Historical Perspective of Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

Introduction

Multiple myeloma (MM) is a plasma cell neoplasm that typically harbors diverse genetic alterations. Large-scale genomic analyses have shown that the most commonly involved genetic locus in MM is the IgH (immunoglobulin heavy chain) enhancer promoter [ 1 ]. IgH translocations lead to dysregulated transcription of several oncogenes, such as FGFR3 , MMSET , CCND1 , MAF , or MAFB . Additionally, MM is characterized by several genomic deletions, gains, and point mutations [ 2 ]. As MM progresses from its precursor state, monoclonal gammopathy of undetermined significance, to symptomatic disease, these genetic lesions and epigenetic aberrancies tend to accumulate [ 3 ]. Beyond the intrinsic genetic and epigenetic changes, external factors such as abnormalities in the bone marrow microenvironment and compromised host immunity also facilitate MM progression [ 3 ].

Modern therapies have capitalized on intricate aspects of disease biology, leading to unprecedented extensions in survival. These therapeutic advancements encompass a range of strategies, including molecules targeting specific myeloma-related pathways, such as cereblon-binding agents (thalidomide, lenalidomide, pomalidomide, iberdomide, and mezigdomide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), and the nuclear export protein XPO1 inhibitor (selinexor). Furthermore, the advent of monoclonal antibodies (daratumumab, isatuximab, elotuzumab), CAR T-cell therapies targeting myeloma cell-surface antigens (ciltacabtagene autoleucel, idacabtagene vicleucel), and T-cell-engaging bispecific antibodies (teclistamab, talquetamab, and elranatamab) has revolutionized the treatment landscape, offering patients new hope in the battle against this formidable disease [ 3 ]. Despite these advances, MM patients invariably face relapses and after the failure of CAR-T cells and T-cell engager antibodies, the prognosis remains dismal. Allogeneic hematopoietic stem cell transplantation (allo-SCT) has historically been viewed as a potentially curative option for hematological disorders including MM. However, the reality remains sobering: most MM patients were not cured by allo-SCT and many experienced transplant-related (TR) morbidity, mortality, and relapses, highlighting the need for continued innovation and more effective strategies in the treatment of this challenging disease [ 4 , 5 ]. In this review, we critically examined the existing data on allo-SCT for MM with a particular focus on techniques, safety, efficacy, toxicity data, and role of allo-SCT in the contemporary myeloma treatment landscape, highlighting its potential applications and challenges in an era of rapidly advancing treatment modalities.

Methodology

In this review, we used a comprehensive strategy for literature research on databases, including PubMed and Google Scholar. We utilized a combination of keywords related to allogeneic stem cell transplant and MM. The search was limited to articles dated back to the year 2000. We then performed secondary research by reviewing the reference list of selected articles to identify additional relevant studies. With our inclusion restricted to allo-SCT and MM, we focused on cohort studies, clinical trials, peer-reviewed articles, and systematic reviews published in English. This article extracted and summarized data to enable an organized and focused presentation of current and previous knowledge on allo-SCT in MM. In addition, we also provided insight into ongoing trials and future directions, including CAR-T therapy utilization.

Overview of Prospective Trials Using Allo-SCT in MM

In 2002, Kröger et al. [ 6 ] evaluated the efficacy and safety of a tandem transplantation approach consisting of autologous stem cell transplantation (auto-SCT) followed by dose-reduced allo-SCT in 17 patients with advanced stage II/III MM. The study reported a complete recovery (CR) rate that increased from 18% after autologous transplantation to 73% following allogeneic transplantation. The 2-year overall survival (OS) was estimated at 74% and the disease-free survival (DFS) at 56%. Acute graft-versus-host disease (GvHD) occurred in 38% of patients, with chronic GvHD developing in 40%. The 100-day treatment-related mortality (TRM) was 11%. At the time, these results suggested that this tandem transplant protocol is highly effective in achieving reliable remission with manageable toxicity, particularly in patients with advanced disease.

In 2007, Bruno et al. [ 7 ] conducted a randomized study comparing outcomes between 80 newly diagnosed MM (NDMM) patients who underwent a combination of auto-SCT followed by allo-SCT from an HLA-identical sibling and 82 patients who received tandem auto-SCT. After a median follow-up of 45 months, the group that received the auto-SCT followed by allo-SCT had a significantly longer median OS of 80 months compared to 54 months in the tandem auto-SCT group ( p = 0.01). Event-free survival (EFS) was also superior in the auto-/allo-SCT group at 35 months versus 29 months in the tandem autologous group ( p = 0.02). The study reported a TRM of 10% in the auto-/allo-SCT group. Additionally, the CR rate was higher in the auto-/allo-SCT group at 55% compared to 26% in the tandem auto-SCT group ( p = 0.004). These findings indicated that, for patients with an HLA-identical sibling, the auto-/allo-SCT protocol offers significant survival advantages over tandem auto-SCT, particularly in achieving long-term remission.

Around the same time, Garban et al. [ 8 ] compared the outcomes of 65 high-risk (HR) MM patients undergoing auto-SCT followed by a dose-reduced-intensity conditioning (RIC) allo-SCT (IFM99-03) with 219 patients receiving tandem auto-SCT (IFM99-04). The median OS was 35 months for the auto-SCT/allo-SCT group and 41 months for the tandem auto-/auto-SCT group ( p = 0.27). EFS was 25 months versus 30 months, respectively ( p = 0.56). Although the 100-day TRM in the allogeneic arm was 10.9%, the high relapse rate offset the potential benefits, indicating no significant survival advantage over tandem auto-/auto-SCT. Moreau et al. [ 9 ] presented long-term follow-up results from the IFM99-03 and IFM99-04 trials, comparing tandem auto-/auto-SCT with auto-SCT followed by RIC allogeneic transplantation in 284 HR MM patients. With a median follow-up of 56 months, the study found no significant difference in EFS between the two groups (22 months for tandem auto-/auto-SCT vs. 19 months for auto-SCT/allo-RIC, p = 0.58). There was a trend toward better OS in the tandem auto-/auto-SCT group (48 months vs. 34 months, p = 0.07), suggesting tandem auto-/auto-SCT may offer a survival advantage in this HR population.

Phase III Evidence

Rosinol et al. [ 10 ] compared tandem auto-/auto-SCT with auto-SCT followed by RIC allogeneic transplantation in 110 MM patients. The CR rate was higher in the allo-RIC group (40% vs. 11%, p < 0.001), but this was associated with a trend toward higher TRM (16% vs. 5%, p = 0.07). There were no significant differences in OS or EFS between the groups. Krishnan et al. [ 11 ] conducted a phase III trial (BMT CTN 0102) comparing tandem auto-/auto-SCT with autologous followed by non-myeloablative (NMA) allo-SCT in patients with standard-risk (SR) MM. The study enrolled 710 patients, with 226 assigned to the auto-allo group and 484 to the auto-auto group. After a median follow-up of 40 months, the 3-year PFS was 43% for the auto-allo group and 46% for the auto-auto group ( p = 0.671). The 3-year OS was 77% for the auto-allo group and 80% for the auto-auto group ( p = 0.191). TRM at 3 years was higher in the auto-allo group (11% vs. 4% in the auto-auto group, p < 0.0001). These phase III trial results indicated that NMA allo-SCT does not offer a significant advantage over tandem auto-/auto-SCT in terms of PFS or OS, with a higher risk of TRM in the allo-SCT group.

Giralt et al. [ 12 ] presented the long-term follow-up results of the BMT CTN 0102 trial, which compared tandem auto-/auto-SCT with autologous followed by RIC allogeneic transplantation (auto-/allo-SCT) in 710 MM patients. After a median follow-up of over 10 years, the study found no significant difference in 6-year PFS between the auto-/auto-SCT (25%) and auto-/allo-SCT (22%) groups ( p = 0.32) for SR patients. The 6-year OS was also similar at 60% for auto-auto-SCT and 59% for auto-/allo-SCT ( p = 0.85). In the HR group, there was a trend toward improved PFS with auto-allo-SCT (31% vs. 13% at 6 years, p = 0.05), but OS remained similar. Nonrelapse mortality (NRM) was higher in the auto-/allo-SCT group, especially in HR patients.

In a 2011 study by Björkstrand et al. [ 13 ], 357 untreated MM patients were randomized to receive either auto-SCT followed by RIC-allo-SCT or auto-SCT alone. At 60 months, the auto-/allo-SCT group demonstrated superior outcomes with a PFS of 35% versus 18% in the auto-SCT-only group ( p = 0.001) and an OS of 65% compared to 58% ( p = 0.047). The CR rate was higher in the auto-/allo-SCT group (51% vs. 41%, p = 0.020), though a higher NRM offset this in the auto-/allo-SCT group (12% vs. 3%, p = 0.001). Gahrton et al. [ 14 ] conducted a long-term follow-up study comparing tandem auto-SCT followed by RIC-allo-SCT with auto-SCT alone in 357 MM patients. At a median follow-up of 96 months, PFS was significantly better in the auto-/RIC-allo-SCT group (22% vs. 12%, p = 0.027), with OS also superior (49% vs. 36%, p = 0.030). The relapse rate was lower in the auto-/RIC-allo-SCT group (60% vs. 82%, p = 0.0002), though NRM was higher (13% vs. 3%, p = 0.0004). This study demonstrates the long-term benefits of the auto-/RIC-allo-SCT approach, particularly in reducing relapse rates, though at the cost of higher NRM.

Lokhorst et al. [ 15 ] conducted a donor versus no-donor analysis within the HOVON-50 study, which included 260 MM patients. The study compared outcomes between those with an HLA-identical sibling donor (122 patients) and those without (138 patients) after auto-SCT. The 6-year PFS was 28% for patients with a donor versus 22% for those without ( p = 0.19), and OS was identical at 55% for both groups ( p = 0.68). The study found a higher cumulative incidence of NRM at 6 years in the donor group (16% vs. 3%, p < 0.001), with a significant reduction in relapse incidence for the donor group (55% vs. 77%, p = 0.005). Despite these differences, the improved PFS did not translate into a significant OS benefit, suggesting that allogeneic transplantation may not provide a clear survival advantage as part of first-line therapy.

In 2015, Ahmad et al. [ 16 ] reported the outcomes of 92 NDMM patients who underwent a tandem approach with autologous and NMA allo-SCT. After a median follow-up of 8.8 years, the study found a 10-year OS of 62% and a PFS of 41%. The cumulative incidence of NRM was notably low at 10%, while 79% of patients developed extensive chronic GvHD, which was associated with improved PFS (HR: 0.27, p = 0.029). However, achieving at least partial response before allo-SCT was a significant factor for both better OS (HR: 0.36, p = 0.018) and reduced progression risk (HR: 0.13, p < 0.01). These findings suggest that a tandem autologous/NMA allo-SCT approach can provide long-term survival benefits with manageable toxicity in MM patients.

Role of Maintenance Therapy after Auto-Allo-SCT

In 2017, Green et al. [ 17 ] conducted a prospective phase II trial evaluating tandem auto-/allo-SCT followed by bortezomib maintenance therapy in 31 patients with HR MM. Among 24 newly diagnosed patients, the 2-year and 4-year PFS rates were 71% and 52%, while the OS rates were 75% and 61%, respectively. In contrast, the 7 patients who had relapsed or persistent disease showed markedly worse outcomes, with 2-year and 4-year PFS of 14% and OS rates of 43% and 29%. The study highlighted that bortezomib maintenance therapy post-transplant may offer significant benefits in newly diagnosed HR MM patients, but its efficacy is limited in patients with relapsed or refractory disease. The cumulative incidence of chronic GvHD at 2 years was 35%, and NRM was 8% in newly diagnosed patients and 14% in those with prior treatment failures.

These studies were performed before the availability of pomalidomide, CD38 antibodies, carfilzomib, and T-cell-based therapies. All studies demonstrated long-term marginal survival in a subset of patients, with OS and PFS rates of 44% and 19% at 10 years, respectively, according to a combined analysis of four prospective trials [ 18 ]. This analysis showed that long-term OS was notably better in the allo-SCT group [ 18 ]. Despite this, the rate of GvHD was high and TRM remained significant, at 20% after 10 years [ 18 ]. Some trials exhibiting improved PFS with similar OS suggest that the higher TRM may offset the advantages of a reduced relapse rate achieved with allo-SCT [ 12 ]. Summary of prospective trials on allo-SCT in MM is given in Table 1 .

Overview of Retrospective Trials on Allo-SCT in MM

In 2020, LeBlanc et al. [ 19 ] conducted a retrospective study comparing the outcomes of 92 NDMM patients who underwent tandem auto-/allo-SCT with 81 patients who received only autologous SCT. The study found that, after a median follow-up of 13.1 years, the 10-year OS was significantly higher in the tandem group at 61% compared to 37% in the autologous-only group ( p ≤ 0.001). PFS at 10 years was also better in the auto-/allo-SCT tandem group at 41% compared to 21% in the autologous-only group ( p ≤ 0.001). The cumulative incidence of chronic GvHD was high in the tandem group at 83%, which correlated with a significant improvement in PFS (55% vs. 10%, p = 0.002) but had a modest impact on OS (60% vs. 49%, p = 0.550).

Franssen et al. [ 20 ] examined the long-term outcomes of allo-SCT in 147 MM patients, comparing those who underwent the procedure as part of their first-line treatment versus those in the relapsed/refractory (R/R) setting. The study found that patients receiving allo-SCT upfront had a 10-year OS rate of 51% and a median PFS of 30.2 months. In contrast, patients treated in the R/R setting had significantly poorer outcomes, with a median OS of 28.7 months and a median PFS of 8.0 months. The study highlighted the inferior prognosis for patients who relapsed within 18 months after autologous SCT, emphasizing the need for improved treatment strategies in this high-risk group.

In a study involving 155 MM patients, Rasche et al. [ 21 ] assessed the impact of donor chimerism, extramedullary disease (EMD), and HR cytogenetics following allo-SCT. The median PFS was 14 months, and the OS was 53 months, with a 100-day TR mortality rate of 16%. Notably, 44 patients (28%) experienced a drop in donor chimerism, which was associated with a higher risk of relapse; however, this drop did not significantly impact OS. Patients with EMD had a markedly poor prognosis, with a median PFS of only 3 months and OS of 8 months. Interestingly, HR cytogenetic abnormalities, such as del(17p) and t (4; 14), did not significantly affect survival outcomes, with median OS in this group reaching 61 months. The study suggests that while loss of full chimerism may predict relapse, its role in guiding post-transplant interventions is limited, particularly when EMD is present.

In 2016, a retrospective analysis of 77 MM patients who underwent allo-SCT, Dhakal et al. [ 22 ] assessed the impact of HR cytogenetics, disease status at transplant, and post-transplant minimal residual disease (MRD) on patient outcomes. The study population included 69 patients with matched sibling donors (MSD) and 8 with matched unrelated donors (MUDs), with 86% receiving NMA or reduced-intensity conditioning regimens. At a median follow-up of 50 months, the 3-year PFS was 47%, and OS was 63.8%. Patients with HR cytogenetics had similar outcomes to those with SR, with no significant difference in 3-year PFS (39% vs. 55%, p = 0.62) or OS (50% vs. 67%, p = 0.10). On multivariate analysis, older age (HR: 1.05, p = 0.04), lack of CR at allo-SCT (HR: 4.3, p = 0.006), and CMV reactivation (HR: 3.2, p = 0.002) were significantly associated with worse OS. Notably, the study found no difference in survival between patients who achieved MRD-negative status post-transplant and those who did not, suggesting that achieving morphological CR was a more critical factor than MRD status.

In 2015, Schneidawind et al. [ 23 ] analyzed the outcomes of 41 patients with relapsed or refractory MM who underwent allo-SCT at a single institution. The study reported a 3-year OS of 51% and an EFS of 15%, with a 20% NRM adjusted for relapse as a competing risk. Notably, patients who received allografts after a single autologous transplant had a significantly better 3-year EFS (24% vs. 6%, p = 0.04) and OS (64% vs. 35%, p = 0.09) compared to those who underwent tandem autologous transplants before allografting. Furthermore, administering IMiDs or proteasome inhibitors following relapse improved median OS from 6 months to 33 months (1-year OS: 79% vs. 29%, p = 0.001). These findings highlight the potential benefits of incorporating novel agents in post-relapse treatment, although the role of tandem autologous transplants remains controversial.

In 2017, Montefusco et al. [ 24 ] conducted a retrospective study on 71 MM patients who underwent allo-SCT with a median follow-up of 100 months. The study found a 5-year PFS of 39% and a 5-year OS of 60%. The cumulative incidence of grade II–IV acute GvHD at day +100 was 13%, and the incidence of chronic GvHD at 5 years was 35%. NRM at 5 years was 12%, while the relapse/progression incidence at 5 years was 65%. On multivariate analysis, age over 55 years and chemorefractory disease at the time of allo-SCT were significantly associated with reduced PFS and OS. The study also evaluated the efficacy of post-transplant salvage therapies, finding that bortezomib, lenalidomide, and pomalidomide offered varying degrees of benefit, with median PFS ranging from 7 to 14 months depending on the therapy.

In 2017, Sobh et al. [ 25 ] analyzed the outcomes of 570 MM patients who underwent allo-SCT following one or two auto-SCT using RIC. The study compared patients receiving grafts from 10/10 HLA-MUDs, 9/10 HLA-mismatched unrelated donors (MMUDs), and cord blood (CB). The 5-year OS rates were 33% for MUD, 39% for MMUD, and 25% for CB recipients. PFS at 5 years was 14% in the MUD group, 27% in the MMUD group, and 4% in the CB group. The relapse incidence at 5 years was significantly lower in the MMUD group (37%) compared to MUD (58%) and CB (69%) groups, indicating a stronger graft-versus-myeloma (GVM) effect in the MMUD cohort. NRM at 5 years was similar across groups, ranging from 27% to 35%. These results suggest that MMUD may offer comparable, if not superior, long-term outcomes to MUD in the context of salvage allo-SCT, despite the traditionally higher risks associated with mismatched donors.

In 2018, Yin et al. [ 26 ] conducted a systematic review and meta-analysis of 61 clinical trials involving 8,698 adult patients with MM who underwent allo-SCT between 2007 and 2017. The study reported pooled OS rates at 1, 2, 3, and 5 years of 70%, 62%, 52%, and 46%, respectively. PFS rates at the same intervals were 51%, 40%, 34%, and 27%. The TRM at 5 years was 27%, with a 100-day TRM of 12%. The incidence of grades II–IV acute GvHD was 34%, and chronic GvHD was reported in 51% of cases. Importantly, the study found that high cytogenetic-risk patients had similar OS and PFS compared to SR patients after allo-SCT, suggesting that allo-SCT may mitigate the adverse effects of HR cytogenetics. However, the lack of consistent survival benefit suggests that allo-SCT should not be considered a standard of care for newly diagnosed or relapsed SR MM patients, but it remains a strong option for HR cases.

In 2018, Htut et al. [ 27 ] conducted a large retrospective study comparing long-term post-relapse survival between patients with MM who underwent tandem auto-/allo-SCT and those who received tandem auto-/auto-SCT. The study included 558 patients in the auto-/auto-group and 264 in the auto-/allo-SCT group, with a median follow-up of 8.5 years. The 6-year post-relapse survival was 44% in the auto-/allo-SCT group compared to 35% in the auto-/auto-SCT group ( p = 0.05). Relapse within 6 months occurred in 46% of the auto-/allo-patients and 26% of the auto-/auto-patients. Multivariate analysis revealed that after 12 months post-relapse, OS was superior in the auto-/allo-SCT group (HR for death in auto/auto = 1.55, p = 0.005). The study highlights the potential benefit of the GVM effect in improving long-term outcomes post-relapse in the auto-/allo-SCT group.

In 2019, Fiorenza et al. [ 28 ] evaluated the impact of the interval between autologous and allogeneic SCT on post-transplant outcomes in MM. The study, involving data from various centers, inspected 93 patients who underwent auto-/allo-SCT. The median time from auto- to allo-SCT was 15 months. Median OS was 3.5 years, with a 3-year OS rate of 45%. The PFS rate at 3 years was 31%. The analysis showed that shorter intervals between auto- and allo-SCT were associated with improved OS ( p = 0.02) and PFS ( p = 0.03). The multivariable analysis confirmed that a longer time between transplants majorly predicted poorer OS and PFS.

Ikeda et al. [ 29 ] assessed the outcomes of 526 patients with MM relapsing after auto-SCT using data from the Japan Society for Hematopoietic Cell Transplantation (2001–2015). This study compared OS between allo-SCT ( n = 192) and auto-SCT ( n = 334). A risk factor scoring system was developed based on response to previous SCT, performance status, and time from prior auto-SCT. In the intermediate-risk subgroup, auto-SCT showed higher OS compared to allo-SCT (28.2% vs. 21.5%, p < 0.004). There were no significant differences in the low- and HR subgroups. Allo-SCT showed long-term survival benefits for some patients, while auto-SCT was generally more beneficial. These findings suggest that auto-SCT might be favored for most patients, though allo-SCT could still be beneficial for specific low-risk cases.

A retrospective analysis of the EBMT database published in 2020 by Hayden et al. [ 30 ] analyzed data from 344 patients aged 40–60 years who had allo-SCT after prior autologous transplant. The retrospective analysis, covering 1991–2012, used Kaplan-Meier curves and Cox proportional-hazards models, with a statistical significance of p < 0.05. The 5-year OS rates were 39% for RIC, 45% for NMA, 19% for myeloablative conditioning (MAC), and 34% for auto-/allo-SCT. MAC was also found to be associated with significantly lower OS ( p = 0.004) and higher mortality risk compared to RIC before 2002 (HR = 4.1, p < 0.001) but not after 2002 (HR = 1.2, p = 0.276). This study concluded that MAC was associated with poorer outcomes before 2003, but there were no significant differences in outcomes observed between conditioning approaches from 2003 to 2012.

The Polish Myeloma Group retrospective analysis in 2020 inspected data from 60 MM patients who received allo-SCT between 1993 and 2016 [ 31 ]. The multicenter retrospective analysis was found to have a median PFS of 9 months and OS of 23 months. Acute GvHD was found in 45% of patients and chronic GvHD in 22%. Chronic GvHD was linked to longer PFS (28 vs. 6 months; p = 0.05) but not with OS (73 vs. 8 months; p = 0.09). Even with high complication rates, allo-SCT showed long-term survival potential, suggesting careful consideration for its use in MM.

Chhabra et al. [ 32 ] published a study in 2020, inspecting 98 patients, their survival outcomes, and factors influencing relapse after allo-SCT in MM. The multicenter retrospective analysis used Kaplan-Meier curves and Cox proportional-hazards models for statistical analysis. The study found a median PFS of 6 months and a 2-year OS rate of 32%. The disease status at relapse majorly affected outcomes, with stable disease associated with better survival ( p < 0.05) as compared to progressive disease. In addition to this, the results show the importance of relapse disease status in predicting survival outcomes post-allo-SCT.

A study published in 2020 [ 33 ] analyzed long-term outcomes and immunoglobulin reconstitution in 95 MM patients who received allo-SCT. Using Kaplan-Meier curves and Cox proportional-hazards models, the study found 2-year OS and PFS rates of 50% (95% CI: 40–60%) and 35% (95% CI: 25–45%), respectively. At 5 years, OS and PFS rates were 38% (95% CI: 28–48%) and 25% (95% CI: 15–35%). Consistent polyclonal immunoglobulin reconstitution was associated with improved OS ( p = 0.03). The results show the significance of immunoglobulin recovery for long-term survival post-transplantation.

A Large Retrospective Study by the Chronic Malignancies Working Party of the EBMT published in 2020 evaluated the efficacy of treosulfan-based conditioning for first-line allo-SCT in MM. The large retrospective analysis included data from 1,200 patients treated with treosulfan or other conditioning regimens. The study found a majorly improved 3-year OS rate of 56% for patients receiving treosulfan-based conditioning compared to 45% with different regimens ( p = 0.02) [ 34 ]. The results show that treosulfan-based conditioning improves survival outcomes in first-line allogeneic transplantation for MM.

In 2020, Park et al. [ 35 ] evaluated the efficacy of allo-SCT in 24 patients with RRMM, with data collected between April 2003 and November 2017. The study used Kaplan-Meier estimates for relapse-free survival (RFS) and OS. Results showed a 2-year RFS of 29.2% (±9.3%) and a 2-year OS of 44.3% (±10.3%). Patients with fewer than 5 prior chemotherapy lines had better RFS and OS. The 1-year cumulative incidence of NRM was 38.3% (±10.1%). The study shows that allo-SCT remains a usable salvage option for HR MM, even though optimal timing needs further investigation. The study does not provide specific p values for the statistical analyses.

A study published in 2020 evaluated lactate dehydrogenase (LDH) and renal function of 100 RRMM patients who underwent allo-SCT as prognostic factors for long-term outcomes of MM patients undergoing allo-SCT. This retrospective study, with a median follow-up of 12.2 years, used a multivariable Cox model to evaluate prognostic factors. Results showed a median OS of 9.2 months and PFS of 5.6 months. Five-year OS was 18.0% and PFS was 16.8% [ 36 ]. The cumulative incidence of 5-year relapse was 45.9%, and NRM was 36.0%. Lower albumin, higher LDH, advanced disease, and mismatched donors predicted reduced OS and PFS. Patients with LDH below the upper limit of normal had a higher 5-year OS (22% vs. 5%, p = 0.004). Lower eGFR correlated with increased NRM (31% vs. 56%, p = 0.02). GvHD did not improve outcomes. The study highlights LDH, renal function, and albumin as major prognostic markers for MM patients undergoing allo-SCT [ 36 ].

A study from the CMWP-EBMT [ 37 ] (2021) analyzed outcomes of 623 NDMM patients with del(17p) and/or t(4;14) who underwent either single auto-SCT ( n = 446), tandem auto-/auto-SCT ( n = 105), or tandem auto-/RIC-allo-SCT ( n = 72) transplants between 2000 and 2015. The study found 5-year OS rates of 51% (95% CI: 45–58%) for single auto-SCT, 60% (95% CI: 49–72%) for auto-/auto-SCT, and 67% (95% CI: 53–80%) for auto-/allo-SCT ( p = 0.187). Five-year PFS was 17% (95% CI: 12–22%) for single auto-SCT, 33% (95% CI: 22–43%) for auto-/auto-SCT, and 34% (95% CI: 21–38%) for auto-/allo-SCT ( p = 0.048). Relapse rates were 82%, 63%, and 56%, respectively, and NRM rates were 1%, 4%, and 10%. Multivariable analysis showed improved PFS with auto-/auto-SCT (HR: 0.44, p = 0.007) and auto-/allo-SCT (HR: 0.45, p = 0.018) compared to single auto-SCT, particularly in t(4;14). For del(17p), auto-/allo-SCT improved PFS (HR: 0.65, p = 0.097), but no significant OS differences were noted.

A single-center experience by Jürgensen-Rauch et al. [ 38 ] analyzed outcomes of RIC-allo-SCT in HR MM patients. This single-center, retrospective study included 50 patients with a median follow-up of 54 months. It reported a 5-year OS rate of 40% and a PFS rate of 30%. NRM was 15% and relapse incidence was 25%. The study showed that RIC-allo-SCT was a safe option, with a low incidence of severe complications, and offered an effective treatment for HR myeloma patients. Specific statistical analysis details, including p values, were not provided, but the findings support RIC-allo-SCT as a good option for this patient population.

Long-term outcome after allo-SCT by Luoma et al. [ 39 ] evaluated 205 MM patients who underwent allo-SCT at a single center from 2000 to 2017. The study divided patients into three groups: upfront allo-SCT (75 patients), tandem auto-/allo-SCT (74 patients), and relapse (56 patients). The median OS was 9.9 years for upfront allo-SCT, 11.2 years for auto-/allo-SCT, and 3.9 years for relapse ( p = 0.015). The median PFS was 2.4 years for both upfront allo-SCT and auto-/allo-SCT groups and 0.9 years for the relapse group ( p < 0.001). The NRM at 5 years was 8% overall, with no significant difference between groups. Post-relapse survival was 4.1 years for upfront allo-SCT and auto-/allo-SCT and 2.6 years for relapse ( p = 0.066). The auto-/allo-SCT showed improved OS in multivariate analysis, and chronic GvHD was beneficial for PFS, OS, and relapse incidence. Late relapses were seen across all groups. The study concluded that auto-/allo-SCT is feasible and beneficial, particularly for younger patients in the upfront setting.

The anticipated survival benefit of allo-SCT must be weighed against potential long-term or delayed side effects from immunosuppression and GvHD, which can affect patientsʼ quality of life. Objective evaluations of these therapy-related limitations and long-term side effects are seldom included in clinical trials, and assessing quality of life, especially in retrospective studies, can be challenging. Long-term side effects of allo-SCT vary widely among patients and should be viewed as a dynamic process with evolving symptom burdens. Typically, allo-SCT is considered mainly for younger, healthier patients due to the intensity of the treatment and expected side effects. However, decisions about the therapy are often based on subjective assessments and the physicianʼs careful consideration of risk factors rather than standardized evaluations of fitness and health. Patients with severe comorbidities are usually excluded from prospective clinical trials, leading to a lack of specific recommendations on which patients might benefit most from allo-SCT. Overview of prospective trials on allo-SCT in MM is given in Table 2 .

Allogeneic Transplant as Salvage Therapy

In a study by Patriarca et al. [ 40 ], authors compared 79 patients undergoing allo-SCT with 90 patients treated with bortezomib and/or immunomodulators. The study showed a 7-year PFS of 18% in the allo-SCT group compared to 0% in those treated with bortezomib and/or IMiDs. The allo-SCT group also demonstrated better OS at 7 years (31% vs. 9%, p < 0.001). An intent-to-treat multicenter analysis examined 169 patients with relapsed MM, with 68 undergoing allo-SCT and 94 receiving novel agents. Comparison between the donor and non-donor groups revealed a 2-year cumulative incidence, PFS, and OS of 41% vs. 81%, 42% vs. 18%, and 54% vs. 53%, respectively. Multivariate analysis identified the absence of a donor as a significant unfavorable factor for PFS but not for OS [ 41 ].

Another prospective study by the European Group for Blood and Marrow Transplantation (EBMT), 49 adults with relapsed MM were treated with allo-SCT following previous auto-SCT. The study reported an OS of 95%, with 5-year PFS and OS of 20% and 26%, respectively, and a 1-year TRM of 25% [ 42 ]. Additionally, in a retrospective study by Bryant et al. [ 43 ], 73 patients underwent allo-SCT. The median OS was 40 months, with estimated OS at 1 and 3 years of 70% (95% CI: 58–79) and 50% (95% CI: 38–62), respectively. The NRM and PFS at 1 year were 22% (95% CI: 13–32) and 53% (95% CI: 41–64), respectively, and at 3 years were 23% (95% CI: 14–34) and 30% (95% CI: 19–41). The study identified older age and GvHD occurring within the first 6 months as factors associated with poorer OS, while a greater number of prior therapies were linked to an increased incidence of relapse.

Challenges with Allo-SCT for Treatment of MM

Compared to autologous SCT, allogeneic SCT has significant issues of TR mortality, morbidity, GvHD risk, association with higher degree of immunosuppression, higher infection risk due to treatment or prophylaxis of GvHD, and high post-transplant myeloma relapse risk. Advancements in allogeneic transplantation, such as the development of NMA or RIC, and the use of alternate donors such as haploidentical donors has significantly expanded the pool of patients who can be considered for transplantation, including those previously deemed unfit due to age or relative frailty. Understandably, the outcomes of previous allo-SCT trials for MM have been limited by several factors such as lack of randomization, pre- or post-transplant lack of access to effective MM therapies, retrospective nature of analysis in many cases, trials often included patients with varying risks, poor GVM effect, and use of variable pre-transplant induction therapies. Many trials were conducted before the routine use of RIC, alternative donors, or availability of effective drugs, immunotherapies including CAR T-cell therapy, and monoclonal antibodies.

CAR-T therapy, in particular, holds significant promise. FDA has approved two autologous CAR-T therapies, which has multiple advantages along with unique limitations or side effects. Allogeneic CAR-T therapy (such as ALLO-715 Universal trial, CB-011 phase 1 trial, Poseida P-BCMA-ALLO1) can address some of these limitations of collection to delivery time, improve efficacy, T-cell exhaustion, and off-the-shelf availability with the possibility of planned repeat dosing but presents unique challenges of the possibility of early graft rejection, lack of cell expansion, rare but potential issues of GvHD, and emerging concern for post-CAR-T therapy secondary malignancies including T-cell leukemia concern. Ongoing trials with allo-CAR-T cells have shown initial promising results [ 44 , 45 ]. Comparatively, recent trials are exploring the incorporation of targeted therapies, such as Wilmsʼ tumor 1 (WT1)-specific T cells, use of daratumumab in combination with lenalidomide, elranatamab, or iberdomide for relapse prevention, and refined conditioning regimens involving agents like bendamustine and fludarabine. Compared to earlier treatment paradigms, which primarily focused on aggressive conditioning and stem cell support, recent innovations reflect a more nuanced approach.

In general, the choice and type of donor used for allo-SCT is vital, impacting TR outcomes including survival, risk of GvHD, the GVM effect, and disease relapse [ 46 ]. MSD were historically preferred due to the lower risk of GvHD. However, studies have shown that haploidentical donors (haplo-SCT) and MUDs are not an inferior alternative to MSD, demonstrating comparable outcomes for PFS, OS, GvHD-free, and relapse rates [ 47 ]. Other factors such as gender mismatch, particularly from female donors to male recipients (FtoM), increase GvHD-related mortality and reduced OS rates ( p = 0.021) need to be kept in mind for donor selection [ 48 ]. Donor’s age also impacts transplant outcomes, comparing outcomes of donors aged 18–30 years versus >45 years, use of younger donors leads to better 5-year OS rates (33% vs. 25%, p = 0.0002), less GvHD risks (30% vs. 34%, p = 0.005), respectively [ 49 ]. Despite improvements in understating these factors, in MM, relapse remains a recurring concern.

Conditioning regimens in allo-SCT for MM are essential for optimizing engraftment and aim to eradicate the residual myeloma cells [ 50 ]. Most patients with the diagnosis of MM are above 60 years of age, and use of MAC, can lead to HR of TRM. RIC or non-myeloablative conditioning carry a HR of disease relapse. However, neither option was found to be superior to the other regarding survival outcomes; risk score-adopted individualized selection of conditioning is recommended in all standard-of-care allo-SCT [ 51 , 52 ]. The most commonly used MM allo-SCT conditioning regimens including fludarabine with melphalan 100–140 mg/m 2 , fludarabine 90–150 mg/m 2 with cyclophosphamide, and fludarabine with total body irradiation-based regimens were commonly used RIC regimens [ 50 ]. Depending on the disease status and recipient characteristics, different combinations of conditioning drugs with varying doses were studied, but none of the approaches showed clear benefits. MAC caused higher TRM and RIC was carefully tailored to accommodate older and heavily treated cohorts, but these approaches failed to show a survival plateau with MAC, RIC, or non-myeloablative conditioning [ 53 ]. Authors recommend against the routine use of allo-SCT for MM treatment even in genetically defined HR cases in the era of highly effective and safer antimyeloma therapies. To overcome the challenges of HR and ultra-HR plasma cell disorders, well-designed randomized prospective future trials are essential. Innovations in induction therapy to achieve MRD negative status, myeloma-specific conditioning therapies, T-cell depletion in grafts, newer post-transplant GvHD prophylaxis approaches such as the use of post-transplant cyclophosphamide with antimyeloma activity, the use of mesenchymal stem cells, natural killer cells, and regulatory T cells, post-transplant antimyeloma maintenance therapy using immunomodulators, CD33 antibodies, BCMA/GPRC5D targeting bispecific antibodies, auto or allogeneic CAR-T cells, new auto-allo-CAR-T combinations need to be tested for better outcomes, lower GvHD-related morbidity, and improvement in long-term survival for patients with aggressive MM [ 18 ].

Conclusion

Over the past decades, there has been a dramatic change in therapeutic options for the treatment of MM. Despite advances in therapeutics, the prognosis is poor for penta-refractory patients who fail CAR-T cells or T-cell engager antibodies. Allo-SCT was postulated to be a potentially curative option in MM due to graft versus malignancy effect, but this approach was associated with historically high TRM, GvHD, and high relapse risk. Meanwhile, newer induction regimens using four drug induction for NDMM followed by auto-SCT and planned long-term maintenance strategies have led to better survival. The results of numerous previous clinical trials investigating allo-SCT in both first-line and relapsed settings have been influenced by several factors, including the retrospective nature of the analyses in many trials, the absence of randomization, and the heterogeneity of patient cohorts. These studies often included patients with varying cytogenetic risks, different induction therapies, and incomplete previous treatment data. Additionally, many trials enrolled patients who had not yet received novel drugs such as bortezomib, immunomodulatory agents, or monoclonal antibodies. Summary of open MM allo-SCT trials is given in Table 3 .

In conclusion, based on the historical data, routine use of allo-SCT cannot be recommended at this point. Research into allo-CAR-T cells, newer, safer conditioning regimens using targeted immunotherapy, improved management of GvHD, newer agents for post-transplant maintenance therapy, and supportive care measures may improve outcomes for MM patients in intelligently designed prospective clinical trials.

Conflict of Interest Statement

Faiz Anwer served as an advisor and speaker for Bristol Myers Squibb, Celgene, and Caribou Biosciences and received research funding from Allogene Therapeutics, Celgene, GlaxoSmithKline, Bristol Myers Squibb, and Caribou Biosciences. Qaiser Bashir received research funding from Stemline, GlaxoSmithKline, and Pfizer.

Funding Sources

This research did not receive specific grants from any public, commercial, or nonprofit funding agencies.

Author Contributions

M.F.A., B.M., and A.Y.C. conceptualized and designed the article. M.F.A., D.S., M.M., and A.N. handled data curation and compiled previous trials. D.M. and B.M. addressed therapeutic challenges, while A.Y.C. compiled ongoing trials. H.M.A. performed revisions and improved the text. M.F.A. composed the abstract, added references, and prepared the final draft according to journal requirements. All authors contributed to resource acquisition, validation, and manuscript writing, including review and editing, had access to and verified the underlying data, critically reviewed the work, and approved the final version for publication, with supervision from Q.B. and F.A., who contributed equally as the last authors.

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