Prognostic Impact of Tandem Autologous Stem Cell Transplantation (ASCT) in Different Response Subgroups after 1^st ASCT

Background

High dose (HD) chemotherapy with melphalan and autologous stem cell transplantation (ASCT) have been considered a standard treatment for newly diagnosed multiple myeloma (MM) patients for more than 30 years. Two-course (tandem) ASCT proved to be beneficial in terms of progression-free and overall survival (PFS and OS, respectively) when compared to single ASCT(Vesole, 1996; Attal, 2003) or conventional therapy(Barlogie, 1997) by some authors, while others described a non-inferiority of single versus tandem ASCT(Mai, 2016). Furthermore, tandem ASCT prolonged OS in patients with less than very good partial response (VGPR) after 1^st ASCT, whereas patients with at least VGPR did not benefit from 2^nd ASCT(Attal, 2003).

Aims

We investigated each response group after 1^st ASCT separately in regard to their survival benefit from 2^nd ASCT. Additionally, we focused on the question whether patients who improved their response status after 1^st ASCT benefit more from 2^nd ASCT compared with those who did not.

Methods

A total of 1115 patients with newly diagnosed MM who had undergone single or tandem ASCT at University Hospital of Heidelberg or other German centers between June 1996 and March 2014 were included. The analysis cohort consisted of patients treated within German-Speaking Myeloma Multicenter Group (GMMG)-HD3 trial(Goldschmidt, 2003) as well as non-trial patients (NTP). All NTP were transplanted at the University Hospital of Heidelberg, whereas GMMG-HD3 patients were enrolled in the trial in Heidelberg and underwent ASCT either here or at other German centers. Patients with progressive disease (PD) after 1^st ASCT and those receiving allogeneic SCT before 1^st PD/ relapse were excluded. PFS and OS were calculated from time of response assessment after 1^st ASCT. If no date had been documented, the date was set to 100 days after 1^st ASCT but before 2^nd ASCT. Effect of 2^nd ASCT was included as time-dependent factor in Cox regression. Remission status was evaluated according to EBMT criteria, which were a primary tool for response evaluation at time of treatment of most patients. Change in response before/ after 1^st ASCT was assessed, excluding patients in CR before 1^st ASCT. Multivariate analysis included patient cohort, age at induction therapy (IT) start, date of treatment start, and novel agents (bortezomib or thalidomide) in IT.

Results

All patients (all response groups after 1^st ASCT taken together) benefited from 2^nd ASCT in terms of PFS and OS (p= 0.0002 and 0.0018, respectively). However, in the subgroup analysis, patients with complete response (CR) after 1^st ASCT did not benefit from tandem ASCT in terms of PFS or OS (p= 0.5563 and 0.1134, respectively). Patients with partial response (PR) after 1^st ASCT showed prolonged PFS (p= 0.0004) and OS (p= 0.0493) when having received tandem ASCT. The group achieving PR, minimale response (MR), or stable disease (SD) after 1^st ASCT (PR/MR/SD) benefited from longer PFS and OS (p= 0.0001 and 0.0043, respectively) after the 2^nd ASCT and the subgroup of MR/SD patients had similar PFS (p= 0.0557) but better OS (0.0022) after tandem compared to single ASCT. Further, patients who improved their response after 1^st ASCT benefited from the 2^nd ASCT in terms of PFS and OS (p= 0.0014 and 0.0213, respectively), whereas those who retained the same response after 1^st ASCT had longer PFS (p= 0.0118) but similar OS (p= 0.1144) compared to single transplanted patients.

Summary and conclusions

Tandem ASCT has been described as beneficial compared to single ASCT in generalas well as for a subgroup of patients with < VGPR after 1^st ASCTby some authors, while others suggested a non-inferiority of single compared to tandem ASCT in newly diagnosed MM patients. Our analysis showed survival benefit for patients with PR, MR/SD, and PR/MR/SD after 1^st ASCT who underwent tandem compared to single ASCT. Patients with CR did not benefit from 2^nd ASCT in terms of PFS/OS. Improvement of the response status after 1^st ASCT was a significant predictive factor for PFS and OS benefit from 2^nd ASCT. Those who retained the same response after 1^st ASCT showed longer PFS but not OS when receiving tandem ASCT. We therefore conclude that patients who achieved PR or worse (except for PD patients, who were excluded from the analysis) after 1^st ASCT undergo 2^nd ASCT, especially if the 1^st ASCT led to improvement of remission, whereas patients who achieved CR after the 1^st ASCT should not receive a tandem ASCT.