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Melphalan dose pre-transplant in MM
Introduction
High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) has been the standard consolidation treatment for patients up to the age of 65 years with newly diagnosed multiple myeloma for over two decades. Initially, high-dose chemotherapy plus ASCT proved superior to conventional chemothera- py.1,2 More recently, the benefit of upfront high-dose chemotherapy plus ASCT has been confirmed in treat- ment approaches incorporating thalidomide analogs and proteasome inhibitors.3-6 High-dose chemotherapy plus ASCT is also commonly used in older patients over the age of 65 years.7,8 However, the superiority of ASCT over non-intensive therapies in older patients remains to be established.9,10
In the trials that demonstrated superiority of autologous transplantation over non-intensive approaches, patients received high-dose chemotherapy with melphalan at a dose of 200 mg/m2 (Mel200).1-6 Mel200 was less toxic than other high-dose combination regimens11,12 and associated with longer progression-free survival and overall survival in patients younger than 60 years, when compared to mel- phalan 100 mg/m2 in a tandem transplant approach.13 Mel200 has therefore been recommended and widely used as standard conditioning therapy for ASCT.14-16 Some studies have linked Mel200 to excess toxicity in older patients and those with renal impairment.17-19 Consequently, a dose of 140 mg/m2 (Mel140) is widely used in clinical practice in older patients and in patients with renal impairment.20-25 However, Mel140 was associat- ed with inferior response or survival rates compared to Mel200 in two very recent studies.24,26 It therefore remains to be determined whether Mel140 and Mel200 are equally effective and tolerable across subgroups of patients.
To address this question we analyzed outcomes of almost 2000 first single autologous transplants for multiple myeloma after conditioning with either Mel140 or Mel200 which were reported to the European Society for Blood and Marrow Transplantation (EBMT). The results of the study indicate that the selection of Mel200 versus Mel140 may have a significant effect on key transplant outcomes, including overall survival.
Methods
Study criteria and data management
The Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study (NCT01362972) is an observational clinical outcome analysis of a defined cohort of patients with lymphoma or multiple myeloma who underwent ASCT between 2008 and 2012, with data reported retrospectively to the EBMT. Patients were eligible for the CALM study if they were ≥18 years old and received their first autologous peripheral blood stem cell transplant using cells mobilized with one of the following mobilization regimens: plerixafor plus granulocyte colony-stimulating factor (G-CSF), plerixafor plus G-CSF plus chemotherapy, G-CSF plus chemotherapy, or G-CSF alone. For this non-planned subgroup analysis, patients were selected from the CALM study population in the EBMT registry if they had a diagnosis of multiple myeloma and received a first single ASCT. Tandem transplants (defined as an ASCT followed by a second transplant within 6 months of the first and no relapse/progression between the two transplants), and patients who received melpha-
lan doses other than 200 or 140 mg/m2, were not included. A total of 2253 patients from the CALM study EBMT registry fulfilled these general criteria. We excluded 289 of these patients from fur- ther analysis because of missing or inconclusive data regarding subsequent transplants (n=213), relapse date (n=67), or renal func- tion (n=9), resulting in a final study population of 1964 patients. The database for this study was closed on December 14, 2016.
The study was performed in accordance with the principles of the Declaration of Helsinki and approved by the Chronic Malignancies Working Party of the EBMT, a non-profit scientific society representing more than 600 transplant centers mainly located in Europe. Data reported to the EBMT are entered, man- aged, and maintained in a central database with internet access housed in Leiden University Medical Center, the Netherlands. Each EBMT center is represented in this database, and all patients whose transplant data are reported by participating centers pro- vide informed consent for transplant-related data to be used for research purposes in an anonymous way.
Statistical analysis
Patients’ characteristics between the two groups (Mel140 and Mel200) were compared using the χ2 test for categorical variables and the Mann-Whitney test for continuous variables. P-values for variables with more than two levels refer to an overall test for the presence of any difference. Overall survival was defined as the time from the date of ASCT to death from any cause. Patients still alive were censored at their last follow up. Progression-free sur- vival was defined as the time between transplantation and pro- gression of disease or death, censoring patients who did not devel- op an event. The probabilities of overall survival and progression- free survival were obtained using the Kaplan–Meier estimator and comparisons were made with the log-rank test. The probabilities of relapse (cumulative incidence of relapse) and death without prior relapse (non-relapse mortality) were calculated by the proper non-parametric estimator for outcomes with competing risk and comparisons made with the Gray test. These methods were also used to compute the cumulative incidence of second primary malignancy considering death without such a prior malignancy as a competing event.
Cox proportional hazards models were used to estimate adjust- ed hazard ratios (HR) for Mel140 compared to Mel200 in terms of overall survival, progression-free survival and the cumulative inci- dence of relapse. Factors included in the multivariable analysis were age at transplant (<65 versus ≥65 years), renal function (nor- mal glomerular filtration rate >50 mL/min versus impaired glomerular filtration rate ≤50 mL/min), prior proteasome inhibitor treatment (yes versus no), status of disease at transplant (complete response/very good partial response versus partial response versus less than partial response), Karnofsky performance score (<90 ver- sus ≥90) and gender. Age was dichotomized with a cut-off of 65 years for comparability with other studies considering that Martingale residuals analysis did not suggest other cut-off points (data not shown). There was no evidence that exclusion of missing values from multivariable analysis induced any bias in the estima- tion of regression coefficients (data not shown).
In order to explore any possible modification of the effect of the melphalan dose in different subgroups, we then fitted a secondary series of Cox models. Each model included melphalan dose, the selected adjustment variables, and the interaction between mel- phalan dose and one of the factors. This procedure returned esti- mated adjusted hazard ratios for Mel140 compared to Mel200 in each subgroup defined by the selected factors, and the results are shown in forest plots.
Due to the partial availability of International Staging System (ISS) and cytogenetic data, the interactions of ISS stage and chro-
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