Снижение дозы по сравнению со стандартными кондиционирования мелфалами для автоматической трансплантации стволовых клеток в множестве миеломы: ретроспективное исследование с одним центром.

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/m 2 (Mel200). This dose has demonstrated proven superiority over both 280 mg/m 2 and 100 mg/m 2 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/m 2 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/m 2 (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/m 2 (MEL180), 160 mg/m 2 (MEL160), and 140 mg/m 2 (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/m 2 ) and the reduced-dose group (140–180 mg/m 2 ). Specifically, the reduced-dose group followed a stepwise dose adjustment protocol with three levels: 180 mg/m 2 (MEL 180), 160 mg/m 2 (MEL 160), and 140 mg/m 2 (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).

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/m 2 ) 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 (×10 9 /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 (×10 9 /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 (×10 6 /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

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.

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

Related definitions

Neutrophil engraftment was designated as the initial occurrence of three consecutive days with an absolute neutrophil count at or above 0.5 × 10 9 /L. Platelet engraftment was characterized as the first day from which a platelet count exceeding 20 × 10 9 /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.

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/m 2 ) 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 (×10 9 /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 (×10 9 /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 (×10 6 /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

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).

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 × 10 6 /kg (reduced-dose group) and 5.72 × 10 6 /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.

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. 1 A). 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/m 2 ) versus standard-dose (200 mg/m 2 ) 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. 1 B). 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. 2 A 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 ) .

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/m 2 ) 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/m 2 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/m 2 ) 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.

Supplementary Material 1

Supplementary figure 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. High Resolution Image

Supplementary figure 2 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/m 2 . High Resolution Image

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.

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.

References

1. Cowan AJ Green DJ Kwok M Lee S Coffey DG Holmberg LA Diagnosis and management of multiple myeloma: A review JAMA 2022 327 5 464 477 10.1001/jama.2022.0003 35103762 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 35103762 10.1001/jama.2022.0003

2. Gerecke C Fuhrmann S Strifler S Schmidt-Hieber M Einsele H Knop S The diagnosis and treatment of multiple myeloma Deutsches Arzteblatt Int 2016 113 27 28 10.3238/arztebl.2016.0470 PMC4973001 27476706 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 10.3238/arztebl.2016.0470 PMC4973001 27476706

3. Gay F Musto P Rota-Scalabrini D Bertamini L Belotti A Galli M 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 2021 22 12 1705 1720 10.1016/s1470-2045(21)00535-0 34774221 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 34774221 10.1016/S1470-2045(21)00535-0

4. Richardson PG Jacobus SJ Weller EA Hassoun H Lonial S Raje NS Triplet therapy, transplantation, and maintenance until progression in myeloma N Engl J Med 2022 387 2 132 147 10.1056/NEJMoa2204925 35660812 PMC10040899 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 35660812 10.1056/NEJMoa2204925 PMC10040899

5. Cavo M Gay F Beksac M Pantani L Petrucci MT Dimopoulos MA 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 2020 7 6 e456 e68 10.1016/s2352-3026(20)30099-5 32359506 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 32359506 10.1016/S2352-3026(20)30099-5

6. Attal M Lauwers-Cances V Hulin C Leleu X Caillot D Escoffre M Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma N Engl J Med 2017 376 14 1311 1320 10.1056/NEJMoa1611750 28379796 PMC6201242 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 28379796 10.1056/NEJMoa1611750 PMC6201242

7. Perrot A Lauwers-Cances V Cazaubiel T Facon T Caillot D Clement-Filliatre L Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: Long-term follow-up analysis of the ifm 2009 trial Blood 2020 136 39 10.1182/blood-2020-134538 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

8. Bensinger WI Becker PS Gooley TA Chauncey TR Maloney DG Gopal AK 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 2016 51 1 67 71 10.1038/bmt.2015.211 PMC4894718 26367217 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 10.1038/bmt.2015.211 PMC4894718 26367217

9. Palumbo A Bringhen S Bruno B Falcone AP Liberati AM Grasso M Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: A prospective, multicenter phase 3 study Blood 2010 115 10 1873 1879 10.1182/blood-2009-09-241737 19965659 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 19965659 10.1182/blood-2009-09-241737

10. Aypar E İzzettin FV Akı Ş Z Sancar M Yeğin ZA Türköz-Sucak G 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 2018 24 4 281 289 10.1177/1078155217697486 29284356 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 29284356 10.1177/1078155217697486

11. Moreau P Facon T Attal M Hulin C Michallet M Maloisel F 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 2002 99 3 731 735 10.1182/blood.v99.3.731 11806971 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 11806971 10.1182/blood.v99.3.731

12. Jeon MJ Yu ES Kim DS Lee BH Lee SR Sung HJ Busulfan and cyclophosphamide for autologous stem cell transplantation in patients with multiple myeloma after proteasome inhibitor and/or immunomodulatory drug treatment Sci Rep 2024 14 1 26847 10.1038/s41598-024-78350-1 39500976 PMC11538328 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 39500976 10.1038/s41598-024-78350-1 PMC11538328

13. Giralt S 200 mg/m(2) melphalan–the gold standard for multiple myeloma Nat Rev Clin Oncol 2010 7 9 490 491 10.1038/nrclinonc.2010.104 20798699 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 20798699 10.1038/nrclinonc.2010.104

14. Straka C Salwender H Knop S Vogel M Müller J Metzner B 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 2021 107 5 529 542 10.1111/ejh.13690 34270825 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 34270825 10.1111/ejh.13690

15. Brioli A vom Hofe F Rucci P Ernst T Yomade O Hilgendorf I 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 2021 56 5 1209 1212 10.1038/s41409-020-01170-0 33299059 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 10.1038/s41409-020-01170-0 33299059

16. Sharma N Benson E Zhao Q Nunnelee J Cottini F Elder P 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 2023 64 7 1315 1321 10.1080/10428194.2023.2213366 37199099 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 37199099 10.1080/10428194.2023.2213366

17. Auner HW Iacobelli S Sbianchi G Knol-Bout C Blaise D Russell NH 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 2018 103 3 514 521 10.3324/haematol.2017.181339 29217776 PMC5830386 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 29217776 10.3324/haematol.2017.181339 PMC5830386

18. Srour SA Milton DR Bashir Q Nieto Y Saini N Daher M Melphalan dose intensity for autologous stem cell transplantation in multiple myeloma Haematologica 2021 106 12 3211 3214 10.3324/haematol.2021.279179 34407606 PMC8634193 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 34407606 10.3324/haematol.2021.279179 PMC8634193

19. Brown Z Scott C Zhang LF Sadek R Clarke A Jillella A 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 2024 24 9 642 647 10.1016/j.clml.2024.05.005 38845275 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 10.1016/j.clml.2024.05.005 38845275

20. Kort J Naleid N Oley F Ignatz-Hoover J Margevicius S Fu P Melphalan 140&nbsp;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 2025 25 7 e443 10.1016/j.clml.2025.02.004 40090795 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 40090795 10.1016/j.clml.2025.02.004

21. Al Hamed R Bazarbachi AH Malard F Harousseau JL Mohty M Current status of autologous stem cell transplantation for multiple myeloma Blood Cancer J 2019 9 4 44 10.1038/s41408-019-0205-9 30962422 PMC6453900 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 30962422 10.1038/s41408-019-0205-9 PMC6453900

22. Ricciuti G Falcone A Cascavilla N Martinelli G Cerchione C Autologous stem cell transplantation in multiple myeloma Panminerva Med 2020 62 4 220 224 10.23736/s0031-0808.20.04114-2 32955179 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 32955179 10.23736/S0031-0808.20.04114-2

23. Al Saleh AS Sidiqi MH Lee J Dispenzieri A Muchtar E Buadi FK 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 2020 55 11 2132 2137 10.1038/s41409-020-0916-3 PMC7606597 32358546 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 10.1038/s41409-020-0916-3 PMC7606597 32358546

24. Parmar SR Bookout R Shapiro JF Tombleson R Perkins J Kim J 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 2014 49 6 761 766 10.1038/bmt.2014.56 24662419 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 10.1038/bmt.2014.56 24662419

25. Talamo G Rakszawski KL Rybka WB Dolloff NG Malysz J Berno T 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 2012 89 2 145 150 10.1111/j.1600-0609.2012.01795.x 22540279 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 22540279 10.1111/j.1600-0609.2012.01795.x

26. Avet-Loiseau H Davies FE Samur MK Corre J D’Agostino M Kaiser MF 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 2025 43 24 2739 2751 10.1200/jco-24-01893 PMC13445576 40489728 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 10.1200/JCO-24-01893 PMC13445576 40489728

27. Dimopoulos MA Merlini G Bridoux F Leung N Mikhael J Harrison SJ Management of multiple myeloma-related renal impairment: Recommendations from the international myeloma working group Lancet Oncol 2023 24 7 e293 e311 10.1016/s1470-2045(23)00223-1 37414019 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 37414019 10.1016/S1470-2045(23)00223-1

28. Lu X Andersen EF Banerjee R Eno CC Gonzales PR Kumar S 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 2025 15 1 86 10.1038/s41408-025-01286-w 40533444 PMC12177088 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 40533444 10.1038/s41408-025-01286-w PMC12177088

29. Auner HW Garderet L Kröger N Autologous haematopoietic cell transplantation in elderly patients with multiple myeloma Br J Haematol 2015 171 4 453 462 10.1111/bjh.13608 26213240 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 26213240 10.1111/bjh.13608

30. Li Y Zhang X Zou Z Xiong Y Gu X Zou R 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 2024 24 1 215 10.1007/s10238-024-01481-2 PMC11384638 39249542 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 10.1007/s10238-024-01481-2 PMC11384638 39249542

31. Rago A Annibali O Tomarchio V Coppetelli U Fazio F Cupelli L 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 2022 109 3 250 256 10.1111/ejh.13804 35617025 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 35617025 10.1111/ejh.13804

32. Vaxman I Visram A Kumar S Dispenzieri A Buadi F Dingli D Autologous stem cell transplantation for multiple myeloma patients aged ≥ 75 treated with novel agents Bone Marrow Transpl 2021 56 5 1144 1150 10.1038/s41409-020-01159-9 33273658 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 10.1038/s41409-020-01159-9 33273658

33. Kowalski KE Wheeler SE Adams CB Voils SA Richards AI 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 2022 28 2 274 281 10.1177/1078155220987623 33435822 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 33435822 10.1177/1078155220987623

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 10.3390/jcm10091841 PMC8123041 33922721