This multicentre study investigated the clinical role of tandem transplantation in patients with MM, with emphasis on the potential role of tandem transplantation in patients with high-risk features defined as ISS III, elevated LDH levels, high-risk FISH, and/or extramedullary disease.[12] Herein, we found that tandem transplantation significantly improved the response status and almost doubled the CR rate when compared with the response status after the first transplantation. Although tandem transplantation was equivalent to single transplantation in the entire population, tandem transplantation was associated with significantly improved PFS in patients with ISS III and high-risk FISH when compared with those receiving maintenance therapy. Additionally, we identified the clinical benefits of tandem transplantation in patients who did not achieve a CR after the first transplantation. To overcome the limitations of the retrospective nature of this study, we performed propensity score matching, which revealed that tandem transplantation was significantly associated with longer PFS than single transplantation.
However, identifying and treating patients with high-risk MM can be challenging.[12] First, a high risk of MM could be stratified by ISS, with approximately one-third of the patients in previous studies and our cohort classified as stage III.[15] Extramedullary disease has also been identified as a prognostic factor.[17] Prognostic value can also be determined by genomic characterisation, such as metaphase karyotyping and FISH. Various cytogenetic abnormalities have been investigated; patients with high-risk cytogenetic abnormalities account for approximately one-quarter of all MM cases and have relatively poor survival outcomes.[18] Despite the promising results with novel agents in triplet or quadruplet induction regimens, high-risk patients continue to experience poor outcomes. For instance, the SWOG S0777 study compared triplet VRd with lenalidomide and dexamethasone (Rd).[19] Despite demonstrating the efficacy of VRd in the overall population, high-risk patients (as defined in our study) showed no significant clinical benefits. Moreover, patients who received intensified induction regimens were found to exhibit significantly improved overall outcomes,[20–23] although none of these strategies could overcome the adverse prognostic impact of high-risk cytogenetics. However, tandem transplantation was found to be efficacious in improving poor prognoses in high-risk patients. Gagelmann et al. studied 488 patients with extramedullary disease and found that patients with varying cytogenetic risk factors who underwent single transplantation had significantly different survival rates, whereas patients with high-risk FISH who underwent tandem transplantation showed clinical outcomes similar to those in the single transplantation group.[13] According to the policies of each institution, 210 patients in the ENM02/HO95 study underwent tandem transplantation, whereas 492 underwent a single ASCT.[11] Patients who underwent tandem transplantation had significantly longer PFS and OS than those who underwent single transplantation. Notably, patients with high-risk cytogenetics who underwent tandem transplantation had a higher chance of survival than those who did not undergo tandem transplantation. In the STaMINA study, tandem transplantation followed by lenalidomide maintenance was associated with a significantly longer PFS than single transplantation followed by consolidation with a maintenance strategy or single transplantation followed by maintenance therapy in the high-risk group.[10] In our study, tandem transplantation was significantly associated with improved PFS in patients with ISS III and high-risk FISH in the subgroup analysis. Therefore, our results are consistent with those of previous studies and support the use of tandem transplantation in selected high-risk populations.
Tandem transplantation is recommended in patients who experience partial improvements after the first ASCT.[24] The IFM92 study randomised 399 patients to receive single or tandem transplantation after induction therapy.[5] The researchers found that patients who did not achieve VGPR after the first ASCT benefited from tandem transplantation. Single and tandem transplantation outcomes did not differ between patients who achieved VGPR or higher. It should be noted that the IFM92 study was conducted before the introduction of novel agents, and most of our patients received novel agent-based induction therapy. In contrast to IFM92, tandem transplantation improved PFS in patients with VGPR after their first ASCT. Our results highlighted the benefits of developing a new response adaptation strategy using these agents. Consolidation and maintenance therapies according to the response status after induction therapy are examples of potential novel approaches.[25,26] With newly developed agents, such as bispecific antibodies and chimeric antigen receptor T-cell therapy, the role of tandem transplantation should be further investigated in future trials to develop highly accurate risk- and response-adapted strategies.[27]
Although our study focused on tandem transplantation, maintenance therapy should also be emphasised. Maintenance therapy significantly improved the OS and PFS in all patients after adjusting for tandem transplantation. In the subgroup analysis, maintenance therapy showed a significant survival benefit in patients who did not achieve CR after the first ASCT. Although maintenance therapy did not demonstrate any clinical benefit in patients with high-risk FISH, it elicited favourable OS results in a subgroup of patients with standard-risk FISH. Patients who underwent tandem transplantation followed by maintenance therapy had the longest median PFS, although the sample size was small. Therefore, appropriate post-ASCT strategies to achieve the best outcome should be assessed based on available drugs, targeted patients, schedule and duration, long-term toxicity, and cost-to-benefit ratio.[28] Compared with maintenance therapy, tandem transplantation has a relatively shorter duration and improved cost-effectiveness. Although 11 patients died within 100 days of tandem transplantation in our study, only one died because of infection, while the remaining deaths occurred due to disease progression. The relatively high mortality rate reflects the refractory nature of high-risk diseases rather than tandem transplantation-related effects. The toxicity profiles of single and tandem transplantations were comparable. Therefore, identifying the most appropriate candidates for tandem transplantation and maintenance therapy after ASCT is necessary. The frailty score, application of an adjusted dose of the conditioning regimen, and patient preference may be important, along with risk stratification and response status.[29]
Our study had several limitations. First, the patients were heterogeneous in age at diagnosis, treatment period, and induction regimen, owing to the retrospective nature of the study. We performed propensity score matching to overcome the possible bias introduced by these factors, given that these factors may affect the treatment offered by physicians. We reported a significant clinical benefit of tandem transplantation, prolonging the median PFS from 13.5 to 30.3 months when compared with single transplantation. Second, we evaluated the response-adapted approach according to response status after the first ASCT. Our results suggest that patients with VGPR may benefit from tandem transplantation after the first ASCT scan. However, we were unable to include the minimal residual disease status, which has recently become a key endpoint in determining therapeutic responses. Future studies assessing the minimal residual disease status may further refine the optimal criteria for tandem transplantation.
In conclusion, tandem transplantation was beneficial in high-risk patients with MM and improved the clinical outcomes in those who did not achieve CR, particularly in those who presented with VGPR after the first ASCT. Further studies are needed to evaluate the clinical role of tandem transplantation in patients with MM.