Dataset Information

Melphalan 140 mg/m² or 200 mg/m² for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.

ABSTRACT: Melphalan at a dose of 200 mg/m² is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m² is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m² and melphalan 140 mg/m² are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m² (n=245) and melphalan 200 mg/m² (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m² in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m²versus melphalan 140 mg/m²: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m² for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m² and melphalan 140 mg/m² patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m² or melphalan 140 mg/m² for key transplant outcomes (NCT01362972).

SUBMITTER: Auner HW

PROVIDER: S-EPMC5830386 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Melphalan 140 mg/m2 or 200 mg/m2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.

Auner Holger W HW Iacobelli Simona S Sbianchi Giulia G Knol-Bout Cora C Blaise Didier D Russell Nigel H NH Apperley Jane F JF Pohlreich David D Browne Paul V PV Kobbe Guido G Isaksson Cecilia C Lenhoff Stig S Scheid Christof C Touzeau Cyrille C Jantunen Esa E Anagnostopoulos Achilles A Yakoub-Agha Ibrahim I Tanase Alina A Schaap Nicolaas N Wiktor-Jedrzejczak Wieslaw W Krejci Marta M Schönland Stefan O SO Morris Curly C Garderet Laurent L Kröger Nicolaus N

Haematologica 20171207 3

Melphalan at a dose of 200 mg/m2 is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m2 and melphalan 140 mg/m2 are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation ep ...[more]

PMID: 29217776

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Project description:The aim of this study was to compare the long-term safety and efficacy of oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) and melphalan 200 mg/m(2) as conditioning regimens for autologous stem cell transplantation in newly diagnosed patients with multiple myeloma in the GEM2000 study.The first 225 patients received oral busulfan 12 mg/kg plus melphalan 140 mg/m(2); because of a high frequency of veno-occlusive disease, the protocol was amended and a further 542 patients received melphalan 200 mg/m(2).Engraftment and hospitalization times were similar in both groups. Oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) resulted in higher transplant-related mortality (8.4% versus 3.5%; P=0.002) due to the increased frequency of veno-occlusive disease in this group. Response rates were similar in both arms. With respective median follow-ups of 72 and 47 months, the median progression-free survival was significantly longer with busulfan plus melphalan (41 versus 31 months; P=0.009), although survival was similar to that in the melphalan 200 mg/m(2) group. However, access to novel agents as salvage therapy after relapse/progression was significantly lower for patients receiving busulfan plus melphalan (43%) than for those receiving melphalan 200 mg/m(2) (58%; P=0.01).Conditioning with oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) was associated with longer progression-free survival but equivalent survival to that achieved with melphalan 200 mg/m(2) but this should be counterbalanced against the higher frequency of veno-occlusive disease-related deaths. This latter fact together with the limited access to novel salvage therapies in patients conditioned with oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) may explain the absence of a survival difference. Oral busulfan was used in the present study; use of the intravenous formulation may reduce toxicity and result in greater efficacy, and warrants further investigation in myeloma patients. (Clinicaltrials.gov identifier: NCT00560053).

Project description:BackgroundHigh-dose melphalan (HDMEL, 200 mg/m2) is considered as the standard conditioning regimen for autologous hematopoietic stem cell transplantation (auto-HSCT) in multiple myeloma (MM). However, whether the combination of melphalan with busulfan (BUMEL) conditioning outperforms HDMEL remains controversy. Accordingly, a systematic review and meta-analysis was carried out to compare the outcomes of HDMEL and BUMEL-based conditioning regimens in newly diagnosed MM patients having undergone auto-HSCT.MethodsA systematic literature search was conducted in PubMed, Embase and Cochrane Library database until July 31, 2021, to identify all eligible studies comparing progression-free survival (PFS), overall survival (OS), optimal treatment response after auto-HSCT, duration of stem cell engraftment and incidence of toxic events between patients undergoing BUMEL-based and HDMEL conditioning regimens. Hazard ratio (HR), mean difference (MD) or odds ratio (OR) corresponding to 95% confidence interval (CI) were determined to estimate outcomes applying RevMan 5.4 software. Publication biases were assessed by performing Egger's test and Begg's test by Stata 15 software.ResultsTen studies with a total of 2855 MM patients were covered in the current meta-analysis. The results of this study demonstrated that patients having received BUMEL-based regimen was correlated with longer PFS (HR 0.77; 95% CI 0.67~0.89, P = 0.0002) but similar OS (HR 1.08; 95% CI 0.92~1.26, P = 0.35) compared with those having received HDMEL. The differences of best treatment response after auto-HSCT and duration of neutrophil or platelet engraftment did not have statistical significance between the two groups of patients. With respect to adverse effects, the patients in BUMEL-based group were less frequently subject to gastrointestinal toxicity while the patients in HDMEL group less often experienced mucositis and infection. No significant difference was observed in hepatic toxicity between the two groups of patients.ConclusionsIn the present study, BUMEL-based conditioning was identified as a favorable regimen for a better PFS and equivalent OS as compared with HDMEL, which should be balanced against higher incidences of mucositis and infection. BUMEL-based conditioning is likely to act as an alternative strategy to more effectively improve auto-HSCT outcomes in MM.

Project description:BackgroundRetrospective studies suggest that conditioning therapy with busulfan plus melphalan could result in longer progression-free survival compared with melphalan alone in patients with multiple myeloma undergoing autologous haemopoietic cell transplantation (auto-HCT). We aimed to test this hypothesis in a randomised trial.MethodsThe primary objective of the study was to compare progression-free survival with conditioning of busulfan plus melphalan with melphalan alone in patients with multiple myeloma. Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease, were randomly assigned (1:1) to treatment. Patients received either busulfan plus melphalan, with a test dose of busulfan 32 mg/m2 followed by pharmacokinetically adjusted doses on days -7, -6, -5, and -4 to achieve a target daily area under the curve (AUC) of 5000 mmol-minute and melphalan 70 mg/m2 per day on days -2 and -1 (total melphalan dose 140 mg/m2), or a melphalan dose of 200 mg/m2 on day -2. Randomisation was performed via a Clinical Trial Conduct Website at the University of Texas MD Anderson Cancer Center. The accrual is complete and final results are presented here. The study is registered with ClinicalTrials.gov, number NCT01413178.FindingsBetween Oct 12, 2011, and March 22, 2017, 205 patients were assessed for eligibility and randomly assigned to treatment. The primary analysis of progression-free survival was measured in 202 patients who received treatment: 104 patients in the busulfan plus melphalan group and 98 patients in the melphalan alone group. 90 days after auto-HCT, 102 (98%) of 104 patients given busulfan plus melphalan and 95 (97%) of 98 patients given melphalan alone achieved partial response or better. The median follow-up in the busulfan plus melphalan group was 22·6 months (IQR 15·2-47·1) and 20·2 months (IQR 8·8-46·6) in the melphalan alone group. Median progression-free survival was 64·7 months (32·9-64·7) with busulfan plus melphalan versus 43·5 months (19·9-not estimated) with melphalan alone (hazard ratio 0·53 [95% CI 0·30-0·91]; p=0·022). There were no treatment-related deaths by day 100 in either group. Grade 2-3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group.InterpretationThese findings, if confirmed in other ongoing studies, suggest that busulfan plus melphalan could replace melphalan alone as the conditioning regimen for auto-HCT in patients with newly diagnosed myeloma.FundingThis study was funded in part by the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant (CA016672).

Project description:Importance:Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma. Observations:The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-naïve high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-naïve FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice. Conclusions and Relevance:In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.

Dataset Information

Melphalan 140 mg/m² or 200 mg/m² for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.

Publications

Melphalan 140 mg/m<sup>2</sup> or 200 mg/m<sup>2</sup> for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.

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