chair ) . Minor variations in eligibility requirements for age , renal function , amount of previous chemotherapy , and time from diagnosis while on some protocol s are noted in the following discussion ; the number of patients affected is also given . The first protocol ( July 1994 to December 1995 ) enrolled 13 patients 60 years of age or younger with serum creatinine values of 176.8 mol/L ( 2.0 mg/dL ) or less ; these patients were treated with melphalan , 200 mg/m2 ( 29 ) . Subsequent protocol s had no restriction for impaired renal function . A second protocol ( April 1995 to October 1996 ) enrolled 28 patients 70 years of age or younger and used a lower dose of melphalan , 100 mg/m2 ( 31 ) . Two protocol s ( January 1996 to June 1998 ) evaluated the use of CD34 + -selected stem cells in 16 patients ( 34 ) . The fifth protocol ( October 1996 to September 2000 ) r and omly assigned 100 previously untreated patients to treatment with high-dose melphalan and stem-cell transplantation immediately or after 2 cycles of oral melphalan and prednisone . There was no age limit for this protocol ; however , melphalan , 140 mg/m2 , was given to patients who were older than 65 years of age or had a cardiac ejection fraction between 0.40 and 0.44 . The sixth protocol ( November 2000 to the present ) has enrolled 29 patients 65 years of age or younger . On this protocol , enough stem cells are collected initially to give a second cycle of chemotherapy within the first year if a complete response has not been achieved after an initial course of melphalan at a dose of 200 mg/m2 . Other patients who met eligibility criteria ( August 1996 to the present ) but were excluded from an active protocol because of previous treatment or time from diagnosis were treated by using the established dosing guidelines . Patients who did not meet eligibility for treatment with high-dose melphalan and stem-cell transplantation were grouped according to reasons for in eligibility and were analyzed for survival . Organ system involvement was defined by physical examination ; postural blood pressure determinations ; st and ardized serologic laboratory measurements of kidney , liver , and endocrine function ; coagulation studies , including factor X levels ; electrocardiography ; echocardiography ; chest radiography ; pulmonary function tests with walking oximetry ; and a 24-hour urine collection for protein excretion . Cardiac involvement was defined by septal or posterior wall thickening of 13 mm or greater on echocardiography or a clinical syndrome of congestive heart failure or cardiac arrhythmia in the absence of preexisting cardiac disease . Renal involvement was diagnosed by proteinuria of 500 mg/24 h or greater or an elevated serum creatinine concentration in the absence of other causes of renal disease . Gastrointestinal involvement was diagnosed by involuntary loss of 10 % of body weight , unexplained diarrhea , hepatomegaly of 4 cm or more below the right costal margin on physical examination , or alkaline phosphatase level 2 or more times the upper limit of normal values . Peripheral neuropathy was diagnosed by symptoms and physical examination or nerve conduction studies , and autonomic neuropathy was defined by orthostatic hypotensiona decrease in systolic blood pressure of 20 mm Hg or greater with upright posture in euvolemic patients . Soft tissue involvement was diagnosed by clinical evidence of macroglossia , soft tissue or subcutaneous deposits , amyloid arthropathy , lymphadenopathy , or nail dystrophy . Coagulation factor X level was considered deficient if it was 50 % or less of normal .  Stem-Cell Collection  and  High-Dose Chemotherapy Peripheral blood stem cells were collected by leukapheresis after mobilization using granulocyte colony-stimulating factor . A minimum yield of 2.0 106 CD34+cells/kg of body weight was required to support high-dose chemotherapy . The patient 's age and cardiac status and the number of stem cells collected determined the melphalan dose ( Figure 1 ) . A dose of 200 mg/m2 was administered to patients who were 65 years of age or younger and who had a cardiac ejection fraction of 0.45 or greater and a stem-cell collection of at least 2.5 106 CD34+cells/kg . A dose of 140 mg/m2 was administered to patients who were older than 65 years of age , who had a cardiac ejection fraction of 0.4 to 0.44 , or who had a stem-cell collection of 2.0 to 2.5 106
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 ?
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 ?