Background
Multiple myeloma (MM) is an incurable plasma cell neoplasm [ 1 ]. However, the introduction of autologous stem cell transplantation (ASCT), proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies has significantly advanced its management. ASCT, which includes a sequence of treatments, including induction therapy, stem cell mobilization, conditioning regimens, single or tandem ASCT, consolidation, and maintenance therapy, significantly prolongs the survival of patients with MM [ 2 – 4 ].
This improved survival of ASCT-eligible patients is attributed to the use of a multifaceted approach, with contributors including risk stratification, novel therapeutic agents, and diverse treatment strategies [ 5 ]. For example, incorporating novel drug classes into induction, mobilization, consolidation, and maintenance elicited more resilient responses. Patients with high-risk MM typically undergo tandem ASCT [ 6 – 8 ], whereas standard-risk patients receive a single ASCT. These advancements improved survival [ 9 , 10 ], but this improvement is often observed in select clinical trial populations, which may distort real-world patient outcomes, as the existing disparities among patient subgroups indicate. Additionally, data from China are lacking.
In recent years, in China, advances in the diagnosis and treatment of MM have transformed the management of patients with ASCT-eligible myeloma. With a deeper understanding of MM, ASCT is being increasingly used in patients with newly diagnosed multiple myeloma (NDMM).
We utilized a database from a referral centre in China to assess changes in clinical characteristics, treatment regimens, response rates and survival rates from January 2007 to December 2023. Additionally, we evaluated tandem ASCT. These real-world data can be used to analyse treatment trends within China to improve clinical practice.
Methods
Patients
This retrospective analysis included all patients who underwent ASCT at the First Affiliated Hospital of Sun Yat-sen University between January 1 st, 2007, and December 31 st, 2023. MM was diagnosed in accordance with the International Myeloma Working Group (IMWG) criteria [ 11 ]. Patients aged < 18 years and those who received induction therapy that was not followed by ASCT were excluded. Patients were grouped into three time cohorts according to ASCT performance year: Cohort 1: 2007–2012; Cohort 2: 2013–2018; and Cohort 3: 2019‒2023. The patient data included clinical and laboratory characteristics at diagnosis, treatment regimen, response to treatment, progression-free survival (PFS), overall survival (OS), and cause of death. The follow-up period ended at death from any cause, loss to follow-up, or 31 December 2023. This study followed the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Medical Faculty. Written informed consent was obtained from all participants before data use.
Treatment
All patients received induction therapy with novel drugs, including PI-based regimens (VD, VCD, PAD, etc.), IMiD-based regimens (RAD, Pom + AD), PI + IMiD-based regimens (VRD, VTD), and Dara-based regimens (Dara + VD, Dara + VRD, etc.). Stem cell mobilization was performed using granulocyte colony-stimulating factor (G-CSF) alone or in combination with chemotherapy (high-dose cyclophosphamide + G-CSF or pegylated G-CSF). Stem cells for two to three transplants were collected. In 2021, plerixafor was added. Pretransplant conditioning involved melphalan (200 mg/m 2 ). During the melphalan shortage (2014–2018), CVB (busulfan, etoposide, and cyclophosphamide) was used. Maintenance therapy began with thalidomide and/or interferon-alpha (IFN-α), gradually shifting to lenalidomide, bortezomib, ixazomib, daratumumab, or carfilzomib and pomalidomide.
Minimal residual disease (MRD) monitoring and dynamics
Bone marrow (BM) MRD was monitored from December 2010 using flow cytometry. BM MRD assessments were performed postinduction and every 3 months during the first year after ASCT and then every 6–12 months thereafter. EDTA (anticoagulant)-treated BM aspirate (2 ml) was washed with PBS three times, and the cell density was then adjusted to ≤ 20 × 10^6/ml. Afterwards, 100 µl of sample was incubated with antibodies against the following proteins: CD38, CD56, CD19, CD20, CD54, CD138, CD45, cytoplasmic κ, and cytoplasmic λ. Abnormal plasma cells were differentiated from normal plasma cells by surface markers and cytoplasmic light chain expression [ 11 , 12 ]. The results were considered positive if ≥ 20 plasma cells with an abnormal phenotype were detected. The sensitivity of our flow cytometry detection method for MRD was 20 per 1–2 × 10^6, equal to 5 × 10^−5 to 10^−5.
Study endpoints and definitions
First, we investigated and evaluated ASCT as a first-line treatment for MM. This included evaluating induction, mobilization, conditioning, and maintenance regimens; CD34 + cell doses; haematological recovery; the number of tandem ASCTs; haematological response, MRD status, progression-free survival (PFS), and overall survival (OS). Treatment efficacy was assessed multiple times after transplantation according to the IMWG criteria [ 13 ]. We performed fluorescence in situ hybridization (FISH) analysis to identify high-risk cytogenetic abnormalities (HRCAs), specifically t(4;14), t(14;16), del(17p), and 1q21 amplification. The definitions of double- and triple-hit myeloma were in accordance with the Mayo Clinic mSMART 3.0 guidelines, referring to patients harbouring two or three concurrent high-risk cytogenetic abnormalities (e.g., t(4;14), t(14;16), del(17p), amp1q21). Extramedullary disease (EMD) was diagnosed by PET/CT, CT, or MRI and defined as soft tissue plasmacytomas outside the bone marrow. EMD included extramedullary extraosseous (EME) and extramedullary bone-related (EMB) diseases. Pattern B of M-protein decline was defined as per our previous publication [ 14 ] as a specific kinetic pattern of monoclonal protein reduction during induction therapy (see Supplemental Table 1), characterized by a serum M-protein decrease ≥ 25% but < 90% after 2 cycles of treatment for nonlight chain MM and a 24-h urine M-protein decrease ≥ 50% after 2 cycles of treatment but not meeting the criteria for Pattern A (a 24-h urine M-protein decrease ≥ 99% after 1 cycle of treatment) for light chain MM. Secondary amyloidosis in multiple myeloma refers to the deposition of amyloid fibrils composed of immunoglobulin light chains in various organs in patients with diagnosed multiple myeloma. Diagnosis is confirmed through pathological biopsy and Congo red staining, where a positive result indicates amyloid protein deposition. Second, we analysed factors affecting survival. PFS was calculated from induction to progression, death, or the last follow-up; OS was calculated from induction to death or the last follow-up.
Statistical methods
Statistical analyses were performed using SPSS 26.0 and R Studio 4.1.2. All p values were 2-sided, and p < 0.05 was considered to indicate statistical significance. Descriptive statistics were used to summarize the baseline characteristics. Patient-, disease-, and ASCT-related variables were analysed across the three cohorts by the year of ASCT. The Mann–Whitney and Wilcoxon tests were used to compare continuous variables. Chi-square tests were used to determine differences between baseline and outcome variables. Survival was analysed using the Kaplan–Meier method, group differences were analysed via the log-rank test, associations between demographic/clinical factors and survival outcomes were analysed via univariate and multivariate Cox regression, and 95% confidence intervals were estimated. The proportional hazards assumption was assessed using Schoenfeld residuals and was found to be satisfied for all Cox models. The haematological response was unchanged due to high collinearity with MRD status in the best responders to ASCT. The restricted mean survival time (RMST) was compared between the groups at 3 or 5 years postinduction. Because the proportion of missing values was small (< 5% for all variables), we primarily adopted a complete-case analysis, excluding patients with missing values from the relevant statistical models.
Results
The analysis included 390 patients with NDMM treated with induction followed by ASCT. Among the three cohorts (2007 to 2012, 20132018, and 2019 to 2023), 79 (20.2%) patients were included in Cohort 1 (2007–2012), 146 (37.4%) were included in Cohort 2 (2013–2018), and 189 (48.4%) were included in Cohort 3 (2019‒2023). The number of patients with NDMM who underwent ASCT increased from tens to nearly two hundred in each cohort (Supplemental Fig. 1).
Demographic and clinical characteristics
Table 1 presents the baseline demographic and clinical characteristics of all the cohorts. The median age at ASCT was 54 years, with 8.5% of patients aged > 65 years. The percentage of patients aged > 65 years at ASCT increased from 5.1% in Cohort 1 to 10.7% in Cohort 3. Most patients had the IgG type M protein (52.3%), followed by the IgA (21.8%) and light chain types (21.5%). Fifty-four patients (14.3%) had R-ISS stage III disease. Table 1 Demographics and clinical details of 390 patients with MM who underwent ASCT in China from 2007‒2023 Total ( N = 390) 2007–2012 ( N = 79) 2013–2018 ( N = 143) 2019–2023 ( N = 168) P value Age, median (range) 54 27–70 53 (27–67) 53 (33–69) 55 (26–69) 0.244 > 65 years old, n (%) 33 (8.5) 4 (5.1) 11 (7.7) 18 (10.7) 0.303 Sex, n (%) 0.065 Male 230 (59.0) 52 (65.8) 90 (62.9) 88 (52.4) Female 160 (41.0) 27 (34.2) 53 (37.1) 80 (47.6) M-protein type 0.649 IgG 204 (52.3) 39 (49.4) 78 (54.4) 87 (51.8) IgA 85 (21.8) 16 (20.3) 29 (20.3) 40 (23.8) Light chain 84 (21.5) 22 (27.8) 32 (22.4) 30 (17.9) Others 17 (4.4) 2 (2.5) 4 (2.8) 9 (6.5) BM plasma cell%, median (range) 24.2 (0.5–94.5) 32.0 (2.0–94.5) 21.5 (0.5–84.5) 24.3 (2–91.5) 0.076 R-ISS stage, n/N (%) 0.572 I 99/378 (26.2) 22/69 (31.9) 33/142 (23.2) 44/167 (26.3) II 225/378 (59.5) 38/69 (55.1) 91/142 (64.1) 96/167 (57.5) III 54/378 (14.3) 9/69 (13.0) 18/142 (12.7) 27/167 (16.2) LDH > 240 U/L, n/N (%) 63/373 (16.2) 10/69 (14.5) 21/141 (14.9) 32/163 (19.6) 0.459 Hypercalcaemia, n/N (%) 39/386 (10.1) 9/79 (11.4) 12/142 (8.5) 18/165 (10.9) 0.708 Renal insufficiency, n (%) 102 (26.2) 22 (27.8) 43 (30.1) 37 (22.0) 0.255 Anaemia, n/N (%) 215 (55.1) 46 (58.2) 79 (55.2) 90 (53.6) 0.790 Platelets < 100*10^9/L, n (%) 20 (6.2) 6 (7.6) 7 (4.9) 7 (4.2) 0.711 Extramedullary disease (EMD), n (%) 100(EME 10) (25.6) 11(EME 2) (13.9) 43(EME 1) (30.1) 46(EME 6) (27.4) 0.019 Secondary amyloidosis 38 (9.7) 2 (2.5) 12 (8.4) 24 (14.3) 0.012 HBsAb positive 61 (15.6) 16 (20.3) 17 (11.9) 28 (16.7) 0.231 Cytogenetic abnormalities, n/N (%) Del(17p) positive 25/338 (7.4) 7/36 (19.4) 7/135 (5.2) 11/167 (6.6) 0.079 Del(13q) positive 117/347 (33.7) 9/39 (23.1) 40/140 (28.6) 68/168 (40.5) 0.107 t(4;14) positive 58/305 (19.0) 1/9 (11.1) 24/130 (18.5) 33/166 (19.9) 0.790 t(14;16) positive 7/305 (1.8) 1/9 (11.1) 2/130 (1.5) 4/166 (2.4) 0.177 t(11;14) positive 31/305 (10.2) 2/9 (22.2) 12/130 (9.2) 17/166 (10.2) 0.552 1q21+ 0.144 Normal copy number 184/305 (60.3) 5/9 (55.6) 81/130 (62.3) 98/166 (59.0) Three copies 83/305 (27.2) 4/9 (44.4) 30/130 (23.1) 49/166 (29.5) Four or more copies 38/305 (12.5) 0/9 (0) 19/130 (14.6) 19/166 (11.5) High-risk cytogenetic abnormalities 114/347 (32.9) 11/39 (28.2) 46/140 (32.9) 57/168 (33.9) 0.791 Double-hit/triple-hit 20/347 (5.8) 1/39 (2.6) 8/140 (5.7) 11/168 (6.5) 0.629 Tandem ASCT, n (%) 24 (6.2) 0 (0) 3 (2.1) 21 (12.5) < 0.001 Other immunochemical subtypes of myeloma included the following: IgD ( n = 15), IgE ( n = 1), and IgM ( n = 1). High-risk cytogenetic abnormalities were defined as the presence of t(4;14), t(14;16), t(14;20), or del(17p). Double-hit/triple-hit was defined as the presence of two or three concurrent high-risk cytogenetic abnormalities Abbreviations : RISS Revised International Staging System, BM Bone marrow, EMD Extramedullary disease, EME Extramedullary extraosseous, HBsAb Hepatitis B virus surface antibody, LDH Lactate dehydrogenase, ASCT Autologous stem cell transplantation *When the total number was less than 390, unevaluable or missing data were excluded, and percentages were calculated after exclusion
Table 1
Demographics and clinical details of 390 patients with MM who underwent ASCT in China from 2007‒2023
Other immunochemical subtypes of myeloma included the following: IgD ( n = 15), IgE ( n = 1), and IgM ( n = 1). High-risk cytogenetic abnormalities were defined as the presence of t(4;14), t(14;16), t(14;20), or del(17p). Double-hit/triple-hit was defined as the presence of two or three concurrent high-risk cytogenetic abnormalities Abbreviations : RISS Revised International Staging System, BM Bone marrow, EMD Extramedullary disease, EME Extramedullary extraosseous, HBsAb Hepatitis B virus surface antibody, LDH Lactate dehydrogenase, ASCT Autologous stem cell transplantation *When the total number was less than 390, unevaluable or missing data were excluded, and percentages were calculated after exclusion
| Total ( N = 390) | 2007–2012 ( N = 79) | 2013–2018 ( N = 143) | 2019–2023 ( N = 168) | P value | |||||
| Age, median (range) | 54 | 27–70 | 53 | (27–67) | 53 | (33–69) | 55 | (26–69) | 0.244 |
| > 65 years old, n (%) | 33 | (8.5) | 4 | (5.1) | 11 | (7.7) | 18 | (10.7) | 0.303 |
| Sex, n (%) | 0.065 | ||||||||
| Male | 230 | (59.0) | 52 | (65.8) | 90 | (62.9) | 88 | (52.4) | |
| Female | 160 | (41.0) | 27 | (34.2) | 53 | (37.1) | 80 | (47.6) | |
| M-protein type | 0.649 | ||||||||
| IgG | 204 | (52.3) | 39 | (49.4) | 78 | (54.4) | 87 | (51.8) | |
| IgA | 85 | (21.8) | 16 | (20.3) | 29 | (20.3) | 40 | (23.8) | |
| Light chain | 84 | (21.5) | 22 | (27.8) | 32 | (22.4) | 30 | (17.9) | |
| Others | 17 | (4.4) | 2 | (2.5) | 4 | (2.8) | 9 | (6.5) | |
| BM plasma cell%, median (range) | 24.2 | (0.5–94.5) | 32.0 | (2.0–94.5) | 21.5 | (0.5–84.5) | 24.3 | (2–91.5) | 0.076 |
| R-ISS stage, n/N (%) | 0.572 | ||||||||
| I | 99/378 | (26.2) | 22/69 | (31.9) | 33/142 | (23.2) | 44/167 | (26.3) | |
| II | 225/378 | (59.5) | 38/69 | (55.1) | 91/142 | (64.1) | 96/167 | (57.5) | |
| III | 54/378 | (14.3) | 9/69 | (13.0) | 18/142 | (12.7) | 27/167 | (16.2) | |
| LDH > 240 U/L, n/N (%) | 63/373 | (16.2) | 10/69 | (14.5) | 21/141 | (14.9) | 32/163 | (19.6) | 0.459 |
| Hypercalcaemia, n/N (%) | 39/386 | (10.1) | 9/79 | (11.4) | 12/142 | (8.5) | 18/165 | (10.9) | 0.708 |
| Renal insufficiency, n (%) | 102 | (26.2) | 22 | (27.8) | 43 | (30.1) | 37 | (22.0) | 0.255 |
| Anaemia, n/N (%) | 215 | (55.1) | 46 | (58.2) | 79 | (55.2) | 90 | (53.6) | 0.790 |
| Platelets < 100*10^9/L, n (%) | 20 | (6.2) | 6 | (7.6) | 7 | (4.9) | 7 | (4.2) | 0.711 |
| Extramedullary disease (EMD), n (%) | 100(EME 10) | (25.6) | 11(EME 2) | (13.9) | 43(EME 1) | (30.1) | 46(EME 6) | (27.4) | 0.019 |
| Secondary amyloidosis | 38 | (9.7) | 2 | (2.5) | 12 | (8.4) | 24 | (14.3) | 0.012 |
| HBsAb positive | 61 | (15.6) | 16 | (20.3) | 17 | (11.9) | 28 | (16.7) | 0.231 |
| Cytogenetic abnormalities, n/N (%) | |||||||||
| Del(17p) positive | 25/338 | (7.4) | 7/36 | (19.4) | 7/135 | (5.2) | 11/167 | (6.6) | 0.079 |
| Del(13q) positive | 117/347 | (33.7) | 9/39 | (23.1) | 40/140 | (28.6) | 68/168 | (40.5) | 0.107 |
| t(4;14) positive | 58/305 | (19.0) | 1/9 | (11.1) | 24/130 | (18.5) | 33/166 | (19.9) | 0.790 |
| t(14;16) positive | 7/305 | (1.8) | 1/9 | (11.1) | 2/130 | (1.5) | 4/166 | (2.4) | 0.177 |
| t(11;14) positive | 31/305 | (10.2) | 2/9 | (22.2) | 12/130 | (9.2) | 17/166 | (10.2) | 0.552 |
| 1q21+ | 0.144 | ||||||||
| Normal copy number | 184/305 | (60.3) | 5/9 | (55.6) | 81/130 | (62.3) | 98/166 | (59.0) | |
| Three copies | 83/305 | (27.2) | 4/9 | (44.4) | 30/130 | (23.1) | 49/166 | (29.5) | |
| Four or more copies | 38/305 | (12.5) | 0/9 | (0) | 19/130 | (14.6) | 19/166 | (11.5) | |
| High-risk cytogenetic abnormalities | 114/347 | (32.9) | 11/39 | (28.2) | 46/140 | (32.9) | 57/168 | (33.9) | 0.791 |
| Double-hit/triple-hit | 20/347 | (5.8) | 1/39 | (2.6) | 8/140 | (5.7) | 11/168 | (6.5) | 0.629 |
| Tandem ASCT, n (%) | 24 | (6.2) | 0 | (0) | 3 | (2.1) | 21 | (12.5) | < 0.001 |
Novel detection methods at our centre have transformed the treatment for patients with myeloma. EMD was observed in 100 (25.6%) patients. The incidence of EMD increased significantly from 13.9% in Cohort 1 to 27.4% in Cohort 3 ( p = 0.019). Secondary light chain amyloidosis was observed in 38 (9.7%) patients, with the incidence increasing from 2.5% to 14.3% over this period ( p = 0.012). The percentage of patients with HRCAs increased over time. Data on HRCAs were available for only 347 patients; 114 (32.9%) had HRCAs, and 20 (5.8%) had double- or triple-hit myeloma. A total of 93.8% of patients underwent single ASCT, whereas 6.2% underwent tandem ASCT. The use of tandem ASCT increased significantly from 0% in Cohort 1 to 12.5% in Cohort 3 ( p < 0.001).
Evolving treatment regimens
Changes in induction
We used various induction therapies to reduce the tumour burden before ASCT from 2007 to 2023 (Fig. 1 A and B). The median number of induction therapy cycles was 4 (range, 1–10): 2007–2012:3 (1–9), 2013–2018:4 (2–10), and 2019–2023:4 (3–8). All patients were treated with agents such as PIs, IMiDs and/or monotherapies. A total of 328 (84.1%), 21 (5.4%), 26 (6.7%), and 15 (3.8%) patients received PI-/IMiD-/PI + IMiD−/Dara-based regimens, respectively. The induction regimens changed from PI-based doublet regimens in Cohort 1 to triplet/quadruplet regimens in Cohort 3. In 2011, the PAD combination (bortezomib + pegylated liposomal doxorubicin + dexamethasone) became the most common treatment (68.0%). The use of the PI + IMiD-based regimen increased. Daratumumab-based regimens emerged in Cohort 3. Some patients with HRCAs in Cohort 3 received a triplet/quadruplet regimen with daratumumab, carfilzomib, and/or pomalidomide. For the IMiD-based regimen, there was a shift from thalidomide to lenalidomide (Fig. 1 B). Lenalidomide reduced haematopoietic stem cell collection; therefore, its use was decreased in Cohort 3. Fig. 1 Changing landscape of treatment in 390 patients with MM receiving ASCT over time from 2007–2023. A and B induction regimens. ( C ) Mobilization regimens ( D ) Maintenance regimens. Dara, daratumumab; PI, proteasome inhibitor; IMiD, immunomodulatory drug; Chemo, chemotherapy. ASCT, autologous stem cell transplantation, HD-CTX, high-dose cyclophosphamide, rhG-CSF, human granulocyte–colony-stimulating factor, IFN, interferon
Stem cell mobilization
We analysed 365 patients who underwent peripheral blood stem cell mobilization, with an overall single-attempt success rate of 93.7% and a mean number of CD34 + cells of 5.3 × 10^6/kg. Most patients (94.2%) received high-dose CTX combined with stimulating agents (Supplemental Fig. 2 and Table 2 ). Mobilization strategies evolved over time, shifting from G-CSF to PEG-rh G-CSF in Cohort 2 and to plerixafor in Cohort 3, where 60 patients with low yields received it successfully (Fig. 1 C). Success rates improved across cohorts (83.6%, 94.9%, and 96.4%), with the median CD34 + collection rate increasing from 3.3 × 10^6/kg in Cohort 1 to 6.2 × 10^6/kg in Cohort 3. Regimen differences were significant ( p < 0.001): G-CSF alone never achieved > 6 × 10^6/kg, whereas HD-CTX + G-CSF or PEG-rhG-CSF with plerixafor frequently did. Table 2 Stem cell doses collected and infusion and Haematopoietic reconstitution parameters Mobilization Success rate of one collection Collected CD34 + cell dose (10 6 /kg), mean (range) Collected CD34 + cell dose ≥ 4*10 6 /kg, n (%) Collected CD34 + cell dose ≥ 6*10 6 /kg, n (%) Total ( N = 390) 93.70% 5.3 (0.1–32.7) 237 (64.9%) 159 (43.6%) 2007–2012 ( N = 79) 83.60% 3.3 (0.9–24.1) 25 (43.1%) 13 (22.4%) 2013–2018 ( N = 143) 94.90% 5.1 (0.1–32.7) 86 (61.9%) 59 (41.3%) 2019–2023 ( N = 168) 96.40% 6.2 (0.3–29.7) 126 (75.0%) 87 (51.8%) Conditioning WBC reconstitution, days, median (range) PLT reconstitution, days, median (range) CD34 + infusion (10 6 /kg) median (range) Total ( N = 415) 10 (6–43) 12(6–180) 2.9 (0.9–24.1) 2007–2012 ( N = 79) 12 (9–43) 13(8–120) 2.7 (0.9–24.1) 2013–2018 ( N = 146) 10 (6–35) 11(6–180) 3.2 (0.9–17.8) 2019–2023 ( N = 190) 10 (8–23) 12(8–66) 2.8 (1.3–15.4)
Table 2
Stem cell doses collected and infusion and Haematopoietic reconstitution parameters
| Mobilization | ||||
| Success rate of one collection | Collected CD34 + cell dose (10 6 /kg), mean (range) | Collected CD34 + cell dose ≥ 4*10 6 /kg, n (%) | Collected CD34 + cell dose ≥ 6*10 6 /kg, n (%) | |
| Total ( N = 390) | 93.70% | 5.3 (0.1–32.7) | 237 (64.9%) | 159 (43.6%) |
| 2007–2012 ( N = 79) | 83.60% | 3.3 (0.9–24.1) | 25 (43.1%) | 13 (22.4%) |
| 2013–2018 ( N = 143) | 94.90% | 5.1 (0.1–32.7) | 86 (61.9%) | 59 (41.3%) |
| 2019–2023 ( N = 168) | 96.40% | 6.2 (0.3–29.7) | 126 (75.0%) | 87 (51.8%) |
| Conditioning | ||||
| WBC reconstitution, days, median (range) | PLT reconstitution, days, median (range) | CD34 + infusion (10 6 /kg) median (range) | ||
| Total ( N = 415) | 10 (6–43) | 12(6–180) | 2.9 (0.9–24.1) | |
| 2007–2012 ( N = 79) | 12 (9–43) | 13(8–120) | 2.7 (0.9–24.1) | |
| 2013–2018 ( N = 146) | 10 (6–35) | 11(6–180) | 3.2 (0.9–17.8) | |
| 2019–2023 ( N = 190) | 10 (8–23) | 12(8–66) | 2.8 (1.3–15.4) |
Conditioning therapy
A total of 415 transplants were performed, including 25 tandem ASCTs; 385 patients received peripheral blood stem cell transplantation, 25 received bone marrow transplantation, and 4 received both. No transplant-related deaths occurred. The median infused CD34 + dose was 2.9 × 10^6/kg, and engraftment was achieved in all patients, with median neutrophil and platelet recovery at 10 and 12 days, respectively. The conditioning regimens included melphalan (Mel, 65.8%) and CVB (34.2%). Compared with Mel, CVB led to faster recovery (neutrophils by 1 day and platelets by 3 days; p < 0.001). Overall, engraftment times improved significantly over time ( p < 0.05), likely reflecting advances in supportive care (Table 2 ).
Changes in maintenance therapy
No ASCT-treated patients received consolidation therapy, whereas 94.9% received maintenance therapy ( n = 370). Thalidomide and/or IFN-a were the predominant maintenance strategies in Cohort 1 but were rare in Cohort 2 and 3 (Fig. 1 D). After 2015, lenalidomide began to be used more frequently in maintenance therapy. During this therapy, most patients were treated with a single- agent. Patients with high-risk MM received maintenance therapy with VD, Dara, or KP, whereas standard-risk patients were treated with lenalidomide.
Response rate and MRD status
The response rates increased after induction and before transplantation (Fig. 2 ). In Cohort 1, 24.1% and 64.6% of patients achieved ≥ CR and ≥ VGPR, respectively; in Cohort 2, 34.3% and 81.1%; and in Cohort 3, 40.5% and 92.3%, respectively. Before 2011, MRD was rarely tested, resulting in 20 patients in Cohort 1 lacking MRD status. For the evaluable patients, the percentages of MRD-negative responses before transplantation were 8.5%, 29.4%, and 29.8%, respectively. Responses at 3 months post-transplant increased steadily. In Cohort 1, 51.9% and 81.0% achieved ≥ CR and ≥ VGPR, respectively, whereas in Cohort 3, 66.1% and 97.6%, respectively, achieved ≥ CR and ≥ VGPR, respectively. Similarly, the best post-HSCT haematological response improved over time, with 68.4% and 87.4% in Cohort 1 and 82.1% and 97.6% in Cohort 3 achieving ≥ CR and ≥ VGPR, respectively. A total of 64.4%, 76.2%, and 80.4% of the patients in the three cohorts exhibited the best post-HSCT MRD-negative responses, respectively. Compared with the response before ASCT, the efficacy of the treatment increased significantly after transplantation and further during maintenance therapy. The efficacy of the triplet or quadruplet drug induction regimens was greater, with higher ≥ VGPR rates (64.5% vs. 85.7%, p < 0.001) than those after VD two-drug induction. Fig. 2 Treatment outline for all patients. ( A ) Haematological response rate according to the year of transplant in the three-year cohort prior to transplantation, three months after ASCT and at the best posttransplant response. ( B ) MRD negativity rate according to the year of transplant in the three-year cohort prior to transplant and at the best posttransplant response. MRD, minimal residual disease; CR, complete response; PR, partial response; VGPR, very good partial response
Survival outcomes
With a median follow-up of 48.4 months, the median PFS (mPFS) and OS (mOS) of the entire cohort were 71.0 and 106.1 months, respectively. Survival outcomes improved significantly across time cohorts in patients who underwent ASCT. The mOS times were 55.1 months in Cohort 1 (2007–2012), 106.1 months in Cohort 2 (2012–2018), and not reached in Cohort 3 (2019–2023), with corresponding 5-year OS rates of 58.23%, 68.46%, and 81.82%, respectively. RMST analysis at 60 months revealed no significant difference between Cohorts 1 and 2 (− 2.14 months, P = 0.321), but Cohort 3 demonstrated a further advantage of 4.13 months over Cohort 2 ( P = 0.015). In patients with high-risk cytogenetic abnormalities (HRCAs), OS also improved over time. The mOS times were 35.6 months, 70.0 months, and not reached in Cohorts 1, 2, and 3, with 5-year OS rates of 9.09%, 53.58%, and 72.53%, respectively. RMST analysis revealed an 8.04-month improvement from Cohorts 1 to 2 ( P = 0.144) and an additional 8.17 months from Cohorts 2 to 3 ( P = 0.015). Similarly, PFS showed consistent gains. The mPFS times were 47.2 months in Cohort 1, 76.1 months in Cohort 2, and not reached in Cohort 3, with 5-year PFS rates of 44.62%, 60.36%, and 87.61%, respectively. RMST analysis revealed a 6.17-month benefit in Cohort 2 compared with Cohort 1 ( P = 0.012) and a further 6.39-month gain in Cohort 3 compared with Cohort 2 ( P = 0.002). Among patients with HRCAs, the mPFS improved from 23.2 months in Cohort 1 to 53.6 months in Cohort 2 and 60.1 months in Cohort 3. The 3-year PFS rates increased from 9.09% to 59.77% and 81.16%, respectively, with RMST confirming significant benefits of 18.61 months (Cohort 2 vs. Cohort 1, P < 0.001) and 10.69 months (Cohort 3 vs. Cohort 2, P = 0.016), respectively (Fig. 3 ). Fig. 3 Patient survival outcomes. ( A ) PFS from initial therapy stratified by three time cohorts (RMST 47.83 m vs. 48.99 m vs. 55.38 m; Cohort 1 vs. Cohort 2, P =0.012; Cohort 2 vs. Cohort 3, P =0.002). ( B ) OS from initial therapy stratified by three time cohorts (RMST 49.83 m vs. 51.97 m vs. 56.10 m; Cohort 1 vs. Cohort 2, P=0.321; Cohort 2 vs. Cohort 3, P =0.015). ( C ) PFS for MM patients with HRCA from initial therapy stratified by three time cohorts (RMST 23.61 m vs. 42.22 m vs. 52.90 m, Cohort 1 vs. Cohort 2 P <0.001, Cohort 2 vs. Cohort 3 P =0.016). ( D ) OS for MM patients with HRCA from initial therapy stratified by three time cohorts (RMST 38.15 m vs. 46.19 m vs. 54.36 m; Cohort 1 vs. Cohort 2, P =0.144; Cohort 2 vs. Cohort 3, P =0.015). PFS, progression-free survival; OS, overall survival; HR, high-risk chromosomal abnormalities (defined as the presence of del(17p) and/or t(4;14) and/or t(14;16) and/or amp1q21); SR, standard risk (defined as the absence of high-risk chromosomal abnormalities)
Analysis of PFS and OS
Tables 3 and 4 and Supplementary Tables 2 and 3 present univariate analyses for PFS and OS, respectively. In the multivariate analysis (MVA) of PFS, factors significantly linked to worse PFS included low platelet counts (HR = 3.07, 95% CI: 1.43–6.59, p = 0.004), EME (extramedullary extraosseous) (HR = 3.53, 95% CI: 1.19–10.48, p = 0.022), and HRCAs (HR = 1.78, 95% CI: 1.20–2.62, p = 0.004). Attained MRD-negative status (HR = 0.48, 95% CI: 0.31–0.74, p < 0.001) significantly improved PFS. In the MVA, worse OS was associated with EME (HR 4.55, 95% CI: 1.74–12.49, p = 0.002), secondary amyloidosis (HR = 2.48, 95% CI: 1.36–4.53, p = 0.003), HRCAs (HR = 1.70, 95% CI: 1.10–2.61, p = 0.016), and low platelet counts (HR = 2.44, 95% CI: 1.11–5.34, p = 0.026). MRD-negative status strongly predicted improved OS (HR = 0.56, 95% CI: 0.35–0.89, p = 0.015), and initial three- or four-drug regimens were significantly more effective than two-drug regimens were, with an HR of 0.39. Table 3 Multivariate analyses of factors associated with PFS PFS Multivariate analysis HR 95% CI p value Platelets < 100*10 9 /L 3.07 1.43–6.59 0.004 Extramedullary extraosseous (EME) 3.53 1.19–10.48 0.022 High-risk chromosomal abnormalities 1.78 1.20–2.62 0.004 Pattern B of M-protein decline 0.65 0.45–0.95 0.027 Best response, MRD- vs. MRD+ 0.48 0.31–0.74 0.001 Table 4 Multivariate analyses of factors associated with OS OS Multivariate analysis HR 95% CI p value Platelets < 100*10^ 9 /L 2.44 1.11–5.34 0.026 Extramedullary extraosseous(EME) 4.66 1.74–12.49 0.002 Secondary amyloidosis 2.48 1.36–4.53 0.003 High-risk chromosomal abnormalities 1.70 1.10–2.61 0.016 Initial treatment regimen, two-drug regimen vs. three-/four-drug regimen 0.39 0.22–0.72 0.003 Best response, MRD- vs. MRD+ 0.56 0.35–0.89 0.015 Abbreviations : CI Confidence interval, HR Hazard ratio, OS Overall survival, PFS Progression-free survival, MRD Minimal residual disease
Table 3
Multivariate analyses of factors associated with PFS
| PFS | Multivariate analysis | ||
| HR | 95% CI | p value | |
| Platelets < 100*10 9 /L | 3.07 | 1.43–6.59 | 0.004 |
| Extramedullary extraosseous (EME) | 3.53 | 1.19–10.48 | 0.022 |
| High-risk chromosomal abnormalities | 1.78 | 1.20–2.62 | 0.004 |
| Pattern B of M-protein decline | 0.65 | 0.45–0.95 | 0.027 |
| Best response, MRD- vs. MRD+ | 0.48 | 0.31–0.74 | 0.001 |
Table 4
Multivariate analyses of factors associated with OS
Abbreviations : CI Confidence interval, HR Hazard ratio, OS Overall survival, PFS Progression-free survival, MRD Minimal residual disease
| OS | Multivariate analysis | ||
| HR | 95% CI | p value | |
| Platelets < 100*10^ 9 /L | 2.44 | 1.11–5.34 | 0.026 |
| Extramedullary extraosseous(EME) | 4.66 | 1.74–12.49 | 0.002 |
| Secondary amyloidosis | 2.48 | 1.36–4.53 | 0.003 |
| High-risk chromosomal abnormalities | 1.70 | 1.10–2.61 | 0.016 |
| Initial treatment regimen, two-drug regimen vs. three-/four-drug regimen | 0.39 | 0.22–0.72 | 0.003 |
| Best response, MRD- vs. MRD+ | 0.56 | 0.35–0.89 | 0.015 |
Tandem ASCT
Patients underwent either single ( n = 365) or tandem ASCT ( n = 23). Since 2018, tandem ASCT has been the first-line treatment for high-risk cytogenetic patients at our centre. The mPFS times for patients with SRCA and HRCAs after a single ASCT were 90.1 and 40.7 months, respectively. mPFS was not reached in the tandem ASCT group, partly because of the small sample size. The mPFS times were similar between patients who underwent SCRA after tandem ASCT and those who underwent single ASCT ( p = 0.983) (Fig. 4 ). In contrast, the mPFS improved in patients with HRCAs after tandem ASCT compared with those after single ASCT ( p = 0.047). The 3-year PFS rates were 86% for single ASCT with SRCA, 59% for single ASCT with HRCA, and 84% for tandem ASCT. RMST analysis at 36 months revealed similar outcomes between tandem ASCT and single ASCT with SRCA (− 1.10 months, P = 0.419), whereas tandem ASCT provided a significant advantage over single ASCT with HRCA (+ 3.06 months, P = 0.048). Fig. 4 Progression-free survival (PFS) was dependent on the transplant schedule and HRCA. The RMST (36 months) was as follows: single ASCT with HRCA vs. single ASCT with SRCA vs. tandem ASCT: 29.98 m vs. 34.14 m vs. 33.04 m. There was no difference in median PFS between patients receiving tandem ASCT vs. single ASCT with SRCA ( p = 0.419). An improvement in median PFS was observed in patients receiving tandem ASCT compared with patients receiving single ASCT with HRCA ( p = 0.048)
Second primary malignancy (SPM)
Thirty patients (7.7%) in the entire cohort developed a second primary malignancy (SPM): 7 patients (8.9%) in Cohort 1, 18 patients (12.6%) in Cohort 2, and 5 patients (3.0%) in Cohort 3. Acute lymphoid leukaemia and myeloid malignancies were the most common SPMs in all three cohorts. Twenty-eight patients who developed SPM received IMiD-based maintenance therapy.
Discussion
ASCT remains central to treating MM. Advances in understanding this cancer, new drugs and drug combinations and better supportive care have improved outcomes in patients with NDMM undergoing ASCT. Notably, no relevant real-world data exist from China [ 8 , 15 – 18 ]. The reason for the lack of real-world data in China is that the percentage of Chinese patients who undergo first-line ASCT is only 12.6–14.4%, which is much lower than the percentages reported in Western countries [ 19 ]. However, the use of ASCT in patients with NDMM has gradually increased in China in recent years. As one of China’s first centres that routinely performs ASCT, we reported outcomes for a single-centre cohort of unselected patients with NDMM and analysed evolving therapies. The number of patients who underwent ASCT increased sharply between 2007 and 2023, and the mPFS (71.0 months) and mOS (106.1 months) times were comparable to those reported for ASCT in Western countries. For example, in the MD Anderson retrospective single-centre study (2005–2021), which included 1,109 patients with NDMM undergoing autoHCT, the median PFS was 38.6 months, and the median OS was 103.8 months [ 20 ]. We observed improved survival for patients with NDMM who received upfront ASCT. Although older and/or high-risk patients are more common in the latter cohorts, they exhibit more resilient responses. Importantly, patients with high-risk NDMM had improved PFS and OS.
Our analysis suggests that ASCT, once limited to individuals aged < 65, is now offered more frequently to elderly patients [ 1 , 17 ]. For example, the rate of enrolment of patients ≥ 65 years of age at our centre increased from 5.1 to 10.7%. The lack of significant differences in OS or PFS between age groups indicates that ASCT benefits extend to those most frequently affected by MM. The lack of a statistically significant adverse effect of age on the outcomes may be due to more effective and safer treatment at induction, careful patient selection, and improved care.
In addition, the increased survival observed over time is more likely related to the increasing proportion of patients attaining a CR and MRD-negative status pre- or post-ASCT. One of the strengths of our study is the use of complete and consistent efficacy evaluation data, including 94.6% of the data for MRD assessment. Our data revealed improved responses across cohorts and a significant correlation between PFS and OS and the response achieved through induction therapy. In this study, patients who achieved an MRD-negative status after induction chemotherapy, transplantation, or maintenance therapy had significantly better PFS and OS. This improvement in response rates was due to the dynamic changes in induction and maintenance regimens.
All our regimens included novel agents such as PIs, IMiDs, or monoclonal antibodies. Although doublet regimens were the predominant chemotherapy regimen in Cohort 1, a transition phase up to Cohort 2 was followed by a complete switch to triplet combinations containing bortezomib. Previous studies have confirmed that these combinations improve OS better than doublet bortezomib and dexamethasone regimens do [ 8 , 21 ]. Three-drug induction regimens with VRD are now the standard of care for patients with NDMM. However, our study revealed that only 6.7% of the patients received induction therapy with a combination of a PI and an IMiD. The relatively small proportion of patients receiving VRD in China is due to limited drug accessibility, delayed approval, reimbursement barriers, and cost. Our previous results indicated that R-containing induction regimens may affect subsequent stem cell collection [ 22 ]. The increased availability of drugs has expanded the diversity of drug combinations. Advancements in the application of novel techniques have enabled delicate risk stratification. Our center’s data revealed a gradual increase in the number of patients with HRCAs, as we started to routinely perform FISH tests as daily management, and more EMD cases occurred because of the start of frequent applications of PET/CT scans. For these patients, more effective treatment options, such as quadruplet regimens incorporating MoAbs (daratumumab), PIs (carfilzomib, ixazomib) and IMiDs (pomalidomide), were used, and increasing numbers of patients may achieve a CR or an MRD-negative status with ASCT. The findings of the GMM-CONCEPT [ 23 ], UK OPTIMISM [ 24 ] and FORTE [ 25 ] studies confirmed the positive effects of these drugs on high-risk patients. In addition, for patients with EMD, we administered localized radiotherapy within six months after transplantation to reduce the risk of relapse.
Efficacy analysis revealed significant improvements in CR rates and MRD-negative status following ASCT, with maintenance therapy showing the greatest benefit. In our study, 94.9% of the ASCT-treated patients received the maintenance regimen, which was a higher percentage than those reported in other studies. However, the optimal maintenance therapy regimen remains underdetermined. Studies have indicated that lenalidomide maintenance improves both PFS and OS [ 26 – 28 ]. Our centre has introduced this drug. However, the use of IMiDs is associated with the risk of SPM. SPM represents an important concern regarding the long-term use of IMiDs. Like in other published cohort studies, in our study, 30 patients (7.7%) in the entire cohort developed SPMs, and 28 patients who developed SPMs received IMiD-based regimen maintenance therapy. In the large Myeloma XI trial, the prevalence of SPMs in patients receiving lenalidomide maintenance was approximately 7–8% at 3–5 years [ 27 ]. Our findings align with these international datasets, confirming that IMiD-based maintenance increases SPM risk. To reduce the use of IMiDs and improve outcomes for high-risk patients, in recent years, our centre has increasingly adopted VD (bortezomib and dexamethasone) maintenance therapy or daratumumab monotherapy for high-risk patients, while ultrahigh-risk patients have been switched to the KP (carfilzomib and pomalidomide) regimen for maintenance.
Our findings are consistent with several published datasets and population-based studies showing improved outcomes over time in patients with NDMM who underwent ASCT. Nevertheless, the results in certain subgroups, particularly those with HRCAs, remain suboptimal [ 29 – 34 ]. In our cohort, compared with standard-risk patients, patients with HRCAs experienced inferior outcomes, similar to the CIBMTR analysis, where high-risk disease was associated with shorter survival (3-year PFS 37% vs. 49% and OS 72% vs. 85%; p < 0.001) [ 35 ]. These results underscore the unmet need for refined risk stratification and novel therapeutic strategies for high-risk MM.
Importantly, we observed encouraging improvements in outcomes for patients with HRCAs in recent years. For example, the median PFS increased from 23.2 to 60.1 months, and the median OS increased from 35.6 months to not reached across cohorts. These gains parallel trends in other studies, where the median PFS improved from 13.7 months (2001–2005) to 36.8 months (2016–2021), and the DETERMINATION trial reported a median PFS of 55.5 months in high-risk patients undergoing ASCT [ 36 ]. In contrast, the IFM study revealed no improvement in OS among high-risk patients across different eras [ 37 ]. The superior outcomes in our cohort are likely attributable, at least in part, to the use of modern induction regimens and maintenance strategies, which were not consistently applied in earlier trials such as IFM.
Changes in stem cell mobilization techniques have also impacted survival in patients with HRCAs. Most patients in this study received high-dose cyclophosphamide (CTX) combined with G-CSF (and with plerixafor from 2021 onwards), which resulted in higher PB stem cell counts. Successful stem cell harvests can be achieved in the vast majority of patients with two ASCT procedures, increasing the proportion of patients eligible for tandem ASCT. Since 2018, planned tandem ASCT has been predominantly performed in patients with HRCAs at our centre. Interestingly, our study also revealed that, in the high-risk subgroup, the benefit of tandem ASCT over single ASCT was statistically significant (40.7 months vs. not reached). Similar to other studies, in the EMN02/HO95 study [ 38 ], for patients with HRCAs, the median PFS times were 46.0 months with double ASCT vs. 26.7 months with single ASCT ( p = 0.062). According to real-world data from Canada [ 8 ], tandem ASCT also significantly increased PFS in high-risk patients. The wider use of tandem ASCT in the latter cohort might have contributed to the increased PFS and OS observed in this study. However, the role of tandem ASCT in the context of modern induction therapy and maintenance needs further investigation.
In this study, we also verified several risk factors for NDMM. In the multivariable analysis, patients with low platelet counts, EME and secondary light chain amyloidosis were included. Furthermore, our previous and present studies indicate that both rapid and slow decreases in M protein levels [ 14 ] during induction therapy predict poor prognosis, which may be indicative of functional high-risk characteristics. Nevertheless, an unmet need was observed in the treatment of patients with myeloma with high-risk factors.
To our knowledge, our study is the largest investigation to date on the treatment and outcomes of an unselected cohort of MM patients who underwent upfront ASCT at a single centre in China. Our study has inherent limitations associated with its retrospective nature, including missing data due to variations in record keeping and data collection. The impact of missing cytogenetic/MRD data in early cohorts may have influenced HRCA analysis and survival estimates. The study population also exhibited significant heterogeneity, making it challenging to account for potential confounders. Additionally, our analysis was limited to patients who underwent upfront ASCT, and the findings may not apply to those who did not receive this treatment modality. Selection bias may have influenced which patients were offered ASCT, particularly tandem ASCT for high-risk patients. The small sample size of patients who received tandem ASCT limits the statistical power of our conclusions regarding this intervention. Nevertheless, this extensive analysis spanning 17 years provides valuable insights into evolving trends in the characteristics of patients with MM undergoing upfront ASCT and their outcomes. In summary, our analysis of more than 390 patients with NDMM who underwent upfront ASCT revealed significant improvements in response rates and survival rates across the three cohorts, including patients with high-risk disease, supporting its role as an effective treatment modality for eligible patients.
Supplementary Information
Additional file 1: Supplemental Figure 1. Increase in the number of patients with MM who underwent ASCT in each time cohort. Supplemental Figure 2. Stem cell doses stratified by mobilization regimen. Supplemental Table 1. Discovery of three M-protein decline patterns. Supplemental Table 2. Univariate and multivariate analyses of factors associated with PFS. Supplemental Table 3. Univariate and multivariate analyses of factors associated with OS.
Abbreviations
Autologous Stem Cell Transplantation
Multiple Myeloma
Progression-Free Survival
Overall Survival
Complete Response
Very Good Partial Response
Minimal Residual Disease
Extramedullary Extraosseous
High-Risk Cytogenetic Abnormalities
Fluorescence In Situ Hybridization
Revised International Staging System
Lactate Dehydrogenase
Granulocyte Colony-Stimulating Factor
Pegylated Granulocyte Colony-Stimulating Factor
Cyclophosphamide
Busulfan/Etoposide/Cyclophosphamide
Immunomodulatory Drug
Proteasome Inhibitor
Monoclonal Antibody
Interferon
Hepatitis B Surface Antibody
Monoclonal Protein
Second Primary Malignancy
Publisher’s Note
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Change history
2/7/2026
The original article has been updated: Figure 4 has been revised.
Change history
2/6/2026
A Correction to this paper has been published: 10.1186/s12885-026-15681-4
Acknowledgements
We would like to express our sincere gratitude to the patients who participated in this study, as well as the medical and research staff at The First Affiliated Hospital of Sun Yat-sen University, for their invaluable assistance in data collection and patient management.
Authors’ contributions
LJ and LXZ designed the study and performed the experiments; CML, LJR, GJL, HBH and KLF collected the data and analysed the data; and LXZ wrote the manuscript.
Funding
This study was supported by the National Natural Science Foundation Youth Science Foundation (No. 82200221) and the National Natural Science Foundation (No. 82470197 and No. 82270209).
Data availability
The datasets analysed in the current study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University. Informed consent was obtained from all participants or their legal guardians before inclusion in the study.
Consent for publication
All the authors consent to the publication of this manuscript in its current form. Consent for publication was obtained from all patients or legal guardians included in the study.
Competing interests
The authors declare no competing interests.
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