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Antonio Palumbo, M.D., Federica Cavallo, M.D., Francesca Gay, M.D., Francesco Di Raimondo, M.D., Dina Ben Yehuda, M.D., Maria Teresa Petrucci, M.D., Sara Pezzatti, M.D., Tommaso Caravita, M.D., Chiara Cerrato, M.D., Elena Ribakovsky, M.D., Mariella Genuardi, M.D., Anna Cafro, M.D., Magda Marcatti, M.D., Lucio Catalano, M.D., Massimo Offidani, M.D., Angelo Michele Carella, M.D., Elena Zamagni, M.D., Francesca Patriarca, M.D., Pellegrino Musto, M.D., Andrea Evangelista, M.S., Giovannino Ciccone, M.D.D., Claudia Crippa, M.D., Paolo Corradini, M.D., Arnon Nagler, M.D., Mario Boccadoro, M.D., and Michele Cavo, M.D.: Autologous Maintenance and Transplantation Therapy in Multiple Myeloma High-dose chemotherapy plus autologous stem-cell transplantation, as compared with conventional chemotherapy, prolongs progression-free survival and general survival among sufferers with diagnosed multiple myeloma newly.1-4 and it is currently the standard of look after patients who are more youthful than 65 years of age. Nevertheless, since autologous stem-cell transplantation has substantial toxic effects and needs prolonged hospitalization, the comparison with much less toxic, administered treatments is normally important orally. Immunomodulatory medications and proteasome inhibitors have improved outcomes in individuals significantly, of whether they meet the criteria for transplantation regardless.5-18 These improvements have raised questions about the part of transplantation in comparison to conventional chemotherapy and about the timing of transplantation, since the survival benefit is not established. Continuous treatment with immunomodulatory drugs and proteasome inhibitors has shown scientific efficacy.19 In three large, randomized studies, continuous therapy with lenalidomide, in comparison with placebo, significantly reduced the risk of disease progression , however the survival benefit was inconsistent.16-18 It is currently not clear whether maintenance therapy after mixture therapy will have the same effect that it can after transplantation. Methods Patients Individuals with symptomatic, measurable, newly diagnosed multiple myeloma who have were 65 years or younger were eligible for this trial. The primary exclusion criteria included a history of various other cancers within days gone by three years and peripheral neuropathy of grade 2 or higher. The analysis was accepted by the institutional review boards of the participating centers and was executed according to the Declaration of Helsinki and the International Meeting on Harmonisation Guidelines once and for all Clinical Practice. All patients provided written educated consent. Study Design and Oversight The study was a randomized, open-label trial with a 2-by-2 factorial style. We recruited patients from November 2007 through July 2009 at 62 centers in Italy and Israel. A straightforward randomization sequence, stratified relating to International Staging Program disease stage20 , was generated by a pc program and implemented through a Web-based procedure. All patients were randomly assigned at enrollment to one of the four groupings, but the outcomes of the random assignment had been concealed until patients reached the finish of the induction period and their eligibility for the consolidation and maintenance regimens was verified. The study was designed by the senior academic authors. The sponsor, Fondazione Neoplasie Sangue Onlus, gathered the data and, in collaboration with the senior educational authors, conducted the info analyses. Celgene provided an unrestricted grant to carry out the trial but had not been mixed up in data collection, evaluation, or the composing of the manuscript. The 1st draft of the manuscript originated by the first author; subsequent drafts had been revised by the 1st three authors. A medical article writer paid by Celgene supplied assistance with the writing of the manuscript to improve clarity and consistency. All authors had full access to the primary data and outcomes of the final analysis, were responsible for this content of the manuscript and your choice to submit it for publication, and vouch for the accuracy and completeness of the info and the fidelity of the analysis to the protocol. The protocol and statistical analysis program are available with the full text of this article at NEJM.org. Research Treatments All individuals received induction therapy comprising four 28-day cycles of lenalidomide in addition dexamethasone . Cyclophosphamide and granulocyte colony-stimulating aspect were utilized to mobilize stem cells.21 The consolidation regimen consisted of six 28-day time cycles of melphalan , prednisone , and lenalidomide , or two 4-month cycles of melphalan at a dosage of 200 mg per square meter of body-surface area accompanied by autologous stem-cell transplantation. Individuals in whom progressive disease developed during induction or consolidation therapy had been treated according to local standards and remained in the trial for later on end result evaluations. Maintenance therapy was initiated within the initial 3 months after completion of consolidation therapy. Maintenance therapy with lenalidomide was administered until disease progression or the advancement of unacceptable adverse effects. Details of dose reductions, medication discontinuations, and treatment schedules are given in Table S1 in the Supplementary Appendix, available at NEJM.org. Information on the anticoagulation regimen previously used have been published. 22 End Factors and Assessments The primary study end point was progression-free survival. Secondary end points included general survival, the entire response rate, the right time to a reply, and safety. Time-to-event end points were estimated from the time of enrollment and from enough time when the random assignment was disclosed . Progression-free survival was calculated before date of disease progression, death from any trigger during treatment, or data censoring at the last date on which the patient was regarded as free from disease progression. Overall survival was calculated until the date of either loss of life from any trigger or data censoring at the last time on which the individual was known to be alive. Response was assessed with the use of the International Uniform Response Criteria for Multiple Myeloma.23 Bone marrow samples were collected at enrollment and analyzed by central laboratories within each national country. These samples were examined for chromosome deletions 13 and 17 and for the t and t translocations by using fluorescence in situ hybridization. No prospective decisions regarding therapy had been based on the results. Adverse occasions were graded based on the National Malignancy Institute Common Terminology Criteria for Adverse Events .24 Statistical Analysis The primary comparison was between high-dose melphalan with stem-cell transplantation and MPR. With a two-sided alpha error of 0.05, we estimated that 400 individuals would need to be enrolled for the study to have a statistical power of 85 percent to detect a hazard ratio of 0.62 and only high-dose melphalan versus MPR , assuming 24 months of accrual, a minimum follow-up time of 1 12 months, and a dropout rate of 5 percent. The secondary assessment was between lenalidomide maintenance therapy no maintenance therapy. We anticipated that approximately 240 sufferers will be qualified to receive a maintenance routine after consolidation treatment. With a two-sided alpha error of 0.05, this sample size got a statistical power of 80 percent to detect a noticable difference from 60 percent to 75 percent in 2-year progression-free survival and only the maintenance group . To estimate the effect of the entire treatment strategy , both progression-free survival and overall survival were approximated for the four groups from the day of study enrollment, in an evaluation that included all enrolled sufferers. All comparative analyses had been performed with an intention-to-treat approach for the two randomized populations: the consolidation-phase populace, which comprised all individuals who were permitted receive high-dose melphalan or MPR , and the maintenance-phase populace, which comprised all sufferers who were eligible to receive lenalidomide maintenance therapy or no maintenance therapy . The safety-analysis population included all patients who received at least one dosage of the analysis treatments. Cox proportional-hazards versions were utilized to estimate hazard ratios and 95 percent self-confidence intervals for the main comparisons. Cox models, modified for International and age Staging System stage, were also utilized to explore any modification of the effect of consolidation or maintenance therapy between subgroups , by using interaction terms. Statistical analyses had been performed by using SAS software, version 8.2 , and Stata software program, version 11.0 . April 30 The data cutoff point was, 2013. Results Patients A complete of 402 patients were enrolled; 399 entered the normal mobilization and induction stage, and 273 remained eligible for random assignment to consolidation therapy with high-dosage melphalan or MPR. By the end of consolidation therapy, 251 individuals were also eligible for the randomized assessment between maintenance therapy no maintenance therapy . Baseline demographic and disease features were well balanced among the procedure groups . At the info cutoff point, 237 individuals acquired disease progression or got died, 45 sufferers were still receiving lenalidomide maintenance therapy, and 24 patients weren’t receiving maintenance therapy. The median duration of follow-up from the proper time of enrollment was 51.2 months . Efficacy In the full total enrolled population , the median progression-free survival from enough time of diagnosis was 54.7 months among individuals who received high-dose melphalan plus lenalidomide maintenance therapy, 37.4 a few months among sufferers who received high-dose melphalan without maintenance therapy, 34.2 months among patients who received MPR plus lenalidomide maintenance therapy, and 21.8 months among patients who received MPR without maintenance therapy . The 5-calendar year overall survival rate was 78.4 percent among patients who received high-dose melphalan plus lenalidomide maintenance therapy, 66.6 percent among sufferers who received high-dosage melphalan without maintenance therapy, 70.2 percent among sufferers who received MPR plus lenalidomide maintenance therapy, and 58.7 percent among individuals who received MPR without maintenance therapy . At the final end of the induction and mobilization phase, the random assignment to high-dose melphalan or MPR was disclosed for the 273 sufferers who were eligible for consolidation therapy. The median progression-free survival was considerably longer among sufferers who received high-dosage melphalan than among patients who received MPR . High-dosage melphalan, in comparison with MPR, was also connected with improvement in the 4-year overall survival price . The progression-free survival benefit associated with high-dose melphalan was constant across all patient subgroups . Among the 251 individuals who were eligible to be included in the second randomized assessment , median progression-free survival was significantly longer with lenalidomide maintenance therapy than without maintenance therapy . Lenalidomide maintenance therapy, as compared with no maintenance therapy, got no significant influence on the 3-calendar year overall survival rate . The beneficial effect of lenalidomide maintenance on progression-free survival was homogeneous in all subgroups except sufferers with stage III disease during diagnosis . Results of the subgroup analysis of general survival are proven in Body S3 in the Supplementary Appendix. Simply no significant differences in progression-free survival were detected between the maintenance and no-maintenance populations in the comparison of high-dose melphalan with MPR , or between the high-dosage melphalan and MPR subgroups in the assessment of lenalidomide maintenance therapy without maintenance therapy . Among patients with relapsed multiple myeloma, the 3-year overall survival rates from the time of relapse were similar across the four treatment groupings . In the MPR group, 98 of 156 individuals received high-dose melphalan at relapse, as prespecified in the treatment protocol. Details of salvage treatment administered in the right period of relapse are given in Desk S3 in the Supplementary Appendix. The complete response rate improved from 15.7 percent after consolidation therapy to 35.7 percent after maintenance therapy in the high-dosage melphalan group and from 20.0 percent after consolidation therapy to 33.8 percent after maintenance therapy in the MPR group . Prognostic factors such as staging and cytogenetic features didn’t affect the grade of the response. Safety During the induction stage, the most typical grade three or four 4 adverse events were neutropenia , anemia , infection , and dermatologic occasions ; one death occurred because of arrhythmia. In total, 27 of 399 individuals discontinued treatment because of adverse events, and 56 . During consolidation therapy, hematologic adverse occasions occurred more frequently in patients who received high-dose melphalan than in those who received MPR. These occasions were mainly grade 3 or 4 4 neutropenia and thrombocytopenia . Other grade three or four 4 adverse events which were more common in sufferers who received high-dosage melphalan were gastrointestinal occasions , attacks , and systemic events . During the maintenance phase, the most typical grade three or four 4 adverse events had been neutropenia , infections , and dermatologic events . Reduced doses of lenalidomide were required in 14.7 percent of patients ; 5.2 percent of individuals discontinued lenalidomide due to toxicity . Eleven patients had a second primary cancer: lung cancers in one patient during induction; prostate cancer in two patients and breast cancers in three sufferers during lenalidomide maintenance therapy; and one case each of myelodysplasia, lung malignancy, bladder cancer, cancer of the colon, and biliary tract tumor after consolidation therapy in patients who were randomly designated to no maintenance therapy. Discussion In this randomized study involving patients with recently diagnosed multiple myeloma, the standard high-dose melphalan consolidation therapy accompanied by stem-cell transplantation, in comparison with MPR, was connected with a significant reduction in the risk of progression or death and prolonged overall survival . Maintenance treatment with lenalidomide, as compared with no maintenance, was associated with a considerably reduced threat of disease progression or loss of life . The very best treatment strategy was associated with a 5-yr rate of progression-free of charge survival from the time of diagnosis of around 48 percent and a standard survival rate of 78 percent among all patients. These outcomes confirm a net scientific benefit of high-dose melphalan administration as consolidation treatment and provide support for the advantage of lenalidomide as continuous treatment. Despite a similar complete response price with both consolidation regimens, high-dosage melphalan improved progression-free survival. Regrettably, the response was assessed with the use of standard laboratory tests, and minimal residual disease had not been monitored with molecular or immunophenotypic techniques, which can have revealed more subtle distinctions in the response, as reported in similar studies.25 The medical benefit was noticed consistently over the various patient subgroups. High-dose melphalan, in comparison with MPR, was associated with significant improvement in overall survival also. Hematologic and nonhematologic adverse events were more frequent with high-dose melphalan than with MPR. Although stem cells were obtained from all sufferers at analysis, stem-cell transplantation was performed in mere 62. Thus, stem-cell transplantation isn’t always feasible during relapse, and the option of delayed transplantation ought to be suggested with caution. The clinical benefit connected with lenalidomide maintenance was in addition to the consolidation regimen. Response prices improved during maintenance therapy in both high-dosage MPR and melphalan groups. As compared with no maintenance, low-dose lenalidomide maintenance delayed relapse by 2 years approximately. Previous studies show that lenalidomide maintenance prolonged the duration of remission by 17, 18, and 19 months,16-18 but an overall survival benefit was observed in only one of the three studies.17 In our research, lenalidomide maintenance, in comparison with no maintenance, was associated with prolonged progression-free of charge survival significantly; no significant improvement in overall survival was mentioned. An extended follow-up study is required to better evaluate the benefit of a delayed clinical relapse and the chance of chemoresistance after maintenance therapy. The advantage of maintenance therapy was seen in most subgroups, but a prespecified subgroup comparison showed no benefit in patients with stage III disease . The price of second major cancers was low, no between-group differences were reported. This scholarly study had some limitations. Second, we investigated only did and lenalidomide not include bortezomib in your skin therapy plan. Bortezomib-centered induction and consolidation regimens in combination with alkylating or immunomodulatory agents have been associated with unprecedented rates of high-quality response and a positive effect on outcomes in sufferers, regardless of whether they meet the criteria for stem-cell transplantation.8,12 Third, placebo had not been administered in the combined group of patients who didn’t receive maintenance therapy, and a blind assessment of progression was not made. Finally, quality-of-life assessments weren’t performed.gov numbers NCT01208766, NCT01191060, and NCT01208662) are evaluating effective drug combinations that add a proteasome inhibitor versus autologous stem-cell transplantation, the benefit of early versus past due transplantation, and the consequences of varying the duration of maintenance therapy. Outcomes of these trials might shed further light upon this important clinical area. In conclusion, we found that consolidation therapy with high-dose melphalan, as compared with MPR, improved progression-free and overall survival, although at a cost of increased toxicity. Our findings concur that high-dose melphalan remains the far better therapeutic option in patients with recently diagnosed multiple myeloma. We discovered that maintenance therapy with lenalidomide also, as compared without maintenance therapy, significantly decreased the risk of disease progression.