Autologous Stem Cell Transplantation in Multiple Myeloma: Is It Still the Gold Standard?

Introduction

Multiple myeloma is a malignancy of clonal plasma cells in the bone marrow, characterized by monoclonal immunoglobulin production, immune suppression, and osteolytic bone lesions. It primarily affects older adults and accounts for approximately 10% of hematologic malignancies. Clinically, multiple myeloma often presents with bone pain, anemia, renal impairment, and increased susceptibility to infections due to marrow infiltration.¹

Over the past 3 decades, the treatment landscape for multiple myeloma has transformed dramatically, converting it from a uniformly fatal disease to a chronic, manageable condition for many patients. While autologous stem cell transplantation (ASCT) has remained a key component of care, the improvement in survival outcomes has been largely driven by advances in therapies administered before and after transplant, particularly induction regimens, maintenance therapy, and salvage treatments.²

High-dose chemotherapy (HDT), most commonly melphalan, is used in conjunction with ASCT to maximize disease eradication with subsequent reinfusion of the patient’s stem cells to restore hematopoiesis.³

While long-term overall survival (OS) data in the context of novel agents are still evolving, ASCT remains one of the most effective strategies for achieving minimal/measurable residual disease (MRD) negativity and durable remissions, supported by both randomized trials and real-world evidence. As novel therapies such as chimeric antigen receptor (CAR) T cells and bispecific antibodies emerge, ongoing clinical trials are redefining the role of ASCT in the treatment paradigm.^4,5

This review, inspired by a keynote lecture presented by Muzaffar H. Qazilbash, MD, during a MedNews Week webinar, explores the role of innovation, precision medicine, and ongoing clinical trial participation, which are the future of multiple myeloma care.⁶ More precise risk stratification and personalization can be made possible with technologies such as genomic profiling and MRD monitoring. As ASCT combines with innovative treatments to enhance outcomes for patients dealing with this complicated cancer, its role is changing rather than decreasing. Herein, we examine the ongoing relevance of ASCT in the treatment of multiple myeloma, highlighting its clinical efficacy, integration with novel therapies, and potential future directions. By evaluating landmark trials, stem cell mobilization strategies, and emerging immunotherapies, we aim to clarify ASCT’s evolving role in this era of newer therapies (Figure).

Rationale for ASCT in Modern-Day Multiple Myeloma

Over the past 2 decades, the expansion of treatment options, including the introduction of targeted therapies and immunomodulatory drugs, has significantly improved patient outcomes.⁷ Despite these developments, the gold standard for eligible patients with newly diagnosed multiple myeloma is ASCT following high-dose melphalan (HDM), which has been shown to have high response rates and long survival periods.⁸

The strength of ASCT lies in its ability to consolidate responses achieved during induction therapy.⁸ Achieving MRD negativity is a strong prognostic indicator in multiple myeloma, and ASCT offers durable responses, including higher rates of MRD negativity.^9-11 For instance, a study observed that MRD negativity increased from 20% pre-ASCT to 49% post ASCT, highlighting the transplant’s role in deepening responses.⁸ The UK phase 3 MYELOMA XI trial (NCT01554852) demonstrated that patients who are MRD negative 3 months post ASCT had a median progression-free survival (PFS) of 44 months compared with 24 months for patients who were MRD positive.⁹ Overall, MRD status serves as a powerful indicator of PFS and OS in multiple myeloma.^9,10

Historically, patients with multiple myeloma survived a median of merely 3 to 4 years. Early applications such as vincristine, melphalan (M), cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin, and prednisone (VMCP/VBAP) showed some improvement. The advent of HDT followed by ASCT was a major turning point, extending median survival to more than 7 to 8 years and substantially enhancing response rates, event-free survival, and OS.¹²

Evidence From Landmark Trials and Real-World Data

Clinical Trials Supporting ASCT

Several large trials over the past decade have reinforced the continued value of ASCT (Table).

The phase 3 DETERMINATION trial (NCT01208662), conducted in the US, demonstrated the continued value of ASCT, even in the era of potent induction regimens such as lenalidomide, bortezomib, and dexamethasone (RVd). Patients who received early ASCT had a median PFS of 67.5 months compared with 46.2 months in those who did not, although OS was comparable at the time of analysis.¹³ The findings highlight the flexibility of ASCT, with early administration offering deeper remission without significantly compromising survival when deferred.

In addition to the US DETERMINATION trial, the French phase 3 IFM 2009 trial (NCT01191060) remains foundational in establishing ASCT’s role in the modern era. It demonstrated that patients who underwent ASCT had significantly longer PFS (47.3 months) than those who did not undergo transplant and instead received a longer course of RVd (35.0 months), despite similar OS outcomes.¹⁴ Early ASCT can deepen and prolong disease control, even when effective triplet induction regimens are used. Importantly, the comparable OS between the 2 arms also introduced the idea that transplant could be deferred in select cases, raising important clinical questions about optimal sequencing. However, the longer PFS in the ASCT group underscores its role in achieving sustained remission, which remains a critical treatment goal in multiple myeloma.

The FORTE trial (NCT02203643), a randomized phase 2 study, evaluated the impact of different carfilzomib-based regimens with or without ASCT in patients with newly diagnosed multiple myeloma. The trial showed that carfilzomib, lenalidomide, and dexamethasone (KRd) induction followed by ASCT led to higher MRD negativity (58%) and longer PFS compared with KRd alone. It also found KRd to be more effective than carfilzomib, cyclophosphamide, and dexamethasone (KCd), and maintenance with carfilzomib plus lenalidomide was superior to lenalidomide alone. These results reinforce the value of ASCT in deepening response even with modern induction therapies.¹⁵

The EMN02/HO95 trial (NCT01208766) further reinforced ASCT’s utility, especially the benefit of tandem transplants. This phase 3 study showed that tandem ASCT led to improved 3-year PFS (72.5%) and OS (88.9%) compared with single ASCT (PFS, 64.0%; OS, 81.5%), particularly in high-risk cytogenetic subgroups.¹⁶ The EMN02 results suggest that intensifying postinduction therapy with tandem ASCT may help overcome some of the adverse biology seen in these patients. This is especially relevant because patients with high-risk multiple myeloma often relapse early and respond poorly to standard therapy. Thus, the trial provides strong evidence for tailoring ASCT strategies based on individual risk profiles.

However, results from the StaMINA trial (NCT01109004) offered a contrasting view. This US-based phase 3 trial compared single ASCT with either a second (tandem) ASCT or RVd consolidation followed by lenalidomide maintenance. It found no statistically significant difference in PFS or OS among the 3 strategies, suggesting that additional post-ASCT interventions may not benefit all patients equally.¹⁷ This apparent discrepancy with EMN02 highlights the importance of patient selection and trial design. While StaMINA enrolled a broader, unselected population, EMN02 emphasized high-risk cytogenetics and deeper stratification. Together, these trials suggest that a one-size-fits-all approach may not be appropriate and that the decision to intensify treatment post ASCT should be individualized. Smaller trials also support the role of consolidation. For example, the Nordic Myeloma Study Group showed modest PFS benefit (27 vs 20 months) for bortezomib consolidation post ASCT, particularly in patients who had not achieved a very good partial response.¹⁸ The idea that patients with suboptimal posttransplant responses may benefit from further therapy to deepen remission emphasizes the importance of response-adapted strategies in ASCT-era multiple myeloma management.

Real-World Outcomes Across Populations

An Italian retrospective study involving 344 patients with multiple myeloma demonstrated that those eligible for ASCT had significantly better long-term survival outcomes. Specifically, the 20-year OS rate was 73% for patients who received 1 or 2 lines of therapy compared with 30% for those who received 3 or more lines.¹⁹

Beyond Italy, the Canadian Myeloma Research Group study reported that patients undergoing ASCT as part of first-line therapy had a median PFS of 35.4 months and a median OS of 126 months. Results were further enhanced by maintenance treatment, especially lenalidomide, with a median OS of 159 months and PFS of 53.7 months.²⁰ Similarly, data from the Australian and New Zealand Myeloma and Related Diseases Registry indicated that ASCT recipients had a median PFS of 45.3 months and OS not reached compared with 35.2 months for PFS and 64.0 months for OS in patients who did not receive ASCT. These benefits were observed across age groups, including patients aged 65 to 70 years.²¹

Timing of Transplant: Early Vs Delayed in the Era of Immunotherapy

The optimal timing of ASCT in newly diagnosed multiple myeloma has been a central question, particularly in the era of novel immunotherapies. The debate centers on whether to perform ASCT early after induction or to reserve it for a later time, such as at relapse. The core of this discussion involves balancing the benefits of a deep, durable response against the lack of an OS advantage and the potential for treatment-related toxicities.

Two pivotal phase 3 trials, IFM 2009 (France) and DETERMINATION (US), compared early vs delayed ASCT in patients with newly diagnosed multiple myeloma.^13,22 Both trials utilized the same induction regimen of RVd, and each enrolled about 700 patients. The key difference in trial design was that IFM 2009 used fixed-duration lenalidomide maintenance for 1 year, whereas DETERMINATION continued lenalidomide until disease progression. Moreover, this difference had important implications at relapse: Almost none of the French patients were lenalidomide-refractory, whereas nearly all US patients were. This affected not only the choice of salvage regimens but also strategies for postsalvage transplant maintenance.

The results showed that early ASCT significantly improved PFS and led to higher rates of MRD negativity. These findings reinforce the notion that early ASCT remains the standard of care for eligible patients and may provide the best opportunity for achieving a deep and durable response in newly diagnosed multiple myeloma. However, neither trial showed an OS advantage, even with extended follow-up. This may be attributed to the effectiveness of salvage therapies in mitigating the differences in long-term outcomes. However, both trials are suggestive that one needs to make a judgment regarding the potential benefits of early ASCT compared with the toxicities of chemotherapy and delayed ASCT, especially because the OS is the same.

In the IFM 2009 trial, for example, 80% of patients in the delayed group eventually received an ASCT at relapse, effectively mitigating the long-term survival differences between the 2 arms. Conversely, only 28% in the DETERMINATION trial’s delayed arm received a transplant. This discrepancy must be interpreted in the context of maintenance: Most French patients progressed after their 1-year lenalidomide maintenance, making salvage ASCT a necessary and feasible option. In contrast, many US patients who received prolonged lenalidomide maintenance did not progress for a much longer period, making salvage ASCT unnecessary for a substantial duration. This highlights a crucial consideration that, while salvage therapies are effective, delaying ASCT carries the risk of losing the opportunity for transplantation altogether, especially for a disease with a median diagnosis age of 69 years, when patients may become too old or frail for HDT and ASCT by the time of relapse.

Yet, the timing of ASCT is not a purely clinical decision. Despite the PFS advantage, physician surveys indicate that OS remains the primary factor in treatment decisions, and many providers were not persuaded to adopt early ASCT solely based on PFS.²³ For older patients, especially those older than 65 years, comorbidities, trust in the oncologist, family input, and concerns about adverse effects influence the decision-making.²⁴ In addition, ASCT improves quality of life (QOL) in patients with newly diagnosed multiple myeloma, likely because it leads to more prolonged remissions and reduces the need for ongoing chemotherapy.²⁵ Although ASCT may take a toll on QOL in the short term, improvements have been reported in the long-term.²⁶ Thus, some patients, especially in high-risk cases, may prefer prioritizing QOL over longevity. This shifts the focus to achieving a delicate balance between the treatment burden and the benefits of deep remission.

The developing therapeutic landscape highlights the need for a personalized approach to the timing of ASCT. This approach should balance clinical trial data with real-world considerations, including the patient’s values, biological risk, and overall treatment goals. Key clinical variables in determining the timing of ASCT include patient age, comorbidities, disease risk profile, and responses to prior treatments. Numerous retrospective studies support this individualized strategy, often relying on physician-mediated surveys. These surveys have identified several factors influencing transplant timing, including patient preference, cytogenetic risk, previous chemotherapy responses, and ECOG performance status.²⁷

Stem Cell Mobilization and Posttransplant Maintenance

Hematopoietic stem cells typically reside in the bone marrow, where they are anchored by interactions involving CXCR4 and stromal- derived factor-1.^28,29 Granulocyte colony-stimulating factor (G-CSF) is frequently administered over 4 days to stimulate the release of stem cells into the peripheral blood. When used in conjunction with plerixafor, a CXCR4 antagonist, stem cell mobilization is significantly enhanced by disrupting these molecular interactions, thereby facilitating collection.^30,31 However, the routine use of plerixafor for all patients poses financial challenges due to its high cost.³² To address these financial concerns, risk-adapted strategies such as the “just-in-time” administration of plerixafor have been adopted. Here, the drug is reserved for patients who demonstrate poor mobilization with G-CSF alone. A study evaluating this strategy reported that selective use of plerixafor in poor mobilizers resulted in effective stem cell collection without substantially increasing overall costs.³³

An alternative strategy involves combining chemotherapy (commonly cyclophosphamide) with growth factors in cases where patients exhibit inadequate mobilization with G-CSF alone. A meta-analysis encompassing 18 studies with a total of 2770 patients with multiple myeloma demonstrated that the combination of cyclophosphamide and G-CSF resulted in higher yields of CD34-positive cells and improved mobilization rates compared with G-CSF alone. However, this regimen was also associated with increased risks of hospitalization and fever during mobilization, indicating a higher toxicity profile.³⁴ Despite the improved mobilization efficiency, the addition of chemotherapy does not appear to confer significant benefits in OS or stem cell quality.³⁵ Furthermore, the use of chemotherapy in stem cell mobilization has been associated with increased toxicity.³⁶

HDM at 200 mg/m² remains the gold standard for conditioning in multiple myeloma due to its favorable efficacy and toxicity profile.³⁷ However, this regimen is associated with significant gastrointestinal toxicity, including diarrhea, vomiting, and mucositis.³⁸ Previous agents such as thiotepa, busulfan, and cyclophosphamide were investigated as alternatives but failed to provide consistent advantages in survival or reduced toxicity.³⁹ Emerging data from The University of Texas MD Anderson Cancer Center suggest that modified conditioning regimens may benefit select high-risk patients younger than 70 years.⁴⁰ It identifies busulfan plus melphalan as a superior conditioning regimen regarding PFS, compared with melphalan alone, although with a higher adverse event burden, hence suggesting that busulfan plus melphalan conditioning can serve as a useful platform for further improvement of transplant outcomes in patients with multiple myeloma.⁴⁰

The approval of lenalidomide as maintenance therapy was granted by the European Medicines Agency and the FDA in 2017.⁴¹ It demonstrates a significant OS benefit and extends PFS in patients with newly diagnosed multiple myeloma.^41-43 However, prolonged use of lenalidomide is associated with an increased risk of secondary malignancies, particularly an increased risk of TP53-mutated myeloid neoplasms.⁴⁴ In patients who are ultra high risk, some clinicians incorporate dual maintenance strategies by adding proteasome inhibitors such as bortezomib. A retrospective study comparing doublet maintenance of bortezomib plus lenalidomide vs lenalidomide alone found that patients with high-risk multiple myeloma did not reap the same survival benefits from lenalidomide maintenance as patients who were standard risk, suggesting that more intensive maintenance regimens may be necessary.⁴⁵ More compelling evidence comes from prospective trials, such as the FORTE trial and the phase 3 TOURMALINE-MM3 trial (NCT02181413). The FORTE trial showed that KRd induction followed by ASCT led to longer PFS compared with KRd alone.¹⁵ The TOURMALINE-MM3 trial, a phase 3, double-blind, randomized trial, showed that ixazomib maintenance post ASCT significantly prolonged PFS compared with placebo, highlighting the potential role of oral proteasome inhibitor–based maintenance.⁴⁶ However, the optimal maintenance strategy remains an area of active investigation.

The phase 2 GRIFFIN trial (NCT02874742) studied the addition of daratumumab to RVd (D-RVd) in patients who were transplant eligible with newly diagnosed multiple myeloma. One group received D-RVd with ASCT and daratumumab-lenalidomide maintenance, while the control group received RVd with ASCT and lenalidomide maintenance. The daratumumab group showed significantly deeper responses, with MRD negativity rates of 62.5% compared with 27.2% in the control group. At a follow-up of 49.6 months, the 4-year PFS was 87.2% in the D-RVd arm vs 70.0% in the RVd-only group. This confirms that adding daratumumab to standard therapy plus ASCT improves both MRD negativity and PFS.⁴⁷

Several important questions on the ideal duration of maintenance remain unanswered. A study found that longer maintenance therapy was associated with improved PFS and OS.⁴⁸ The MRD2STOP trial (NCT04108624) is a pragmatic study evaluating maintenance therapy cessation guided by MRD negativity in multiple myeloma. Discontinuation in patients with multiple myeloma and multimodal MRD less than 10^–6 resulted in a low rate of disease progression or MRD resurgence.⁴⁹ These findings suggest that MRD status can be used as a biomarker to guide maintenance therapy decisions.⁵⁰

The Future of ASCT in Multiple Myeloma Care

More recently, the evolution of immune-based therapies, including CAR T-cell therapies for B-cell maturation antigen and bispecific antibodies, has opened a new era in the management of multiple myeloma, producing deep and durable responses even in patients with relapsed/refractory multiple myeloma.^51,52 These therapies show promise as potential alternatives to ASCT. However, long-term data regarding their durability and curative potential in the frontline setting are still lacking.

Earlier trials that used idiotype vaccines made from the patient’s own M protein combined with their own activated autologous T cells showed some immune activation with minimal toxicity. However, it did not result in any significant clinical improvements for disease management.⁵³ Nevertheless, it laid the foundation for creating today’s genetically engineered T cells, such as CAR T cells, as well as immune-engaging therapies such as bispecific antibodies, and antigen-specific T or natural killer cells.

Multiple ongoing trials are studying the role of immunotherapy in complementing or even replacing ASCT in patients with high-risk newly diagnosed multiple myeloma. New clinical trials, such as the phase 3 CARTITUDE-6 trial (NCT05257083), compare ciltacabtagene autoleucel (cilta-cel) with transplant, followed by lenalidomide maintenance.⁵⁴ Similarly, the phase 1 KarMMa-4 trial (NCT04196491) is testing idecabtagene vicleucel (ide-cel) as a frontline therapy, potentially offering an alternative to transplant.⁵⁵ These efforts aim to produce lasting responses that might allow patients to live without continual treatment, drug-related toxicities, T-cell exhaustion, complex manufacturing processes, high costs, and limited accessibility.⁵⁶

History has shown the risk of prematurely discarding effective therapies. Two decades ago, the emergence of thalidomide and bortezomib led to early predictions of ASCT’s obsolescence, predictions that proved incorrect.⁵⁷ Such errors of judgment highlight the necessity for evidence-based change as opposed to speculative enthusiasm.

While it is plausible that in the next decade or 2, immune-based and targeted therapies may entirely replace transplant, especially as MRD-directed and risk-adapted approaches reach maturity, ASCT remains the only modality that has incontrovertibly proven advantages in transplant-eligible patients with newly diagnosed multiple myeloma.⁵⁸ When combined with modern induction and maintenance regimens, ASCT offers unmatched disease control and depth of response.⁵⁹

The future of multiple myeloma therapy is undoubtedly exciting, with transformative treatments on the horizon. However, ASCT has consistently proven its value through decades of trials and real-world evidence, a feat that newer therapies have yet to replicate in the frontline setting. Until that standard is met, ASCT remains an indispensable pillar of multiple myeloma treatment. Any shift away from transplant should be influenced not by trends or enthusiasm, but by rigorous clinical confirmation and an insistence on sustaining patient survival outcomes.⁶⁰

Conclusion

ASCT continues to be a cornerstone in the treatment of multiple myeloma, offering patients a meaningful chance at deeper responses and longer remissions. It has helped shape the way we approach and improve care for this complex disease. Recent data from the EMN02/HO95 trial reaffirm its benefit, demonstrating significant improvements in both PFS and OS, even in the pre–novel agent era.⁶¹ The trial also underscores the value of PFS as a meaningful end point. Simultaneously, emerging results from the phase 2 GMMG-CONCEPT study (NCT03104842) suggest that transplant-free regimens, such as isatuximab-KRd, can achieve profound MRD negativity in high-risk newly diagnosed multiple myeloma, regardless of transplant status.⁶² These findings reflect growing interest in nontransplant approaches for selected populations.

The future of multiple myeloma therapy may lie in MRD-guided, response-adaptive trials, which aim to identify patients who could safely defer or avoid transplant without compromising outcomes. This signals a broader shift toward personalized treatment strategies where ASCT is increasingly seen not as a stand-alone intervention but as part of an integrated, multimodal approach.

Meanwhile, immunotherapies, particularly CAR T cells and bispecific antibodies, continue to show promise, especially in relapsed/refractory multiple myeloma. Despite high response rates with agents such as ide-cel and cilta-cel, challenges remain regarding durability, toxicity, cost, and access.⁶³ In contrast, ASCT retains a favorable safety and efficacy profile and serves as a complementary modality to these emerging treatments. Additional strategies, such as drug repurposing, using agents such as thalidomide, statins, and celecoxib, are also under investigation to address resistance and relapse.⁶⁴ Many of today’s standards began as experimental approaches fueled by academic curiosity. Continued scientific engagement, particularly from the next generation of clinician- researchers, will be essential to sustain progress. The integration of traditional therapies with innovation, informed by MRD monitoring, genomic profiling, and patient-centered trial design, represents the future of multiple myeloma care.

In conclusion, while ASCT may no longer be the sole cornerstone of therapy, it remains a vital component of treatment. Its optimal utility will lie in strategic integration within an increasingly precise and dynamic treatment framework. Through thoughtful collaboration between established and novel approaches, the goal of durable remission, and ultimately a cure, moves ever closer.

Acknowledgment

We thank Dr Muzaffar H. Qazilbash for his insights provided during the MedNews Week keynote conference.

Corresponding author

Taha Kassim Dohadwala, MS5,

David Tvildiani Medical University,

Lubliana 60, Tbilisi 0159, Georgia

Email: tahakdohadwala@gmail.com

Phone: +995 592276776

ORCID ID: 0009-0005-3456-3148

Author Contributions

TKD and JG contributed equally to the conception, literature review, drafting, and initial writing of the manuscript. SN, RV, and IP supported data analysis, figure preparation, and literature synthesis. VC, CP, and YL equally contributed to supervision, project guidance, and critical revision of the manuscript for important intellectual content. All authors reviewed and approved the final version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No patient data were directly utilized in this study.

Conflicts of Interest

The authors declare no conflicts of interest.

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