Prognostic factors for survival in tandem vs single auto-SCT — a retrospective study

There remains a question mark over the survival benefit of single vs tandem autologous stem cell transplantation (auto-SCT) in patients with newly diagnosed multiple myeloma (NDMM). While tandem auto-SCT is used routinely in the MM setting, it has not been verified which patients benefit from the additional SCT and which do not.

A study by Joanna Blocka and colleagues evaluated which patient response groups, following the first auto-SCT, would benefit from a second (tandem) auto-SCT. It was hypothesized that improvement of response status rather than depth of response following initial auto-SCT would impact patient survival in tandem vs single auto-SCT.

Study design

• Patients with NDMM treated with high-dose chemotherapy and single or tandem auto-SCT between June 1996 and May 2016 (N = 978) were included in the analysis
  • Trial patients were from the German Speaking Myeloma Multicenter Group (GMMG) HD4 trial and received transplant in Heidelberg University Hospital or other GMMG centers (n = 323)
  • Non-trial patients (NTP) received transplant at Heidelberg University Hospital (n = 655)
• Primary endpoints: progression-free survival (PFS) and overall survival (OS)
• Response improvement was defined as reaching ≥ 1 response level deeper than that determined prior to auto-SCT
• Induction therapy regimens included
  • vincristine, doxorubicin, and dexamethasone (VAD)
  • bortezomib, doxorubicin, and dexamethasone (PAD)
  • thalidomide, doxorubicin, and dexamethasone (TAD)
  • bortezomib, cyclophosphamide, and dexamethasone (VCD)
  • novel agents, such as bortezomib, thalidomide, lenalidomide
• A multivariate analysis was conducted to determine the relationship between response improvement to auto-SCT and age, novel agents used during induction or maintenance therapy, elevated lactate dehydrogenase (LDH) level, International Staging System (ISS) score, and cytogenetic profile

Results

Patient characteristics

• Of the total patient cohort (Table 1), 53% received a single auto-HCT and 47% received tandem auto-HCT

Table 1. Baseline characteristics and treatment history of patients receiving single and tandem auto-SCT¹

 Response to auto-SCT

• Table 2 presents patient responses prior to first auto-SCT (following induction therapy) and after first auto-SCT
• When comparing the characteristics of patients who improved response to first auto-SCT with those who did not
  • the number of patients receiving induction therapy with novel agents, such as thalidomide, bortezomib, and lenalidomide, compared to those who did not significantly differed (p = 0.02)
  • No significant differences were observed in relation to sex, age, ISS, LDH levels, cytogenetic profile, and number of induction therapy

Table 2. Outcomes before and after first auto-SCT for patients receiving single/tandem auto-SCT¹

Tandem vs single auto-SCT

• By the median follow-up (86 months), 445 deaths and 765 PFS events were recorded
• PFS, but not OS, was significantly improved in patients that had undergone tandem vs single auto-SCT (PFS: hazard ratio [HR] 0.80 [95% CI, 0.67 –0.96], p = 0.01)
  • Interaction tests showed depth of response was not associated with significantly different survival benefit to tandem auto-SCT
• Multivariable analysis of all patients showed
  • patients achieving a very good partial response (VGPR) following first auto-SCT had improved PFS with tandem vs single auto-SCT (HR 0.50 [95% CI, 0.35–0.73], p < 0.001) but not OS
  • no PFS or OS benefit of tandem auto-SCT was observed for patients in CR, nCR, ≤ PR after first auto-SCT
  • PFS and OS after second auto-SCT was significantly superior in patients achieving an improved response to first auto-SCT vs those who did not
    • PFS: HR 0.64 (95 % CI, 0.48–0.85), p = 0.002
    • OS: HR 0.69 (95 % CI, 0.48–0.99), p = 0.04
    • In patients who did not improve their response after first auto-SCT, no benefit in terms of PFS or OS was observed
  • Cytogenetic characteristics did not significantly influence PFS or OS, irrespective of auto-SCT treatment in interaction tests

Prognostic factors for survival

• When considering the entire study cohort, a number of prognostic factors for OS and PFS were observed (Table 3)
• Multivariate analysis of patients achieving an improvement in response following first auto-SCT identified further factors that influenced PFS and OS (Table 4)
• Maintenance therapy did not have a significant impact on OS and PFS, irrespective of response following first auto-SCT

Table 3. Prognostic factors associated with PFS and OS¹

 Table 4. Multivariate analysis of prognostic factors for PFS and OS by patient response improvement to first auto-SCT¹

Conclusion

Response improvement, but not depth of response, following initial auto-SCT is a significant prognostic factor for PFS following tandem vs auto-SCT. The authors note that this likely reflects a difference in patient susceptibility, at a cellular level, to high-dose chemotherapy.

Fewer patients in the population achieving an improved response following first auto-SCT had received novel agents as part of induction therapy. This may indicate that an improvement had already been achieved with these new regimens prior to first auto-SCT. While the use of novel agents in induction therapies make the results of this analysis less applicable to some clinical practices, economic limitations mean that the use of high-dose chemotherapy and auto-SCT are a core part of the treatment of patients with NDMM and therefore remain clinically relevant. By identifying a specific subset of patients who benefit from tandem auto-SCT, the results of this study may mean some patients can avoid the unfavorable side effects of a less effective therapy.