Introduction: - Melphalan at a dose of 200mg/m2 is considered the standard autograft dose in patients with multiple myeloma without significant co-morbidity. This drug was formulated in the early years before the era of novel agent induction and maintenance. Considering the deeper remission of novel agents and prevailing refractory gram-negative sepsis in most Indian setups, we compared 140mg/m2 (MEL140)vs. 200mg/m2(MEL200) of Melphalan in Indian myeloma patients who achieved a complete remission before transplant without having any significant co-morbidity.
Methods and results: - We analysed myeloma autograft patients from September 2014 to August 2017. 42 patients received MEL200, and 43 patients received MEL140. Diabetes on oral medications was randomised equally on both sides. The median age of patients in MEL200 was 52 years, and MEL140 was 53.6 years. There were 60% and 55% of males in MEL200 vs. MEL140, respectively. ISS-III patients was 48% and 49% in MEL200 vs. MEL140, respectively. The standard induction regimen was three to four cycles of RvD chemotherapy. Around 16% of patients in the MEL140 group had a creatinine clearance between 30-50ml/min. The mobilisation regimen followed was five days of GCSF based mobilisation. The stem cell cut-off was kept to a minimum of 2 x 106/CD34+ve cells/kg body weight. Overall, 12% of patients in both groups needed a second-day stem cell collection. Three-year overall survival, progression-free survival, the incidence of relapse, rate of refractory sepsis, the time difference in hematopoietic recovery, and secondary cancers were compared between two groups.
In outcome analysis, there was no transplant-related mortality in both groups. The mean day of engraftment was around Day +9 in MEL140 vs. Day +11 in MEL200. The rate of Gram-Negative Bacilli sepsis was around 14% in MEL140 vs. 27% in Mel200 (p 0.02). These findings were reflected in the use of high-end antibiotics like Colistin and Fosfomycin in such patients. There was a delay in engraftment, which may have been confounded by sepsis. The median progression-free survival was 26.1 months in MEL200and 27.2 months in the MEL140 group. The cumulative incidence of relapse at three years was not significantly different between the Mel200 (33.3%) and Mel140 (34.9%) groups. The adjusted HR for relapse was 0.98. Subgroup analysis suggests that in overall survival, progression-free survival, and cumulative incidence of relapse, there was no significant advantage associated with Melphalan 200 mg/m2. Age, renal status, proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the two melphalan dose groups. One patient in the MEL200 group developed -5q deletion Myelodysplastic syndrome after five years of transplant.
Discussion:
This study was conducted taking into account the changing scenario in myeloma induction and maintenance to novel agents and increasing rate of resistant gram-negative sepsis in Indian febrile neutropenic patients. As we can achieve a deeper remission before transplant, we formulated to compare lower dose melphalan to prevent a stormy post-transplant course and prevent patients succumbing to sepsis. This may not be an issue in western countries where gram-negative sepsis rates are lower. The biggest worry for us is not compromising the myeloma outcome due to lower doses of Melphalan in fit patients who achieve complete remission. This study concluded that there is not much of a difference in overall survival, Progression-free survival, and cumulative incidence of relapse at three years among MEL200 vs. MEL140.
Conclusion: - We conclude that Melphalan autograft at a dose 140mg/m2 can achieve comparable responses to 200mg/m2 in Indian myeloma patients who are taken to transplant post complete remission. We need a more prominent multicentric study and a longer follow-up to recommend MEL140 as a standard of care in Indian settings.
References:
Auner HW et al. 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. Haematologica. 2018;103(3):514-521.
Saunders IM et al A lower dose of Melphalan (140 mg/m2) as preparative regimen for multiple myeloma in patients >65 or with renal dysfunction. Blood. 2013;122:5536.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
