High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is the standard of care in patients aged <70 years diagnosed with multiple myeloma (MM).1 Randomised controlled trials have consistently shown a progression-free survival (PFS) benefit from ASCT and is still of additional value compared to newly introduced therapeutics.2, 3 HDM can be administered in 1 day (200 mg/m2) or over 2 consecutive days (100 mg/m2/day). Although the 1-day regimen (lower area under the curve) has been shown to result in significantly less gastrointestinal toxicity,4 it is not completely clear whether this administration strategy has any deleterious effects on efficacy, compared to the 2-day regimen. In the present retrospective cohort study, we compared the efficacy of 1- and 2-day HDM followed by ASCT in patients with MM in two transplantation centres with a different HDM strategy during the same period.

Data from two academic centres in Amsterdam that have recently merged were used for the analysis, with one of the centres using the 1-day regimen and the other the 2-day regimen. A total of 265 patients with MM divided over the 1-day group (n = 174, Centre A) and 2-day group (n = 91, Centre B) treated between July 2017 and February 2020, were included in the study (Data SI). The primary endpoint was the proportion of patients with at least a very good partial response (≥VGPR) at day ±90 post-ASCT. Secondary endpoints were overall survival (OS), PFS, duration of hospitalisation post-ASCT, engraftment period of neutrophils and platelets, and complications (other than mucositis) during hospitalisation. While induction therapy and supportive care were similar between the two centres, there were some differences in mobilisation and collection of CD34+ cells between the two centres. The main differences were a lower dose of cyclophosphamide and a later start and shorter duration of granulocyte-colony stimulating factor (G-CSF) at Centre A. Centre A used cyclophosphamide 1250 mg/m2 for mobilisation, started G-CSF 10 µg/kg on day 8 until CD34+ cells collection planned for day 11. Centre B used cyclophosphamide 2000 mg/m2 as mobilisation chemotherapy (day 1) and G-CSF 10 µg/kg was administered on day 4 until CD34+ cells collection on day 11.

The patients’ characteristics of both groups are summarised in Table I. Age, sex, cytogenetic risk status, performance status, treatment lines, number of previous ASCTs and response status pre-ASCT were comparable between the groups. The proportion of patients undergoing tandem ASCTs was also comparable between the groups (10% and 9% in the 1- and 2-day dosing groups respectively). Also type of induction chemotherapy and maintenance treatment after ASCT were comparable between the groups (Table SI). The proportions of patients who achieved ≥VGPR were not significantly different (84% vs. 80%, P = 0·25) between the 1-day and 2-day groups (Table SII). The 2-year OS was 91% versus 89% and PFS was 78% versus 75%, which were similar in the 1- and 2-day dosing groups (Fig 1A,B). There were no differences in the incidence of haematological adverse events between the groups (Table SIII). There was no statistically significant difference in time (days) to platelet engraftment between the two groups [median (interquartile range, IQR) 17 (14–20) in the 1-day group vs. 16 (15–17) days in the 2-day group]. The median (IQR) time to neutrophil engraftment was significantly longer in the 1-day group than the 2-day group, at 18 (15–20) versus 14 (13–16) days (P = 0·002). The median (range) number of re-infused CD34+ cells was significantly higher in the 2-day group compared to the 1-day group, at 3·4 (2·0–12·0) versus 2·50 (1·02–7·97) × 106/kg (P < 0·0001). A significant negative linear correlation between the CD34+ cell counts and time to neutrophil engraftment was observed (R = −0·24, P < 0·0001). The median number of hospitalisation days post-ASCT was 18 days in the 1-day group and 15 days in the 2-day group (odds ratio 1·22, 95% confidence interval 1·10–1·35; P < 0·0001). Incidence of infectious complications (intervention indicated) was comparable between the 1- and 2-day groups (20% vs. 25%, P = 0·63). Incidence of febrile neutropenia and intensive care unit admissions did not differ significantly between both groups.

Table I. Patients’ characteristics. Characteristic 1-day dosing HDM (n = 174) 2-day dosing HDM (n = 91) P Sex, males, n (%) 106 (61) 63 (69) 0·18 Age at ASCT, years, median (IQR) 62 (56–66) 61 (55–65) 0·33 Cytogenetics/FISH at diagnosis, n (%) High risk 34 (20) 17 (19) 0·62 Standard risk 115 (66) 64 (70) Unknown 25 (15) 10 (11) Serum monoclonal antibodies, n (%) IgG 94 (54) 55 (60) 0.21 IgA 29 (17) 21 (23) IgM 1 (.5) 1 (1) Kappa 26 (15) 7 (8) Lambda 17 (10) 6 (7) Non-secretory 7 (4) 1 (1) WHO performance score*, n (%) 0 100 (60) 44 (48) 0.20 1 61 (36) 42 (46) 2 6 (4) 5 (6) Disease status at time of ASCT, n (%) (s)CR/CRu 19 (11) 12 (13) 0.36 VGPR 97 (56) 41 (45) PR 56 (32) 37 (41) PD 2 (1) 1 (1) ORR (≥PR), n (%) 172 (99) 90 (99) 0·73 Number of ASCT, n (%) 1 139 (80) 74 (81) 0.78 2 35 (20) 17 (19) Previous treatment lines, n (%) 1 136 (78) 69 (76) 0·67 ≥2 38 (22) 22 (24) ASCT, autologous stem cell transplantation; CR, complete response; CRu, complete response unconfirmed; FISH, fluorescence in situ hybridisation; HDM, high-dose melphalan; Ig, immunoglobulin; IQR, interquartile range; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; VGPR, very good partial response; WHO, World Health Organization.

Kaplan–Meier curves comparing OS (A) and PFS (B) by HDM dosing groups. CI, confidence interval; HDM, high-dose melphalan; OS, overall survival; PFS, progression-free survival.

Our present study confirms the findings of Parmar et al.4 showing similar efficacy with 1-day administration of HDM as compared to 2-day administration. While Parmar et al.4 compared the 1-day protocol with historical data of 2-day protocol, our present study compares the two protocols applied simultaneously in two centres, which, except for the administration of HDM and apheresis protocols, have comparable treatment protocols and supportive care. The only difference found between the groups was a significant delay in median neutrophil engraftment time (resulting in longer hospitalisation period) in the 1-day HDM group. A possible explanation for this difference might be the lower number of re-infused CD34+ cells in the 1-day group, which might have been caused by the differences in mobilisation and collection protocol of the two centres. We observed a negative correlation between neutrophil engraftment time and the CD34+ cell dose (R = −0·24). This is in accordance with findings in previous studies, showing a faster engraftment with increasing number of re-infused CD34+ cells.5, 6

In conclusion, the use of 1-day HDM as consolidation treatment in patients with MM resulted in equal disease response, PFS and OS as compared to 2-day HDM. Based on the results of the present study and earlier findings of reduced toxicity, HDM in 1 day might result in reduced toxicity but comparable efficacy as compared to 2-day HDM. Interestingly, our present results also confirmed that higher counts of re-infused CD34+/enucleated cells results in faster neutrophil engraftment and shorter hospitalisation.

Acknowledgments

We would like to thank all the physicians, nurses, and data managers at both centres who contributed to this study.

Author contributions

Mesire Aydin, Man Wai Tang, Erfan Nur and Ellen Meijer designed the research study. Mesire Aydin, Man Wai Tang and Erfan Nur analysed the data. Mesire Aydin, Man Wai Tang and Erfan Nur drafted the manuscript. Mariëlle J. Wondergem, David C. de Leeuw, Jurgen J. Wegman, Bart J. Biemond, Niels W. C. J. van de Donk, Sonja Zweegman and Ellen Meijer critically revised the manuscript and all authors approved the final version.

Conflict of interest

No conflict of interest to declare.