Abstract
This retrospective, single‑center study evaluated the efficacy and safety of a reduced‑dose melphalan conditioning regimen (140–180 mg/m2) for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) ineligible for the standard dose (200 mg/m2). Clinical outcomes were compared between patients receiving reduced‑dose versus standard‑dose melphalan over a five-year period, with pre‑specified subgroup analyses based on age and renal function. The results demonstrated that despite less favorable baseline characteristics in the reduced-dose group, both overall survival (OS) and progression-free survival (PFS) met comparable criteria relative to the standard group. The reduced-dose regimen was associated with a significantly improved safety profile, characterized by lower rates of mucositis, fewer febrile episodes, and accelerated platelet engraftment. In conclusion, for MM patients unable to tolerate standard-dose conditioning, particularly those with compromised baseline status, a reduced-dose melphalan regimen offers a clinically effective and safer alternative that maintains therapeutic efficacy while reducing treatment-related toxicity.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00277-026-06909-1.
Keywords: Multiple myeloma, Autologous stem cell transplantation, Melphalan, Dose reduction
Introduction
Multiple myeloma (MM) remains an incurable hematologic malignancy that imposes substantial healthcare utilization and economic burden [1, 2]. In this time of new agents, autologous stem cell transplantation (ASCT) continues to be the standard of care for transplant-eligible patients with MM. Evidence from phase II/III clinical trials including FORTE [3], DETERMINATION [4], EMN02/HOVON-95 [5], and IFM2009 [6, 7] demonstrates that ASCT provides superior outcomes compared to chemotherapy-only regimens in terms of progression-free survival (PFS), overall survival (OS), and minimal residual disease (MRD) negativity.
For patients with normal renal function, the standard pre-transplantation conditioning regimen for ASCT remains melphalan 200 mg/m2 (Mel200). This dose has demonstrated proven superiority over both 280 mg/m2 and 100 mg/m2 dosing regimens [8, 9]. Although various conditioning regimens have been investigated, such as high-dose melphalan plus bortezomib [10], 8 Gy total body irradiation plus 140 mg/m2 melphalan [11], and busulfan and cyclophosphamide [12], none have shown a superior comprehensive profile in efficacy or safety relative to melphalan monotherapy [13].
However, for elderly or comorbid patients, the toxicity of the standard dose often renders it unsuitable, and there remains a lack of clear standards for reduced-intensity conditioning prior to transplantation. Melphalan at 140 mg/m2 (MEL140) is broadly adopted in clinical treatment, but studies on its efficacy have yielded inconsistent results. A post-hoc subgroup analysis of two randomized controlled trials (RCTs) by Straka et al. [14] suggested that cumulative melphalan dose affects both OS and PFS after transplantation. Several retrospective studies have reported inconsistent results about the impact of reduced-dose melphalan on prognosis. For instance, the study by Brioli et al. [15] indicated that MEL200 benefits longer OS and PFS. Sharma et al. [16] found that although dose reduction might reduce toxicity, it could compromise OS. Conversely, Auner et al. [17] and Srour et al. [18] observed no significant differences in OS or PFS between MEL140 and MEL200. More recently, retrospective analyses by Brown et al. [19] and Kort et al. [20] confirmed comparability between the MEL140 and MEL200 regimens in terms of efficacy, toxicity, or even rates of MRD negativity.
Based on current evidence and clinical experience regarding melphalan dose reduction, our center has adopted a stepwise dose reduction strategy. Guided by patient-specific factors, including age, organ function, and comorbidities, an appropriate reduced dose is selected from three predefined levels: 180 mg/m2 (MEL180), 160 mg/m2 (MEL160), and 140 mg/m2 (MEL140). Given the persistent uncertainty surrounding the impact of dose reduction on transplantation outcomes, this study aims to evaluate the safety and efficacy of these different melphalan dose levels in MM patients undergoing ASCT, thereby providing an evidence-based foundation for individualized conditioning therapy.
Methods
Patient selection and study design
157 MM patients who received ASCT at our center were enrolled in this retrospective study from January 2019 until June 2024. Data were collected retrospectively up to the end of follow-up on June 30, 2025, including diagnosis, prior therapies, pre-transplant disease status, Eastern Cooperative Oncology Group (ECOG) score, stem cell mobilization, conditioning regimens, survival outcomes, and relapse. The ethical approval for this study was granted by the Institutional Review Board of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. This study is in accordance with ethical principles of the Declaration of Helsinki, and all procedures compliant with the ethical standards.
Treatment strategy
All patients received melphalan (Evomela®) as the sole preparative regimen, with the cohort split by the actual administered dose into the standard-dose group (200 mg/m2) and the reduced-dose group (140–180 mg/m2). Specifically, the reduced-dose group followed a stepwise dose adjustment protocol with three levels: 180 mg/m2 (MEL 180), 160 mg/m2 (MEL 160), and 140 mg/m2 (MEL 140).
The individualized melphalan dosage was determined through a multidimensional clinical assessment. The primary evaluation framework incorporated four core parameters: age, chronic kidney disease (CKD) stage, ECOG score, and the Hematopoietic Cell Transplantation–Comorbidity Index (HCT‑CI). Additional considerations included the depth of pre‑transplant disease remission, the presence of high‑risk cytogenetic abnormalities, and active infection status. Within this framework, the final dose was jointly decided by two clinicians, with no single factor being exclusively determinative. Specifically, doses were titrated upward for patients with high‑risk cytogenetics or suboptimal responses (failure to achieve VGPR) to induction therapy, and downward for those with severe active infections. Based on this comprehensive evaluation, patients were stratified into four conditioning intensity levels: standard dose (MEL200), mild reduction (MEL180), moderate reduction (MEL160), or significant reduction (MEL140).
Prior to transplantation, all patients received standard preparatory care in laminar airflow rooms, including hydration, urine alkalinization, prostaglandin E administration, cytomegalovirus (CMV) prophylaxis, and antifungal prophylaxis [21, 22]. Melphalan was administered as a single intravenous infusion, with the time interval to stem cell reinfusion individually adjusted under the patient’s clinical assessment. The reinfusion procedure was performed within a standardized window of 24 to 72 h following the completion of melphalan infusion [23–25].
After transplantation, all patients received standardized and individualized supportive care, including intravenous immunoglobulin (total dose 20 g). Throughout the treatment course, additional supportive measures, such as thrombopoietin (TPO), granulocyte colony-stimulating factor (G-CSF), and blood component transfusions, were administered as needed, guided by the patients’ hematological parameters. Anti-infective therapy was also provided according to the patient’s symptoms and infection markers. Following successful engraftment, maintenance therapy was initiated according to individualized risk stratification.
Related definitions
Neutrophil engraftment was designated as the initial occurrence of three consecutive days with an absolute neutrophil count at or above 0.5 × 109/L. Platelet engraftment was characterized as the first day from which a platelet count exceeding 20 × 109/L was sustained for seven straight days in the absence of transfusion support. In this study, relevant scoring systems, line of therapy, efficacy evaluation, and treatment-related toxicities in MM patients undergoing ASCT were all determined according to the International Myeloma Working Group (IMWG) criteria. Renal impairment was assessed based on the pre-transplant glomerular filtration rate (GFR) and classified using the chronic kidney disease (CKD) staging criteria. High-risk cytogenetic abnormalities were defined as the presence of one or more of the following: (t(4;14), t(14;16), t(14;20), del(17p), TP53 mutation, or gain of 1q21). Extramedullary disease was defined as the presence of plasmacytomas or myeloma cell infiltrates in organs or tissues outside the bone marrow [26–28].
Statistical analysis
We performed all statistical analyses utilizing the software packages SPSS 27.0, R 4.3.3, and GraphPad Prism 9.5. Descriptive statistics are presented as medians and ranges. Group comparisons involved the Pearson chi-square test for categorical variables and the Wilcoxon test for continuous measures. OS was measured from transplantation to any-cause death or last follow-up, and PFS to disease progression or death. Kaplan-Meier estimates were generated for survival probabilities, with log-rank testing for group differences. Identification of independent prognostic factors for OS and PFS was accomplished through a multivariate Cox proportional hazards model. Statistical significance was defined as a p value of < 0.05. As this is a retrospective observational study comparing outcomes between groups, it was not designed or powered as a formal non-inferiority trial.
Results
Baseline patient characteristics
157 patients with MM who underwent ASCT were recruited and stratified into two groups: a reduced-dose (n = 57) and a standard-dose (n = 100) group. In the reduced-dose group, there were 24 patients receiving MEL140, 15 receiving MEL160, and 18 receiving MEL180. The baseline characteristics of the two cohorts are presented in Table 1, with detailed characteristics of the reduced-dose group provided in Table S1. Baseline characteristics were comparable between groups, with the exception of two significant differences. Patients in the reduced-dose group demonstrated a significantly older age distribution, with a higher proportion aged ≥ 60 years at transplantation compared to the standard-dose group (31.6% vs. 15.0%; p = 0.014). Specifically, among patients aged ≥ 65 years, those in the MEL140 subgroup accounted for 10.5% (with the oldest patient being 72 years old), whereas in the MEL200 subgroup this proportion was 5.0% (with the oldest patient being 67 years old). Renal function also varied notably: although no patients in either group had stage 4–5 renal impairment, the reduced-dose group had a higher combined prevalence of stage 2 (28.1% vs. 13.0%) and stage 3 (10.5% vs. 7.0%) renal impairment (overall p = 0.035).
Table 1.
Main characteristics in MM patients receiving ASCT
| Melphalan dose | |||
|---|---|---|---|
| Reduced Dose (n = 57) | Standard Dose (n = 100) | P value | |
| Sex (Female) | 19 (33.3) | 43 (43.0) | 0.233 |
| Age at ASCT (≥ 60 years) | 18 (31.6) | 15 (15.0) | 0.014 |
| Age at ASCT (≥ 65 years) | 6 (10.5) | 5 (5.0) | 0.192 |
| Age at ASCT (≥ 70 years) | 1 (1.8) | 0 (0.0) | 1.000 |
| BMI (≥ 24 kg/m2) | 19 (33.3) | 27 (27.0) | 0.402 |
| ISS stage | |||
| I | 29 (50.9) | 51 (51.0) | 0.991 |
| II | 17 (29.8) | 29 (29.0) | |
| III | 11 (19.3) | 20 (20.0) | |
| Light chain type (Lambda) | 26 (45.6) | 45 (45.0) | 0.941 |
| High-risk cytogenetic | 15 (26.3) | 29 (29.0) | 0.719 |
| t (14; 20) | 2 (3.5) | 1 (1.0) | 0.618 |
| t (4; 14) | 6 (10.5) | 4 (4.0) | 0.204 |
| Del (17p) | 2 (3.5) | 3 (3.0) | 1.000 |
| t (14; 16) | 4 (7.0) | 5 (5.0) | 0.601 |
| TP53 | 1 (1.8) | 5 (5.0) | 0.557 |
| 1q gain | 15 (26.3) | 16 (16.0) | 0.118 |
| Extramedullary infiltration | 6 (10.5) | 10 (10.0) | 0.859 |
| Pre-ASCT ECOG score ≥ 2 | 16 (28.1) | 29 (29.0) | 0.901 |
| HCT-CI ≥ 2 | 9 (15.8) | 13 (13.0) | 0.628 |
| Induction treatment | |||
| VRD | 20 (35.1) | 30 (30.0) | 0.923 |
| VCD | 9 (15.8) | 15 (15.0) | |
| VTD | 7 (12.3) | 16 (16.0) | |
| D-VRD/VCD/VTD | 18 (31.6) | 35 (35.0) | |
| Other regimens | 3 (5.3) | 4 (4.0) | |
| Pre-ASCT disease status (PR or poorer) | 17 (29.8) | 29 (29.0) | 0.913 |
| Pre-ASCT Minimal Residual Disease positivity | 20 (35.1) | 40 (40.0) | 0.542 |
| Time to ASCT from diagnosis (≥ 1 year) | 5 (8.8) | 18 (18.0) | 0.116 |
| Line of Therapy (≥ 2) | 22 (38.6) | 35 (35.0) | 0.652 |
| Mode of stem cell mobilization | |||
| G-CSF | 29 (50.9) | 56 (56.0) | 0.291 |
| G-CSF+Plerixafor | 15 (26.3) | 16 (16.0) | |
| G-CSF+VP-16 | 8 (14.0) | 22 (22.0) | |
| G-CSF+CTX | 5 (8.8) | 6 (6.0) | |
| Pre-ASCT renal function (by eGFR) stage | |||
| 1 | 35 (61.4) | 80 (80.0) | 0.035 |
| 2 | 16 (28.1) | 13 (13.0) | |
| 3 | 6 (10.5) | 7 (7.0) | |
| 4 | 0 (0.0) | 0 (0.0) | |
| 5 | 0 (0.0) | 0 (0.0) | |
| Pre-ASCT active infection | 5 (8.8) | 4 (4.0) | 0.216 |
| Pre-ASCT White Blood Cell Count (×109/L) | 4.57 (2.77, 8.09) | 4.52 (1.34, 14.81) | 0.974 |
| Pre-ASCT Hemoglobin level (g/L) | 114 (69, 153) | 114.5 (67, 165) | 0.895 |
| Pre-ASCT Platelet (×109/L) | 198 (68, 524) | 188.5 (72, 441) | 0.776 |
| Pre-ASCT LDH (≥ 245 U/L) | 3 (5.3) | 11 (11.0) | 0.225 |
| Rest day between conditioning and stem cell infusion | 1 (0, 2) | 1 (0, 2) | 0.790 |
| Infused CD34+cell (×106/Kg) | 5.91 (3.53, 15.75) | 5.72 (2.12, 18.02) | 0.923 |
Data are no. of patients (%), or median (range)
Abbreviations: MM, multiple myeloma; ASCT, autologous stem cell transplantation; BMI, body mass index; ISS, International Staging System; ECOG, Eastern Cooperative Oncology Group performance status; PR, partial response; eGFR, estimated glomerular filtration rate; G-CSF, granulocyte colony-stimulating factor; VP-16, etoposide; CTX, cyclophosphamide; LDH, lactate dehydrogenase
Stem cell mobilization, collection, and transplant procedure
Stem cell mobilization was uniformly conducted with G-CSF. Adjunct mobilization agents were utilized in a subset of patients, including plerixafor (19.7%), etoposide (19.1%), and cyclophosphamide (7.0%). Following melphalan conditioning, autologous stem cells were infused within 0–2 days. The CD34⁺ cell infusion doses were comparable between two groups, with median values of 5.91 × 106/kg (reduced-dose group) and 5.72 × 106/kg (standard-dose group), respectively (p = 0.923).
Treatment-related toxicity
Regarding hematologic toxicity, a significantly shorter platelet engraftment time was demonstrated in the reduced-dose group against the standard-dose group (median 12 vs. 13 days, p = 0.038). However, no significant differences were observed between the two cohorts in terms of time to neutrophil engraftment, rates of engraftment failure, or transfusion requirements for red blood cells and platelets during hospitalization. While all patients experienced non-hematologic toxicities of varying grades, the overall incidence was lower in the reduced-dose group. This difference reached statistical significance for three specific adverse events: fever (65.0% vs. 82.0%, p = 0.016), oral mucositis (31.6% vs. 52.0%, p = 0.013), and diarrhea (28.1% vs. 52.0%, p = 0.004). The incidence of other types of non-hematologic toxicities has not shown statistically significant differences in the two cohorts (Table 2). The main treatment-related toxicity of the reduced-dose group is presented in Table S1.
Table 2.
Treatment-related toxicity
| Reduced Dose (n = 57) | Standard Dose (n = 100) | P value | ||||||
| Hematological Toxicity | Neutrophil Engraftment Time | 11 (7, 25) | 12 (7, 145) | 0.304 | ||||
| Platelet Engraftment Time | 12 (8, 50) | 13 (8, 345) | 0.038 | |||||
| Neutrophil Engraftment Failure | 2 (3.5) | 2 (2.0) | 0.960 | |||||
| Platelet Engraftment Failure | 3 (5.3) | 8 (8.0) | 0.748 | |||||
| Total | Grade 1-2 | Grade 3-5 | Total | Grade 1-2 | Grade 3-5 | P value | ||
| Non-hematological Toxicity | Fever | 37 (65.0) | 30 (52.6) | 7 (12.3) | 82 (82.0) | 63 (63.0) | 19 (19.0) | 0.016 |
| Oral Mucositis | 18 (31.6) | 18 (31.6) | 0 (0.0) | 52 (52.0) | 51 (51.0) | 1 (1.0) | 0.013 | |
| Nausea | 26 (45.6) | 25 (43.9) | 1 (1.8) | 53 (53.0) | 52 (52.0) | 1 (1.0) | 0.373 | |
| Vomiting | 24 (42.1) | 24 (42.1) | 0 (0.0) | 40 (40.0) | 38 (38.0) | 2 (2.0) | 0.796 | |
| Diarrhea | 16 (28.1) | 14 (24.6) | 2 (3.5) | 52 (52.0) | 48 (48.0) | 4 (4.0) | 0.004 | |
| Constipation | 4 (7.0) | 4 (7.0) | 0 (0.0) | 9 (9.0) | 9 (9.0) | 0 (0.0) | 0.895 | |
| Renal function deterioration | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (1.0) | 1 (1.0) | 0 (0.0) | 1.000 | |
| Liver Function Abnormality | 4 (7.0) | 4 (7.0) | 0 (0.0) | 6 (6.0) | 5 (5.0) | 1 (1.0) | 1.000 | |
| Arrhythmia | 3 (5.3) | 3 (5.3) | 0 (0.0) | 8 (8.0) | 8 (8.0) | 0 (0.0) | 1.000 | |
| Electrolyte Disturbance | 36 (63.2) | 36 (63.2) | 0 (0.0) | 60 (60.0) | 60 (60.0) | 0 (0.0) | 0.696 | |
Data are no. of patients (%); Group comparisons were performed using the Pearson chi-square test for categorical variables and the Wilcoxon rank-sum test for continuous measures
Survival and recurrence
The day 100 post-transplant evaluation showed generally similar treatment responses in both groups. Specifically, 145 patients (92.4%) across both cohorts had achieved a response of very good partial response (VGPR) or better status (92.0% in the standard-dose group vs. 93.0% in the reduced-dose group, p = 0.824). The rate of conversion from MRD-positive to negative after treatment was also similar between the two groups (80.0% in the standard-dose group vs. 80.0% in the reduced-dose group, p = 1.000). After a median follow-up of 25.37 months, the median OS had not been reached in either group, with no statistically significant difference observed (p = 0.197; Fig. 1A). The estimated 2-year OS rate was 0.886 (95% CI: 0.803–0.977) in the reduced-dose group and 0.889 (95% CI: 0.822–0.962) in the standard-dose group.
Fig. 1.
Kaplan-Meier survival analysis of MM patients undergoing ASCT. A Overall survival (OS) and B Progression-free survival (PFS) for patients conditioned with reduced-dose (140–180 mg/m2) versus standard-dose (200 mg/m2) melphalan
Disease recurrence was documented in 8 (reduced-dose group) and 21 (standard-dose group) patients. Owing to the small cohort size in the reduced-dose group, we did not perform further subgroup analyses. Data on patients with relapse and death are provided in Table S1. The median PFS was 56.8 months in the standard-dose group but was not reached in the reduced-dose group; however, the log-rank test indicated no statistically significant difference between groups (p = 0.702, Fig. 1B). The estimated 2-year PFS rates were 0.832 (95% CI: 0.710–0.976) for the reduced-dose group and 0.813 (95% CI: 0.730–0.904) for the standard-dose group. To account for observed baseline imbalances in age and renal function, we performed pre specified stratified analyses. The log-rank test demonstrated no significant differences in OS or PFS between the reduced-dose and standard-dose groups across all predefined subgroups based on these characteristics (Fig. 2A H).
Fig. 2.
Age-stratified subgroups:(based on pre‑ASCT age). Panels A & B: OS analyses. A: Younger subgroup (patients aged < 60 years). B: Older subgroup (patients aged ≥ 60 years). Panels C & D: PFS analyses. C: Younger subgroup (patients aged < 60 years). D: Older subgroup (patients aged ≥ 60 years). Renal function-stratified subgroups (based on pre‑ASCT eGFR): Panels E & F: OS analyses. E: Normal renal function subgroup (CKD stage 1). F: Abnormal renal function subgroup (CKD stage 2 or 3). Panels G & H: PFS analyses. G: Normal renal function subgroup (CKD stage 1). H: Abnormal renal function subgroup (CKD stage 2 or 3).
Multivariate Cox regression analysis
Univariate and multivariate Cox regression analyses were used to investigate independent prognostic factors in OS and PFS. In the multivariate analysis for OS, older age (HR 3.162, 95% CI: 1.234–8.100; p = 0.016), high-risk cytogenetics (HR 3.366, 95% CI: 1.361–8.325; p = 0.009), and renal function stage ≥ 3 (HR 4.493, 95% CI: 1.458–13.847; p = 0.009) were independent adverse factors. For PFS, high-risk cytogenetics (HR 4.278, 95% CI: 2.001–9.147; p < 0.001), and positive MRD status (HR 4.785, 95% CI: 1.361–16.822; p = 0.015) emerged as independent risk factors. However, the melphalan dose wasn’t the influential factor for OS (p = 0.204) or PFS (p = 0.725) (Table 3). In subgroup analyses of patients with MRD-positive status or high-risk cytogenetic abnormalities, no significant differences in OS and PFS were observed across the conditioning intensity groups (Figure S1). Similarly, within the reduced dose cohort, OS and PFS did not differ significantly among the MEL140, MEL160, and MEL180 subgroups (Figure S2).
Table 3.
Multivariate Cox proportional-hazard regression analyses of OS and PFS
| OS | PFS | |||||||
|---|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | Univariate | Multivariate | |||||
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | |
| Sex (Female) | 1.620 (0.622, 4.220) | 0.323 | 1.163 (0.559, 2.240) | 0.686 | ||||
| Age at ASCT (≥ 60 years) | 3.962 (1.604, 9.788) | 0.003 | 3.162 (1.234, 8.100) | 0.016 | 1.050 (0.398, 2.770) | 0.922 | ||
| BMI (≥ 24 kg/m2) | 0.248 (0.057, 1.073) | 0.162 | 0.743 (0.315, 1.755) | 0.498 | ||||
| ISS stage | ||||||||
| I | 1 | 1 | ||||||
| II | 0.442 (0.145, 1.342) | 0.150 | 0.484 (0.190, 1.231) | 0.128 | ||||
| III | 0.330 (0.075, 1.458) | 0.144 | 0.806 (0.315, 2.059) | 0.652 | ||||
| Light chain type (Lambda) | 1.238 (0.515, 2.978) | 0.633 | 1.287 (0.620, 2.670) | 0.498 | ||||
| High-risk cytogenetic | 3.020 (1.253, 7.280) | 0.014 | 3.366 (1.361, 8.325) | 0.009 | 5.671 (2.684, 11.983) | <0.001 | 4.278 (2.001, 9.147) | <0.001 |
| Extramedullary infiltration | 1.750 (0.232, 13.217) | 0.587 | 2.930 (0.683, 12.576) | 0.148 | ||||
| Pre-ASCT ECOG score ≥ 2 | 1.926 (0.771, 4.813) | 0.161 | 1.626 (0.744, 3.555) | 0.223 | ||||
| HCT-CI ≥ 2 | 2.209 (0.789, 6.184) | 0.131 | 1.607 (0.636, 4.062) | 0.316 | ||||
| Pre-ASCT disease status (PR or poorer) | 0.589 (0.196, 1.764) | 0.344 | 4.431 (2.082, 9.429) | <0.001 | 1.043 (0.350, 3.106 ) | 0.940 | ||
| Pre-ASCT Minimal Residual Disease positivity | 1.656 (0.687, 3.992) | 0.261 | 6.466 (2.739, 15.265) | <0.001 | 4.785 (1.361, 16.822) | 0.015 | ||
| Time to ASCT from diagnosis (≥ 1 year) | 0.692 (0.198, 2.418) | 0.565 | 0.408 (0.121, 1.377) | 0.148 | ||||
| Line of Therapy (≥ 2) | 0.991 (0.379, 2.591) | 0.985 | 0.538 (0.204, 1.419) | 0.210 | ||||
| Pre-ASCT renal function (by eGFR) stage | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 2 | 1.938 (0.609, 6.165) | 0.262 | 1.407 (0.419, 4.718) | 0.581 | 0.879 (0.259, 2.988) | 0.837 | ||
| 3 | 3.407 (1.074, 10.808) | 0.037 | 4.493 (1.458, 13.847) | 0.009 | 1.346 (0.393, 4.606) | 0.636 | ||
| Pre-ASCT active infection | 0.828 (0.110, 6.208) | 0.854 | 1.101 (0.260, 4.655) | 0.896 | ||||
| Pre-ASCT White Blood Cell Count (×109/L) | 1.052 (0.914, 1.210) | 0.481 | 0.958 (0.810, 1.132) | 0.613 | ||||
| Pre-ASCT Hemoglobin level (g/L) | 0.977 (0.950, 1.006) | 0.119 | 0.988 (0.963, 1.012) | 0.322 | ||||
| Pre-ASCT Platelet (×109/L) | 1.000 (0.995, 1.005) | 0.998 | 1.000 (0.996, 1.004) | 0.955 | ||||
| Pre-ASCT LDH (≥ 245 U/L) | 0.609 (0.146, 2.550) | 0.498 | 0.942 (0.374, 2.369) | 0.899 | ||||
| Rest day between conditioning and stem cell infusion | 1.508 (0.819, 2.776) | 0.187 | 1.083 (0.649, 1.809) | 0.760 | ||||
| Infused CD34+cell (×106/Kg) | 1.032 (0.916, 1.162) | 0.609 | 1.039 (0.944, 1.144) | 0.436 | ||||
| Melphalan dose (Standard Dose) | 0.563 (0.232, 1.367) | 0.204 | 1.158 (0.511, 2.623) | 0.725 | ||||
Abbreviations: OS, overall survival; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval. For other abbreviations, see Table 1 footnote
Discussion
In clinical practice, reduced-dose melphalan is frequently utilized as a conditioning regimen for elderly or comorbid MM patients undergoing ASCT [29–32]. However, its long-term prognostic impact remains incompletely defined. This study evaluated the efficacy and safety of an individualized stepwise reduced-dose melphalan regimen (140–180 mg/m2) as conditioning for ASCT. The findings indicate that this approach maintained comparable survival outcomes to the standard dose, demonstrated consistent efficacy across subgroups stratified by age and renal function, and was associated with a significantly improved safety profile.
Although the sample size limited subgroup comparisons among the specific reduced-dose tiers (MEL140, MEL160, MEL180), the reduced-dose cohort (140–180 mg/m²) overall achieved comparable OS and PFS. This is consistent with a growing body of recent retrospective evidence. Studies by Auner et al. [17] (MEL140, n = 245; MEL200, n = 1719; OS: p = 0.73; PFS: p = 0.57) ,Srour et al. [18] (MEL140, n = 76; MEL200, n = 621; OS: p = 0.17; PFS: p = 0.50), Brown et al. [19] (MEL140, n = 240; MEL200, n = 82; Relapse: p = 0.3661; PFS: p = 0.2335), and Kort et al. [20] (MEL140, n = 82; MEL200, n = 151; OS: p = 0.3; PFS: p = 0.31) all confirmed that melphalan dose (MEL140) was not associated with prognosis. These collective findings align with our results, suggesting that reduced-intensity conditioning might not compromise intermediate-term survival outcomes in this patient population.
Conversely, some studies have reported a significant impact of melphalan dose. Straka et al. [14] (MEL140, n = 124; MEL200, n = 216) found that the cumulative melphalan dose affected both OS (p = 0.019) and PFS (p = 0.0141) in overall cohort level. In the bortezomib consolidation treatment group, there was no statistically significant difference in PFS or OS, whereas in the observation group, MEL200 still showed significantly better PFS (p = 0.0015) and OS (p = 0.0315) than MEL100/140. This key finding suggests that effective post‑ASCT consolidation therapy may mitigate the potential negative impact of dose reduction, offering a rationale for dose adjustment in patients planned for such therapy. Although the study designs differ, both their work and ours support the overarching principle that overall treatment strategy, including both conditioning and subsequent therapies, constitutes a modifiable and compensatory framework.
The study by Brioli [15] (MEL200, n = 191; MELRed, n = 122) also found that the MEL200 group demonstrated significantly longer OS (p = 0.001) and PFS (p < 0.001). Similarly, the study by Sharma et al. [16](MEL140, n = 127; MEL200, n = 803) indicated a link between melphalan dose and OS (p = 0.04). Notably, after adjustment for baseline imbalances, the association between melphalan dose and OS or PFS was attenuated to varying degrees in both studies. Brioli et al. [15] suggested that MEL200 associated merely with prolonged PFS, while Sharma et al. [16] found that MEL200 continued to demonstrate a survival benefit only in younger patients with normal renal function and poor response to induction therapy.
The discrepancy between their adjusted results and our null finding for dose effect may be attributed to our prospective, multi-parameter dose-selection strategy. By individually tailoring the dose within the 140–180 mg/m2 range based on age, CKD stage, and comorbidity scores, we may have better optimized the efficacy-toxicity balance for each patient, allowing those with poorer baseline status to achieve outcomes comparable to the standard-dose group. Furthermore, the profound baseline disparities (older age, worse renal function, more comorbidities) in the reduced-dose groups of earlier studies may exert a residual confounding effect on long-term outcomes that is difficult to fully eliminate through statistical adjustment.
In the contemporary management of MM, advanced age, high-risk cytogenetics, and renal impairment are well-established adverse prognostic factors for OS, while high-risk cytogenetics, extramedullary disease, and pre-transplant MRD positivity reliably predict shorter PFS [14–20]. The role of melphalan dose intensity as an independent prognostic factor remains ambiguous. The conflicting results across studies, including those identifying it [14, 15] as significant and those refuting it [17–20], likely stem from heterogeneity in treatment eras, evolving supportive care, patient selection criteria for dose reduction, and importantly, whether dose reduction was applied uniformly or through an individualized, risk-adapted approach as in our study.
Regarding safety, our findings corroborate earlier reports [15, 17–19]. The reduced-dose regimen significantly lowered the incidence of key non-hematologic toxicities, particularly oral mucositis and fever, attributable to decreased systemic drug exposure. The earlier platelet engraftment observed in our reduced-dose cohort, a finding not commonly emphasized, may be influenced by center-specific supportive care protocols. Crucially, as melphalan is renally cleared, dose reduction in patients with pre-existing renal impairment offers a logical pharmacokinetic rationale for renal protection [33, 34], potentially explaining the comparable post-ASCT renal injury rates between our groups despite worse baseline renal function in the reduced-dose cohort.
Our study has limitations. Its retrospective design introduces potential selection bias and unmeasured confounding. The median follow-up of 25.37 months is relatively short for assessing long-term survival in MM. The sample size within each reduced-dose tier precluded a powered comparison of outcomes across MEL140, MEL160, and MEL180. Furthermore, although our dose-selection strategy is structured around core clinical parameters, it operates as a qualitative clinical tool without a fully validated quantitative scoring system. This methodological limitation may constrain its generalizability across treatment centers and necessitates prospective validation in future studies.
In conclusion, an individualized, stepwise reduced-dose melphalan regimen (140–180 mg/m2) for ASCT conditioning achieved similar survival outcomes while significantly reducing treatment-related toxicity compared to the standard dose. Prospective studies are warranted to validate the prognostic implications of stratified dose reduction and to explore its impact in broader patient populations and in combination with modern consolidation and maintenance therapies.
Supplementary Information
Below is the link to the electronic supplementary material.
Subgroup analyses of OS and PFS in MM patients undergoing ASCT. A: OS in MRD-positive subgroup; B: PFS in MRD-positive subgroup; C: OS in high-risk cytogenetics subgroup; D: PFS in high-risk cytogenetics subgroup.
Kaplan-Meier survival analysis of MM patients undergoing ASCT. (A) OS and (B) PFS for patients conditioned with four different doses of melphalan: 140, 160, 180, and 200 mg/m2.
Acknowledgements
The authors of this study would like to thank all the study participants for their contributions.
Author contributions
Yifan Yao and Shan Zhang: These authors contributed equally as co-first authors. They participated in study design, data acquisition, interpretation, and methodology development, and were responsible for drafting and critically revising the manuscript.Ziying Li: Assisted in study conceptualization and critically reviewed and edited the manuscript.Lili Luo, Xuan Lu, Huafang Wang (co-corresponding authors): Jointly conceptualized and supervised the study, oversaw clinical management and diagnostic processes, curated key clinical and imaging data, and finalized the manuscript. They share equal responsibility as co-corresponding authors for the integrity of the work, correspondence, and data accuracy.
Funding
This study was supported by the National Key Research and Development Program of China grant 2022YFC2304600 and National Natural Science Foundation of China (Grant No. 82100143 & No.82300248).
Data availability
Data are available upon reasonable request from the corresponding author.
Declarations
Ethics statement
Approved by the Medical Ethics Committee of Huazhong University of Science and Technology. The study followed the Declaration of Helsinki, and all participants provided informed consent.
Competing interests
The authors declare no competing interests.
Footnotes
Yifan Yao and Shan Zhang share first authorship.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Lili Luo, Xuan Lu and Huafang Wang contributed equally as co-corresponding authors.
Contributor Information
Lili Luo, Email: lilyluo0914@126.com.
Xuan Lu, Email: luxuan20@126.com.
Huafang Wang, Email: whf2019@hust.edu.cn.
References
- 1.Cowan AJ, Green DJ, Kwok M, Lee S, Coffey DG, Holmberg LA et al (2022) Diagnosis and management of multiple myeloma: A review. JAMA 327(5):464–477. 10.1001/jama.2022.0003 [DOI] [PubMed] [Google Scholar]
- 2.Gerecke C, Fuhrmann S, Strifler S, Schmidt-Hieber M, Einsele H, Knop S (2016) The diagnosis and treatment of multiple myeloma. Deutsches Arzteblatt Int 113:27–28. 10.3238/arztebl.2016.0470 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Gay F, Musto P, Rota-Scalabrini D, Bertamini L, Belotti A, Galli M et al (2021) Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (forte): A randomised, open-label, phase 2 trial. Lancet Oncol 22(12):1705–1720. 10.1016/s1470-2045(21)00535-0 [DOI] [PubMed] [Google Scholar]
- 4.Richardson PG, Jacobus SJ, Weller EA, Hassoun H, Lonial S, Raje NS et al (2022) Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med 387(2):132–147. 10.1056/NEJMoa2204925 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA et al (2020) Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (emn02/ho95): A multicentre, randomised, open-label, phase 3 study. Lancet Haematol 7(6):e456–e68. 10.1016/s2352-3026(20)30099-5 [DOI] [PubMed] [Google Scholar]
- 6.Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M et al (2017) Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 376(14):1311–1320. 10.1056/NEJMoa1611750 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Perrot A, Lauwers-Cances V, Cazaubiel T, Facon T, Caillot D, Clement-Filliatre L et al (2020) Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: Long-term follow-up analysis of the ifm 2009 trial. Blood 136:39. 10.1182/blood-2020-134538 [Google Scholar]
- 8.Bensinger WI, Becker PS, Gooley TA, Chauncey TR, Maloney DG, Gopal AK et al (2016) A randomized study of melphalan 200 mg/m(2) vs 280 mg/m(2) as a preparative regimen for patients with multiple myeloma undergoing auto-sct. Bone Marrow Transpl 51(1):67–71. 10.1038/bmt.2015.211 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Palumbo A, Bringhen S, Bruno B, Falcone AP, Liberati AM, Grasso M et al (2010) Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: A prospective, multicenter phase 3 study. Blood 115(10):1873–1879. 10.1182/blood-2009-09-241737 [DOI] [PubMed] [Google Scholar]
- 10.Aypar E, İzzettin FV, Akı Ş Z, Sancar M, Yeğin ZA, Türköz-Sucak G (2018) Comparison of conditioning regimen toxicities among autologous stem cell transplantation eligible multiple myeloma patients: High-dose melphalan versus high-dose melphalan and bortezomib. J Oncol Pharm Pract 24(4):281–289. 10.1177/1078155217697486 [DOI] [PubMed] [Google Scholar]
- 11.Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F et al (2002) Comparison of 200 mg/m(2) melphalan and 8 gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: Final analysis of the intergroupe francophone du myélome 9502 randomized trial. Blood 99(3):731–735. 10.1182/blood.v99.3.731 [DOI] [PubMed] [Google Scholar]
- 12.Jeon MJ, Yu ES, Kim DS, Lee BH, Lee SR, Sung HJ et al (2024) Busulfan and cyclophosphamide for autologous stem cell transplantation in patients with multiple myeloma after proteasome inhibitor and/or immunomodulatory drug treatment. Sci Rep 14(1):26847. 10.1038/s41598-024-78350-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Giralt S (2010) 200 mg/m(2) melphalan–the gold standard for multiple myeloma. Nat Rev Clin Oncol 7(9):490–491. 10.1038/nrclinonc.2010.104 [DOI] [PubMed] [Google Scholar]
- 14.Straka C, Salwender H, Knop S, Vogel M, Müller J, Metzner B et al (2021) Full or intensity-reduced high-dose melphalan and single or double autologous stem cell transplant with or without bortezomib consolidation in patients with newly diagnosed multiple myeloma. Eur J Haematol 107(5):529–542. 10.1111/ejh.13690 [DOI] [PubMed] [Google Scholar]
- 15.Brioli A, vom Hofe F, Rucci P, Ernst T, Yomade O, Hilgendorf I et al (2021) Melphalan 200 mg/m2 does not increase toxicity and improves survival in comparison to reduced doses of melphalan in multiple myeloma patients. Bone Marrow Transpl 56(5):1209–1212. 10.1038/s41409-020-01170-0 [DOI] [PubMed] [Google Scholar]
- 16.Sharma N, Benson E, Zhao Q, Nunnelee J, Cottini F, Elder P et al (2023) Survival outcomes following autologous stem cell transplant with melphalan 140 mg/m(2) versus 200 mg/m(2) preparative regimens in patients with multiple myeloma. Leuk Lymphoma 64(7):1315–1321. 10.1080/10428194.2023.2213366 [DOI] [PubMed] [Google Scholar]
- 17.Auner HW, Iacobelli S, Sbianchi G, Knol-Bout C, Blaise D, Russell NH et al (2018) Melphalan 140 mg/m(2) or 200 mg/m(2) 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 103(3):514–521. 10.3324/haematol.2017.181339 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Srour SA, Milton DR, Bashir Q, Nieto Y, Saini N, Daher M et al (2021) Melphalan dose intensity for autologous stem cell transplantation in multiple myeloma. Haematologica 106(12):3211–3214. 10.3324/haematol.2021.279179 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Brown Z, Scott C, Zhang LF, Sadek R, Clarke A, Jillella A et al (2024) Assessing outcomes in patients with multiple myeloma postautologous stem cell transplantation: Contrasting the effects of melphalan dosages at 200 mg/m(2) versus 140 mg/m(2). Clinical lymphoma. myeloma Leuk 24(9):642–647. 10.1016/j.clml.2024.05.005 [DOI] [PubMed] [Google Scholar]
- 20.Kort J, Naleid N, Oley F, Ignatz-Hoover J, Margevicius S, Fu P et al (2025) Melphalan 140 mg/m(2) is safe and effective for frail and older multiple myeloma patients with comparable rates of minimal residual disease negativity. Clin lymphoma myeloma Leuk 25(7):e443. 10.1016/j.clml.2025.02.004 [DOI] [PubMed] [Google Scholar]
- 21.Al Hamed R, Bazarbachi AH, Malard F, Harousseau JL, Mohty M (2019) Current status of autologous stem cell transplantation for multiple myeloma. Blood Cancer J 9(4):44. 10.1038/s41408-019-0205-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Ricciuti G, Falcone A, Cascavilla N, Martinelli G, Cerchione C (2020) Autologous stem cell transplantation in multiple myeloma. Panminerva Med 62(4):220–224. 10.23736/s0031-0808.20.04114-2 [DOI] [PubMed] [Google Scholar]
- 23.Al Saleh AS, Sidiqi MH, Lee J, Dispenzieri A, Muchtar E, Buadi FK et al (2020) Differences in engraftment with day-1 compared with day-2 melphalan prior to stem cell infusion in myeloma patients receiving autologous stem cell transplant. Bone Marrow Transpl 55(11):2132–2137. 10.1038/s41409-020-0916-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Parmar SR, Bookout R, Shapiro JF, Tombleson R, Perkins J, Kim J et al (2014) Comparison of 1-day vs 2-day dosing of high-dose melphalan followed by autologous hematopoietic cell transplantation in patients with multiple myeloma. Bone Marrow Transpl 49(6):761–766. 10.1038/bmt.2014.56 [DOI] [PubMed] [Google Scholar]
- 25.Talamo G, Rakszawski KL, Rybka WB, Dolloff NG, Malysz J, Berno T et al (2012) Effect of time to infusion of autologous stem cells (24 vs. 48 h) after high-dose melphalan in patients with multiple myeloma. Eur J Haematol 89(2):145–150. 10.1111/j.1600-0609.2012.01795.x [DOI] [PubMed] [Google Scholar]
- 26.Avet-Loiseau H, Davies FE, Samur MK, Corre J, D’Agostino M, Kaiser MF et al (2025) International myeloma society/international myeloma working group consensus recommendations on the definition of high-risk multiple myeloma. J Clin oncology: official J Am Soc Clin Oncol 43(24):2739–2751. 10.1200/jco-24-01893 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Dimopoulos MA, Merlini G, Bridoux F, Leung N, Mikhael J, Harrison SJ et al (2023) Management of multiple myeloma-related renal impairment: Recommendations from the international myeloma working group. Lancet Oncol 24(7):e293–e311. 10.1016/s1470-2045(23)00223-1 [DOI] [PubMed] [Google Scholar]
- 28.Lu X, Andersen EF, Banerjee R, Eno CC, Gonzales PR, Kumar S et al (2025) Guidelines for the testing and reporting of cytogenetic results for risk stratification of multiple myeloma: A report of the cancer genomics consortium plasma cell neoplasm working group. Blood Cancer J 15(1):86. 10.1038/s41408-025-01286-w [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Auner HW, Garderet L, Kröger N (2015) Autologous haematopoietic cell transplantation in elderly patients with multiple myeloma. Br J Haematol 171(4):453–462. 10.1111/bjh.13608 [DOI] [PubMed] [Google Scholar]
- 30.Li Y, Zhang X, Zou Z, Xiong Y, Gu X, Zou R et al (2024) Modest survival benefits of autologous stem cell transplantation in multiple myeloma with renal impairment: A critical appraisal of the pre-antibody era. Clin experimental Med 24(1):215. 10.1007/s10238-024-01481-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Rago A, Annibali O, Tomarchio V, Coppetelli U, Fazio F, Cupelli L et al (2022) Autologous stem cell transplantation in multiple myeloma patients over 70 years: A gimema lazio working group experience in a retrospective case-control study. Eur J Haematol 109(3):250–256. 10.1111/ejh.13804 [DOI] [PubMed] [Google Scholar]
- 32.Vaxman I, Visram A, Kumar S, Dispenzieri A, Buadi F, Dingli D et al (2021) Autologous stem cell transplantation for multiple myeloma patients aged ≥ 75 treated with novel agents. Bone Marrow Transpl 56(5):1144–1150. 10.1038/s41409-020-01159-9 [DOI] [PubMed] [Google Scholar]
- 33.Kowalski KE, Wheeler SE, Adams CB, Voils SA, Richards AI (2022) Evaluating the incidence of engraftment syndrome with different melphalan formulations in adult multiple myeloma and immunoglobulin light chain amyloidosis patients undergoing autologous hematopoietic cell transplantation. J Oncol Pharm Pract 28(2):274–281. 10.1177/1078155220987623 [DOI] [PubMed] [Google Scholar]
- 34.Poczta A, Rogalska A, Marczak A (2021) Treatment of multiple myeloma and the role of melphalan in the era of modern therapies-current research and clinical approaches. J Clin Med 10(9). 10.3390/jcm10091841 [DOI] [PMC free article] [PubMed]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Subgroup analyses of OS and PFS in MM patients undergoing ASCT. A: OS in MRD-positive subgroup; B: PFS in MRD-positive subgroup; C: OS in high-risk cytogenetics subgroup; D: PFS in high-risk cytogenetics subgroup.
Kaplan-Meier survival analysis of MM patients undergoing ASCT. (A) OS and (B) PFS for patients conditioned with four different doses of melphalan: 140, 160, 180, and 200 mg/m2.
Data Availability Statement
Data are available upon reasonable request from the corresponding author.