Abstract
Background/Aim
Allogeneic (allo-) hematopoietic cell transplantation (HCT) may confer a survival advantage in a selected population of patients with relapsed and refractory multiple myeloma (R/R MM), however, additional data are needed to identify the patients who will benefit the most.
Patients and Methods
Between January 2000 and December 2024, 32 patients with R/R MM underwent allo-HCT at the Asan Medical Center, Seoul, Korea, and were included in this retrospective study.
Results
Before allo-HCT, complete remission (CR) achievement tended to be associated with better overall survival (OS) compared to partial response and refractory status (67.7% vs. 31.7% and 16.7% at 5 years, respectively, p=0.079). The OS rate was significantly higher in patients who underwent prior autologous (auto-) HCT compared to upfront allo-HCT (47.3% vs. 0% at 5 years, p=0.016). In multivariate analysis, upfront allo-HCT without previous auto-HCT was a significant adverse factor for OS [hazard ratio (HR)=6.248, 95% confidence interval (CI)=1.541-25.330, p=0.010]. In addition, the number of chemotherapy (≥3) before allo-HCT was a significantly independent adverse factor for OS (HR=2.854; 95%CI=1.071-7.602; p=0.035).
Conclusion
In R/R MM after auto-HCT, allo-HCT for patients who attained CR following less than three lines of chemotherapy can still be a promising treatment option with long-term survival.
Keywords: Multiple myeloma, hematopoietic stem cell transplantation, cumulative incidence of relapse, overall survival
Introduction
Multiple myeloma (MM) is the third most common hematologic malignancy, with over 1,900 cases diagnosed annually in South Korea (1). and the second most common hematologic malignancy, with over 35,000 cases diagnosed annually in the United States (2). MM still remains mostly incurable clonal plasma cell disorder characterized by the presence of monoclonal proteins that cause anemia, osteolytic bone disease, and renal failure, despite three key therapeutic classes: immunomodulatory imide drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs). Recently, for patients with relapsed and refractory MM (R/R MM), several trials with chimeric antigen receptor T-cell (CAR-T) therapies (3, 4) and bispecific antibodies (5, 6) have demonstrated the benefit of overall survival (OS). In addition, emerging therapies including antibody drug conjugate (ADC) targeting B-cell maturation antigen (BCMA) had shown promise in combination regimens among patients with R/R MM (7).
Nevertheless, for many patients, both CAR-T therapies and bispecific antibodies may be unsuitable because of financial limitations or insurance reimbursement issues in South Korea. Alternatively, allogeneic (allo-) hematopoietic cell transplantation (HCT) may confer a survival advantage in a selected population of MM patients with recurrence after heavy pre-treatments and/or refractory disease (8, 9). However, additional data are needed to identify the patients who will benefit the most. To improve outcomes of allo-HCT in patients with R/R MM, it is important to identify specific factors that can predict post-transplant outcomes, to select appropriate candidates for allo-HCT and adopt treatment strategies to reduce relapse and recurrence. Recently, treatment-related mortality (TRM) and the incidence of graft-versus-host disease (GVHD) have been decreasing through better supportive treatment, and GVHD prevention strategies (10). Therefore, the present study aimed to investigate post-transplant outcomes and prognostic factors for allo-HCT in patients with R/R MM.
Patients and Methods
Source of data.Between January 2000 and December 2024, 32 patients with R/R MM underwent allo-HCT at the Asan Medical Center (AMC), Seoul, Korea, and were included in this retrospective study. This retrospective analysis was approved by the Institutional Review Board (IRB) of the AMC (2025-0571). As a retrospective research, the consent of the study subjects was waived. Data collection was completed in June of 2025.
Patients and treatment.Data were collected from AMC’s HCT registry on relevant prognostic variables, patient characteristics, and treatments received. As a salvage therapy, the allo-HCT option was provided in high-risk R/R MM, if a donor for allo-HCT was available, and the patient had a generally good condition. At physician’s discretion, patients received either low-intensity conditioning (RIC) or myeloablative conditioning (MAC) therapy in accordance with the definition of international workshop criteria (11). The conditioning regimens included Bu/Flu (busulfan 3.2 mg/kg/dose intravenously for two days plus fludarabine 30 mg/m2/day intravenously for six days), and Flu/Mel (fludarabine 30 mg/m2/day intravenously for five days plus melphalan 100 mg/m2 intravenously for one day). Antithymocyte globulin (ATG) 3.0 mg/kg intravenously over six h daily on day -3 to -1. The inclusion of ATG at conditioning regimen is determined according to the GVHD risk, donor type, HLA concordance, patient’s overall condition, and physician’s determination. Granulocyte colony-stimulating factor (GCSF) (450 mcg) was administered from day five to neutrophil recovery. Cyclosporine with or without short-course methotrexate (MTX) or tacrolimus plus MTX was used for GVHD prophylaxis. Infection prevention was administered using a common protocol under the standard policy of AMC.
End-points and definitions.Bone marrow engraftment was defined as absolute neutrophil levels of at least 500/μl for the first three consecutive days. Complete remission (CR) was defined as negative immunofixation in the serum and urine as well as the loss of any soft tissue plasmacytomas and <5% plasma cells in bone marrow (12). Partial response (PR) was defined as a 50% reduction in serum M-protein and a 90% or more reduction in 24 h urinary M-protein or if plasmacytomas were present at baseline, a more than 50% reduction in the size of those lesions was also required. Progressive disease (PD) was defined as a 25% or more increase from the lowest response value in any one or more of the following: 1) serum M-component and/or (the absolute increase must be greater than 0.5 g/dl), 2) urine M-component and/or (the absolute increase must be greater than 200 mg/24 h), 3) only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved free light chain (FLC) levels. The absolute increase must be at least 10 mg/dl, 4) bone marrow plasma cell percentage; the absolute percentage must be >10%, 5) clear occurrence of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas, 6) occurrence of hypercalcemia (corrected serum calcium >11.5 mg/dl). Overall survival (OS) was defined as the time from the date of allo-HCT to the date of death or the last follow up. Event-free survival (EFS) was defined as the time from the date of allo-HCT to the date of relapse or MM progression or death from any cause.
Statistical analysis.Survival curves for OS and EFS were estimated using the Kaplan-Meier method and compared using a log-rank test to access differences between groups. Univariate and multivariate analyses for OS and EFS were conducted using the log-rank test and the Cox proportional hazards model, respectively. Variables with a p-value <0.1 in the univariate analyses were included in the multivariate analyses. Statistical analyses were performed with SPSS version 22.0 software (IBM Corp., Armonk, NY, USA). The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) following HCT was calculated using R statistical software (version 4.1.3), with cumulative incidence estimates adjusted for competing risks. Gray’s test was used to assess differences between groups according to CIR and NRM. All reported p-values are two-sided, and p-value of <0.05 were considered statistically significant.
Results
Patient characteristics.The clinical characteristics of the 32 patients with R/R MM who underwent allo-HCT are summarized in Table I. The cohort consisted of 20 male (62.5%) and 12 female (37.5%) patients. The median age at allo-HCT was 54 years (range=29-65 years), with 20 patients (62.5%) aged ≥50 years. According to the international staging system (ISS), 10 patients (31.2%) were Stage 1, 11 (34.4%) were Stage 2, and 11 (34.4%) were Stage 3. The minority of patients (12.5%) had a Karnofsky score ≤70. Cytogenetic risk analysis, available for 27 patients, showed 16 (59.0%) with standard risk and 25 (78.1%) with high risk.
Table I. Clinical characteristics of patients with relapsed multiple myeloma who received allogeneic hematopoietic cell transplantation.
aAt the time of diagnosis of relapse multiple myeloma. ISS: International staging system; BMI: body mass index; Ig: immunoglobulin; HCT: hematopoietic stem cell transplantation; FluMel: fludarabine and melphalan; BuFlu: busulfan and fludarabine; ATG: anti-thymocyte globulin; MAC: myeloablative conditioning; RIC: reduced intensity conditioning; TNC: Total nucleated cells; MTX: methotrexate.
Regarding prior treatments, 28 patients (87.5%) had undergone at least one prior autologous (auto-) HCT. The median time from diagnosis to allo-HCT was 3.3 years (range=0.5-15.0 years). For those with prior auto-HCT (n=27), the median time from auto-HCT to allo-HCT was 3.5 years (range=0.7-14.9 years). At the time of allo-HCT, 14 patients (43.8%) were in complete response (CR), 13 (40.6%) were in partial response (PR), and five (15.6%) were refractory. The median number of prior chemotherapy lines before allo-HCT was two (range=1-5), with 19 patients (59.3%) receiving 1-2 lines and 13 patients (40.7%) receiving 3-5 lines.
A total of 32 patients were treated with non-total body irradiation-based conditioning regimens: Flu/Mel in 68.8% and Bu/Flu in 31.2%. Seventeen patients (53.1%) received allo-HCT from matched sibling donors, 34.3% from matched unrelated donors, and 12.5% from haploidentical family donors. In vivo T cell depletion was performed in 17 patients (53.1%) with ATG. The majority of patients (90.6%) received reduced intensity conditioning (RIC). All grafts were from peripheral blood stem cells. The median total nucleated cell (TNC) dose was 12.2×108/kg, and the median CD34+ cell dose was 7.6×106/kg. GVHD prophylaxis included cyclosporine plus methotrexate (MTX) in 26 patients (81.2%), cyclosporine alone in five patients (15.6%) and tacrolimus plus MTX in one patient.
Post-allo-HCT outcomes.With a median follow-up of 80.5 months for surviving patients, the median OS was 42.9 months, and the median EFS was 12.0 months (Figure 1A and B). The 5-year probability of OS and EFS rates were 43.0% and 31.1%, respectively. Figure 1C and D illustrates the cumulative incidence of NRM and CIR. The cumulative incidence of NRM remained low, with approximately 10% at five years. There were three NRMs, and the patients died of infection, acute pancreatitis, and accidental death, respectively.
Figure 1.
Post-allogeneic (allo-) hematopoietic cell transplantation (HCT) outcomes of patients with relapsed/refractory (R/R) multiple myeloma (MM). (A) Overall survival of patients with R/R MM after allo-HCT; (B) Event-free survival of patients with R/R MM after allo-HCT; (C) Cumulative incidence of non-relapse mortality of patients with R/R MM after allo-HCT; (D) Cumulative incidence of relapse of patients with R/R MM after allo-HCT.
The CIR showed a steady increase, reaching approximately 60% by 40 months after allo-HCT. Post-transplant response significantly influenced the cumulative incidence of relapse; patients achieving CR post-transplant had a lower incidence of relapse compared to those with non-CR (p=0.001).
Univariate analysis. Univariate analysis based on various clinical factors was summarized in Table II. Figure 2A-F illustrates the survival probabilities based on various clinical factors. Patients without prior auto-HCT showed significantly worse OS compared to those with a history of previous auto-HCT (0% vs. 47.3% at 5 years, p=0.016) (Figure 2A). Patients without prior auto-HCT showed no difference in EFS compared to those with a history of previous auto-HCT (p=0.252) (Figure 2B). The number of chemotherapy lines (<3) before allo-HCT demonstrated a tendency towards better OS (53.2% vs. 28.8% at five years, p=0.059) and EFS (43.1% vs. 15.4% at five years, p=0.064) compared to those receiving three or more lines of chemotherapy (Figure 2C and D). Additionally, even though the statistical difference was not significant, the CR achievement before allo-HCT tends to be associated with better OS compared to PR and refractory status (67.7% vs. 31.7% and 16.7% at five years, respectively, p=0.079). Post-transplant response was a significant prognostic factor for OS; patients who achieved CR post-transplant had significantly better OS compared to those with non-CR (p=0.009) (Figure 2E), whereas patients who achieved CR post-transplant had significantly better EFS compared to those with non-CR (p=0.020) (Figure 2F). Post-transplant response significantly influenced the CIR; patients achieving CR post-transplant had a lower CIR compared to those with non-CR (48.3% vs. 88.8% at 5 years, p=0.001). There was no difference in the transplant outcomes between ABO incompatibility and ABO compatibility in this study. There was also no difference in the OS (p=0.334), EFS (p=0.879), CIR (p=0.618) between matched donor and haploidentical familial donor in this study. The patients who received from haploidentical family donor had a higher NRM compared to those who received from matched donor (50.0% vs. 5.8% at five years, p=0.014). The CR achievement before allo-HCT tends to be associated with better OS compared to PR and refractory status (67.7% vs. 31.7% and 16.7% at five years, respectively, p=0.079). The CD34+ cell dose also impacted EFS; patients receiving a CD34+ dose of ≥10×106/kg demonstrated a tendency towards better EFS than those receiving <10×106/kg (p=0.084).
Table II. Univariate analysis of non-relapse mortality (NRM), cumulative incidence of relapse (CIR), event-free survival (EFS) and overall survival (OS) for post-transplant outcomes.
Auto-HCT: Autologous hematopoietic stem cell transplantation; allo-HCT: allogeneic hematopoietic stem cell transplantation; CR: complete remission; PR: partial response; BMI: body mass index; CTx: chemotherapy; GVHD: graft versus host disease; HCT: hematopoietic stem cell transplantation; Flu/Mel: fludarabine and melphalan; Bu/Flu: busulfan and fludarabine; ATG: anti-thymocyte globulin; MAC: myeloablative conditioning; RIC: reduced intensity conditioning.
Figure 2.
Survival probabilities based on various clinical factors. (A) Overall survival according to previous auto-HCT; (B) Event-free survival according to previous auto-HCT previous line of chemotherapy; (C) Overall survival according to previous line of chemotherapy; (D) Event-free survival according to previous line of chemotherapy; (E) Overall survival according to posttransplant response; (F) event-free survival according to posttransplant response.
Multivariate analysis.Multivariate analysis presented in Table III identified several independent prognostic factors. For CIR, post-transplant non-CR was a significant risk factor [hazard ratio (HR)=4.222, 95% confidence interval (CI)=1.976-9.018, p<0.001] and three or more lines of chemotherapy before allo-HCT (HR=2.701, 95%CI=1.072-6.809, p=0.035) were associated with worse outcomes. For EFS, post-transplant non-CR was a significant risk factor (HR=3.230, 95%CI=1.304-8.004, p=0.011) were associated with worse outcomes. Upfront allo-HCT without previous auto-HCT was a significant adverse factor for OS (HR=6.248, 95%CI=1.541-25.330, p=0.010), and three or more lines of chemotherapy before allo-HCT (HR=2.854, 95%CI=1.071-7.602, p=0.035) was significant adverse prognostic factor for OS.
Table III. Multivariate analysis cumulative incidence of relapse (CIR), event-free survival (EFS) and overall survival (OS) for post-transplant outcomes.
Auto-HCT: Autologous hematopoietic stem cell transplantation; CR: complete remission; PR: partial response; CTx: chemotherapy.
Long-term survivors.The characteristics of patients who achieved long-term survival are shown in Table IV. A 60-year-old man survived 9 years after allo-HCT despite a relapse, with treatment including ixazomib, lenalidomide, and dexamethasone (IRD) and radiotherapy after allo-HCT. A 59-year-old woman relapsed 1.7 months after allo-HCT but later showed a 5-year survival with subsequent chemotherapies including KRD (carfilzomib + lenalidomide + dexamethasone), daratumumab, and pom/dex (pomalidomide + dexamethasone). A 60-year-old female patient achieved 149.5 months of EFS without relapse. These cases highlight the potential for extended survival in select patients.
Table IV. Characteristics of patients who achieved long-term survival.
RTx: Radiotherapy; Auto-HCT: autologous hematopoietic cell transplantation; PAD: bortezomib + doxorubicin + dexamethasone; VAD: vincristine + doxorubicin + dexamethasone; MPT: melphalan + prednisone + thalidomide; HD: high dose dexamethasone; Flu: fludarabine; Mel: melphalan; ATG: anti-thymocyte globulin; IRD: ixazomib + lenalidomide + dexamethasone; TD: thalidomide + dexamethasone; KRD: carfilzomib + lenalidomide + dexamethasone; KD: carfilzomib + dexamethasone; Pom/dexa: pomalidomide + dexamethasone; Bu: busulfan; VD: bortezomib + dexamethasone.
Discussion
The present study reports the long-term outcomes of patients with R/R MM who received allo-HCT following multiple relapses or primary refractoriness. Compared to Caucasian patients with MM, we demonstrated favorable outcomes of allo-HCT in patients with R/R MM (13). In R/R MM patients, patients who undergo auto-HCT show good OS after allo-HCT. Patients who obtained CR before allo-HCT tended to have higher OS (there is no statistical significance in this study). As expected, achievement of CR after allo-HCT was associated with superior OS post allo-HCT. This is consistent with a previous study reporting the predictive role of CR in both progression-free survival (PFS) and OS (14). Patients receiving less than three lines of chemotherapy before allo-HCT showed superior OS and lower relapse rate, compared to the heavily treated patients (≥3 lines of chemotherapy). In a previous single-center study by Chhabra et al., lines of therapy pre-alloHCT (1 to 2 versus >2) were not associated with improved OS, and the occurrence of acute GVHD before relapse significantly affected post relapse survival (15). The reason for this difference is thought to be the effect of analyzing only those who recurred after allo-HCT in the previous study.
According to a previous study by Richardson et al. about the role of auto-HCT in triplet therapy [bortezomib, lenalidomide and dexamethasone (VRD)] for newly diagnosed patients with MM, VRD plus auto-HCT was associated with longer PFS than VRD alone despite no OS benefit (16). Given that there were four patients who did not receive auto-HCT before allo-HCT, the reasons for undergoing up-front allo-HCT were primary refractory disease in three patients and failure of stem cell collection in one patient. First, in a 44-year-old woman who was treated with two cycles of VTD induction, primary refractoriness was confirmed. The disease of a 29-year-old man was primary refractory after melphalan + prednisone (MP) for two cycles and vincristine + doxorubicin + dexamethasone (VAD) for four cycles. A 52-year-old man had progressive disease after MP and VAD. A 57-year-old man received up-front allo-HCT after induction chemotherapy with bortezomib, thalidomide, and dexamethasone (VTD) due to failure of autologous stem cell collection.
Systemic total body irradiation (TBI) has widely used as an essential component of conditioning therapy in allo-HCT for many years and, higher doses of TBI can reduce disease recurrence while risking more severe toxicity (17). In a previous study, the median OS from allo-HCT was 28.8 months (95%CI=8.0–49.5) in relapsed patients with MM who had submyeloablative conditioning regimen with TBI (18). In this study, it was shown that median OS using conditioning regimens without TBI was superior to that with TBI, given that the treatment of MM had been reformed with new treatments in recent years. In our study, non-TBI conditioning regimens consisted of Flu/Mel or Bu/Flu, with 68.8% of patients receiving Flu/Mel and 53.1% receiving ATG. Although there were no statistically significant differences in OS or EFS between the Flu/Mel and Bu/Flu groups, Flu/Mel tended to show more favorable outcomes. These findings support the use of Flu/Mel as a preferred conditioning regimen for allo-HCT in patients with R/R MM. Moreover, when comparing RIC with MAC, there were no notable differences in relapse rate, OS, or EFS. Given the advanced age and high comorbidity burden often seen in MM patients undergoing allo-HCT, RIC may be a more appropriate and safer approach in this population.
In the IFM99-03 trial, patients received dose-reduced conditioning consisting of busulphan 2 mg/kg daily administrated orally over two days, fludarabine 25 mg/m2 daily for five days, and ATG 2.5 mg/kg daily on days –5, –4, –3, –2, and –1, followed by allo-HCT on day 0 (19). However, allo-RIC conditioned with fludarabine 25 mg/m2 for five days and melphalan 70 mg/m2 for two days was introduced in the prospective PETHEMA study (20). Although there are few studies of allo-HCT in patients with MM comparing BuFlu versus FluMel (21), in this study, the group who had conditioning with Bu/Flu tended to have higher recurrence rate. There was no difference in the post-transplant survival outcomes when the haploidentical family donor was compared to the matched donor in this study. It was found that any donor was not an obstacle to transplantation, given that haploidentical cell transplantation is feasible for patients without a matched donor. Given that the autologous and conventional chemotherapy arms do not demonstrate a plateau (22), it is worthy that the allogenic curve was flat at 38.2% in this study.
Study limitations. First, the MM FISH test is a molecular genetic test that helps predict the prognosis of patients with MM and establish a treatment plan, but the FISH test is not included in this study. Second, due to the retrospective nature of study and small number of patients included, the statistical significance was not obtained in NRM multivariate analysis, given that only three patients had NRM after allo-HCT. However, we showed relatively favorable survival outcomes with a long-term follow-up duration after allo-HCT at a single center.
In conclusion, in R/R MM after auto-HCT, allo-HCT for patients who attained CR following less than three lines of chemotherapy can still be promising treatment option with long-term survival. However, for patients with aggressive primary refractory MM or those with heavily treated (≥3rd line of chemotherapy) R/R MM, allo-HCT is discouraging, and novel therapies are recommended.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
Authors’ Contributions
All Authors contributed to the study’s conceptualization or design, or to the acquisition, analysis, or interpretation of data, and/or participated in drafting or critically revising the manuscript, and each has approved the final version.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
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