Patients eligible for transplant

Bortezomib consolidation therapy confers distinct PFS benefit in newly diagnosed MM patients

In a letter to the editor of Leukemia, published in March 2017, Hermann Einsele and colleagues from the Julius-Maximilians-University of Würzburg present the case for the use of bortezomib as consolidation therapy for newly diagnosed multiple myeloma (MM) patients, following autologous stem cell transplantation (ASCT). Data were analyzed from two bortezomib phase 3 trials that assessed NDMM patients after ASCT, and stratified according to age and prior treatment regimens. Studies were carried out in 47 departments across Germany, between October 2006 and May 2013. The primary endpoint was progression free survival (PFS) from the start of induction therapy. Secondary endpoints assessed were event-free survival (EFS), from start of induction to start of new chemotherapy or death, response rates, overall survival (OS), quality of life, and safety.

Key Findings
  • pts (n=371) randomly assigned to receive:
    • consolidation therapy (n= 186): four 35-day cycles of intravenous bortezomib 1.6 mg/m2 (days 1, 8, 15, and 22) or
    • observation arm: no therapy (n= 185)
    • 14 withdrew consent and are excluded from efficacy analysis
  • Cytogenetic changes were assessed by FISH
  • Unfavorable genetics (del13q, t(4:14) or del17p)= 39%; High-risk cytogenetics (t[4;14] or del17p) = 16%
  • All data points are given as: bortezomib arm vs. observation arm
  • Median PFS = 33.6 vs. 27.8 months                                                                                                    HR = 0.75; 95% CI, 0.59–0.97; P = 0.0243
  • Median PFS (sensitivity analysis) = 23.1 vs. 17.2 months                                                           adjusted HR = 0.70; (95% CI, 0.54–0.89); P = 0.0046
  • Shorter PFS for pts with unfavorable cytogenetics vs. no cytogenetic changes: adjusted HR = 1.46; (95% CI, 1.03–2.08); P = 0.034)
  • PR at randomization versus ≥ VGPR: adjusted HR = 1.35; (95% CI, 1.03–1.77); P = 0.032
  • Pts with < VGPR at randomization benefited significantly from bortezomib consolidation: HR = 0.58 (95% CI, 0.53-1.05); median PFS = 33.3 vs. 24.5 months
  • PFS improvements were observed regardless of cytogenetic status:
    • no changes: HR = 0.77; 95% CI, 0.47–1.27; P = 0.297
    • del 13q, t(4;14), del 17p: HR = 0.66; 95% CI, 0.41–1.05; P = 0.074
    • t(4;14), del 17p: HR = 0.61; 95% CI, 0.30– 1.22; P = 0.154
  • EFS (from induction to start of second-line treatment) = 37.8 vs. 34.3 months;                          adjusted HR = 0.74; 95% CI, 0.57–0.96; P = 0.024
  • pts with ≥ VGPR at the end of treatment/observation = 62% vs. 48%; P = 0.003
  • Discontinuation due to AEs = 15% (28 pts) of bortezomib-treated pts: nausea (3%), diarrhea (3%), vomiting (3%), polyneuropathy (2%), and disease progression (2%)
  • Serious AE s = 11% vs. 17% and included: herpes zoster: 3% vs. 4%, disease progression 1% vs. 4% and pneumonia 1% vs. 2%
  • Polyneuropathy, peripheral neuropathy, and peripheral sensory neuropathy = 18% vs. 6%
  • Deaths during post-treatment follow-up (30–60 months after the end of treatment visit) = 25% (47 pts) vs. 30% (56 pts)
  • No treatment-related deaths

Consolidation therapy with bortezomib (administered over a period of 5 months, 4 cycles), was well-tolerated and highly effective in delaying disease progression (6-month increase in PFS), as well as improving the quality of response in NDMM patients. Of note, improvements were seen in high-risk subsets: < VGPR after HDT/ASCT, del13q, t[4;14] or del17p, and, t(4;14), del 17p for which prognosis is generally low. In addition, a favorable response was independent of prior bortezomib treatment in the induction therapy.

References
  1. Einsele H. et al. Response-adapted consolidation with bortezomib after ASCT improves progression-free survival in newly diagnosed multiple myeloma.Leukemia. 2017 Apr 18. DOI: 10.1038/leu.2017.83. [Epub ahead of print]
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