ASH 2018 | Long-term follow-up of double vs single ASCT in patients with newly diagnosed multiple myeloma

The 60th American Society of Hematology (ASH) Annual Meeting was held in San Diego, California, from 1–4 December 2018. On Saturday 1 December 2018, an oral abstract session was held entitled: Clinical Autologous Transplantation: Results: Multiple Myeloma: Upfront Autologous Transplantation, which focused on updates of advanced clinical trials for newly diagnosed multiple myeloma (NDMM).

Results arising from clinical trials regarding the use of a single or double autologous stem cell transplant (ASCT) for young and/or fit patients with NDMM are conflicting, possibly due to differences in the design of the trials. To address this issue Michael Cavo from S Orsola’s University Hospital’s Bologna University School of Medicine in Bologna, Italy, and collaborators, performed an integrated efficacy analysis of patient-level data from three European phase III trials, which had used bortezomib, thalidomide, and dexamethasone (VTd) or bortezomib, doxorubicin, and dexamethasone (PAd) as induction therapies, prior to ASCT. After treatment with ASCT, patients had received bortezomib-based consolidation and/or maintenance treatment. Patients had been assigned to receive a single (ASCT-1) or a double (ASCT-2) ASCT depending on the design of the trial or treatment policy of cooperative groups participating in the same study. The three trials used for this study were the GIMEMA MMY-3006, the PETHEMA/GEM and the HOVON65MM/GMMG-HD41 and the presented data resulted from a 10-year follow-up period.

Results are described as ASCT-1 versus (vs) ASCT-2 unless otherwise indicated.

Study Design:

• Total number of patients randomized to either VTD or PAD = 909
• Patients in each ASCT group = 501 vs 408
• Median age: ASCT-1 = 58 years (range, 53–62); ASCT-2 = 58 (range, 52–61)
• Patients with ISS stage III = 20% vs 17%
• Patients with high-risk cytogenetics (cyto) [t(4;14) and/or del(17p)] = 18% vs 23%

Key Data:

• Median follow-up = 117 months (interquartile range [IQR], 91–126)
• Median progression-free survival (PFS) = 38 vs 47 months (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.65–0.89, P = 0.001)
  • Patients with high-risk cyto: 20 vs 36 months (HR, 0.67; 95% CI, 0.46–0.97, P = 0.032)
  • Patients with ISS stage II-III: 33 vs 40 months (HR, 0.82; 95% CI, 0.67–1.00, P = 0.052)
• Overall survival (OS) (estimated 10-year probability) = 42% vs 55% (HR, 0.69; 95% CI, 0.56–0.84, P < 0.001)
  • Patients with high-risk cyto: 40 vs 80 months (HR, 0.54; 95% CI, 0.36–0.83, P = 0.004)
  • Patients with ISS stage II-III: 78 vs 106 months(HR, 0.73; 95% CI, 0.57–0.93, P = 0.011)
• Independent predictors for prolonged PFS derived from a multivariate Cox regression analysis:
  • ASCT-2: HR, 0.81; 95% CI, 0.66–0.99, P = 0.048
  • ISS stage low vs high: HR, 0.62; 95% CI, 0.48–0.80, P < 0.001
  • Absence of high-risk cyto: HR, 0.57; 95% CI, 0.45–0.73, P < 0.001
  • Platelet (PLT) count > 150.000/mmc: HR, 0.74; 95% CI, 0.54–0.99, P = 0.049
  • Complete response (CR) recorded anytime throughout treatment (best CR): HR 0.53; 95% CI, 0.43–0.64, P < 0.001
• These independent predictors were also significantly related to longer OS:
  • ASCT-2: HR, 0.75; 95% CI, 0.57–0.98, P = 0.036
  • ISS stage low vs high: HR, 0.66; 95% CI 0.47–0.90, P = 0.01
  • Absence of t(4;14) and/or del(17p): HR, 0.55; 95% CI, 0.41–0.73, P < 0.001
  • PLT count > 150.000/mmc: HR, 0.54; 95% CI, 0.38–0.78, P = 0.001
  • Best CR: HR, 0.55; 95% CI, 0.43–0.72, P < 0.001
• Based on HR estimates of three leading predictors of outcomes (ISS stage II+III, high-risk cyto and failure to achieve best CR) patients were stratified into three subgroups:
  • Low-risk (20%, none of the 3 adverse variables); median PFS = 87 months; 10-year OS rates = 78%
  • Intermediate-risk (42%, 1 adverse variable); median PFS = 53 months; 10-year OS rates = 53%
  • High-risk (38%, 2 or 3 adverse variables); median PFS = 27 months; 10-year OS rates = 32%
• In the low-risk subgroup: The ASCT-2 group vs the ASCT-1 group showed a trend to improved PFS, but not OS (HR, 0.66; 95% CI, 0.41–1.07, P = 0.093)
• In the intermediate subgroup: No difference was observed between the ASCT-1 and ASCT-2 groups in terms of PFS and OS
• In the high-risk subgroup: Assignment to ASCT-2 vs ASCT-1 significantly prolonged both median PFS (32 vs 20 months; HR, 0.71; 95% CI, 0.54–0.93, P = 0.012) and OS (80 vs 48 months; HR, 0.58; 95% CI, 0.42–0.80, P = 0.001)
• In the ultra-high-risk subset (patients with all three adverse variables):assignment to ASCT-2 vs ASCT-1 resulted in a two-fold increased median PFS (35 vs 14 months; HR, 0.40; 95% CI, 0.21–0.79, P = 0.008) and 56% reduction in the risk of death (26% vs 6% estimated 10-year OS probability; HR, 0.44; CI, 0.21–0.90, P = 0.025)

Conclusions

A 10-year long follow-up analysis of three phase III clinical trials incorporating bortezomib-based triplets as induction treatments prior to ASCT, reveals superiority of ASCT-2 over ASCT-1 in terms of PFS and OS, particularly in subgroups of patients with predictors of high-risk multiple myeloma.

References

Cavo M. et al. Double Vs Single Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: Long-Term Follow-up (10-Years) Analysis of Randomized Phase 3 Studies. 2018 Dec 1; Oral Abstract #124: ASH 60th Annual Meeting and Exposition, San Diego, CA.