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Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study.

ABSTRACT: 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).

SUBMITTER: Lahuerta JJ

PROVIDER: S-EPMC2966914 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study.

Lahuerta Juan José JJ Mateos Maria Victoria MV Martínez-López Joaquin J Grande Carlos C de la Rubia Javier J Rosiñol Laura L Sureda Anna A García-Laraña José J Díaz-Mediavilla Joaquín J Hernández-García Miguel T MT Carrera Dolores D Besalduch Joan J de Arriba Felipe F Oriol Albert A Escoda Lourdes L García-Frade Javier J Rivas-González Concepción C Alegre Adrían A Bladé Joan J San Miguel Jesús F JF

Haematologica 20100727 11

<h4>Background</h4>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.<h4>Design and methods</h4>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 ...[more]

PMID: 20663944

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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).

Dataset Information

Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study.

Publications

Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study.

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