The decline of transplant for relapsed myeloma

In this issue of Blood, Baertsch et al report no significant progression-free survival (PFS) or overall survival (OS) benefit from salvage autologous transplantation compared with lenalidomide/dexamethasone (LEN/DEX) in the intention-to-treat (ITT) population after an extended follow-up of the ReLApsE trial.¹ 

The optimal management of relapsed and/or refractory multiple myeloma (RRMM) in patients who have previously received frontline high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) remains a subject of ongoing debate. According to guidelines, salvage HDCT/ASCT (sHDCT/ASCT) is often recommended, especially for patients with a long time to progression after frontline HDCT/ASCT (TTP1), but triplet therapies and chimeric antigen receptor T-cell (CAR-T) therapies are also increasingly advocated.^2,3 The UK Myeloma X Relapse Intensive trial provided evidence supporting the efficacy of sHDCT/ASCT over a suboptimal cyclophosphamide regimen for patients with RRMM.⁴ However, the German-Speaking Myeloma Multicenter Group (GMMG) ReLApsE trial offered crucial insights into the role of sHDCT/ASCT in the era of novel therapies.⁵ This phase 3 randomized controlled trial compared survival outcomes between sHDCT/ASCT followed by lenalidomide maintenance and continuous LEN/DEX in RRMM and now has nearly 8 years of follow-up. The study challenges prior assumptions regarding the benefits of a salvage transplantation. The results of the LEN/DEX arm were consistent with the long-term outcomes observed in the LEN/DEX arm of the POLLUX study (median PFS of 17.5 months).⁶ The absence of PFS/OS benefit was consistent across subgroup analyses, including patients stratified by TTP1 (time from the first day of treatment to disease progression), a common criterion for selecting candidates for sHDCT/ASCT. Remarkably, even patients with extended TTP1 (>48 months) did not show a significant survival advantage with sHDCT/ASCT, calling into question the guideline recommendations for its use in this subgroup.

The lack of benefit observed in the transplant arm is further highlighted by a 29% dropout rate before sHDCT/ASCT, largely due to disease progression, adverse events, and patient withdrawal. Although landmark analyses at the time of sHDCT/ASCT suggested improved outcomes in patients who underwent the procedure, these benefits were not sustained with long-term follow-up. Unfortunately, there was substantial use of posttrial sHDCT/ASCT in the control arm, complicating the interpretation of survival outcomes. It is also important to note that virtually all patients enrolled in this study had received single or tandem transplant as frontline therapy. The same German group has also reported that the pretransplantation rescue regimen that includes more active triplet regiments such as carfilzomib/LEN/DEX significantly improves outcomes,⁷ suggesting that LEN/DEX before sHDCT/ASCT is not an optimal reinduction regimen. The absence of benefit with sHDCT/ASCT should therefore be interpretated with this limitation in mind.

These findings have important implications for clinical practice. The lack of a PFS or OS benefit with sHDCT/ASCT raises questions about its routine use in RRMM, especially given the increasing availability of highly effective alternatives, such as anti-CD38 monoclonal antibodies-based triplets, carfilzomib-based regimens, and CAR-T therapies, with reported PFS ranging from 28 to over 33 months in trials like CANDOR, IKEMA, or CARTITUDE-4.^8,9 Furthermore, although the trial confirms the prognostic value of TTP1 for patients in both arms of the trial, it challenges its predictive utility for selecting patients who would benefit the most for sHDCT/ASCT. In resource-limited settings or for patients who desire fixed-duration therapies, sHDCT/ASCT may still be considered, although maintenance therapy is required to achieve meaningful PFS benefits. However, the quality-of-life burden associated with sHDCT/ASCT should be carefully weighed against the availability of less toxic alternatives.

The ReLApsE trial highlights the need for further research into personalized treatment strategies for RRMM, as well as research into the optimal sequence for first- and second-line therapies. Although no ongoing randomized controlled trials directly compare sHDCT/ASCT with modern regimens or CAR-T therapies, retrospective analyses and real-world data could help refine patient selection. Additionally, studies investigating the role of deferred transplantation in frontline therapy, particularly for patients receiving quadruple regimens that include anti-CD38 monoclonal antibodies, are warranted.

The extended follow-up of the GMMG ReLApsE trial casts doubt on the utility of sHDCT/ASCT in RRMM following frontline HDCT/ASCT, regardless of the length of TTP1. These findings underscore the importance of prioritizing novel, less burdensome therapies over sHDCT/ASCT in most clinical scenarios, supporting a drastic reduction in the use of salvage transplantation in routine practice.

In the frontline setting, HDCT/ASCT is also facing increasing scrutiny, particularly in patients who achieve exceptional responses to induction therapy, such as undetectable minimal residual disease (as observed in the Intergroupe Francophone du Myélome MInimal residual Disease Adapted Strategy trial). If autologous transplantation is excluded for patients who are negative for minimal residual disease from the frontline setting, would it reclaim a role in relapsed disease in the future? Time and further clinical trials will tell.

Conflict-of-interest disclosure: A.P. and C.T. disclose conflict of interest from AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, Sanofi, and Takeda.