Patients non-eligible for transplant

Results from a pooled analysis comparing once-weekly with twice-weekly carfilzomib therapy in elderly patients with newly diagnosed multiple myeloma

Carfilzomib, a second-generation proteasome inhibitor, has shown clinical activity in patients with relapsed/refractory (R/R) multiple myeloma (MM), demonstrated by approvals from the US Food and Drug Administration (FDA), in combination with dexamethasone in a once-weekly dosing schedule, and the European Medicines Agency (EMA), in combination with dexamethasone, or lenalidomide and dexamethasone in a twice-weekly schedule. Due to the clinical efficacy displayed in the R/R setting, the exploration of carfilzomib therapy in the frontline setting has begun with trials in patients with transplant-ineligible newly diagnosed MM (NDMM).1,2

Dr. Sara Bringhen from the Division of Hematology, University of Torino, Torino, Italy, and colleagues, published in Haematologica, the results of a pooled analysis of two multicenter phase I/II trials comparing once-weekly (NCT01857115) with twice-weekly (NCT01346787) carfilzomib therapy in elderly patients (median age = 72 years; range, 55–86) with transplant-ineligible NDMM.3

Enrolled patients (n = 121; 63 [once-weekly carfilzomib] and 58 [twice-weekly carfilzomib]) received (n = 119; 63 [once-weekly carfilzomib] and 56 [twice-weekly carfilzomib]) nine, four-week induction cycles of carfilzomib (either once-weekly at 70 mg/m2 on days 1, 8, and 15; or twice-weekly at 36 mg/m2 on days 1, 2, 8, 9, 15, and 16), cyclophosphamide (300 mg, oral, on days 1, 8, and 15), and dexamethasone (40 mg on days 1, 8, 15, and 22). Following induction, patients received maintenance (n = 90; 47 [once-weekly carfilzomib] and 43 [twice-weekly carfilzomib]) with single-agent carfilzomib at same dose and schedule as the induction regimen.

Key findings:

All findings are shown as once-weekly carfilzomib group versus twice-weekly carfilzomib group, where applicable

Efficacy

  • Median follow-up time of pooled cohort: 39 months (range, 31–47)
  • In the intention-to-treat population, median progression-free survival (PFS): 35.7 months (95% CI, 23.7–not reached [NR]) vs 35.5 months (95% CI, 24.3–NR)
  • 3-year median overall survival (OS) was not reached in both groups
  • No significant difference in PFS was seen during induction: 52% vs 43%, HR = 0.76, P = 0.38
  • No significant difference in OS was seen during induction: 78% vs 73%, HR = 0.71, P = 0.36
  • A greater reduction in risk of progression or death seen in once-weekly group: HR = 1.17, P = 0.72 vs HR = 0.52, P = 0.12
  • Median maintenance treatment duration: 17 months (range, 4–28) vs 20 months (range, 7–32), P = 0.17
  • Patients achieving at least a partial remission (PR): 92% vs 90%, P = 0.76
    • Including patients obtaining complete remission (CR) or better: 22% vs 29%, P = 0.41
  • Median time to PR: 1.9 months vs 1.2 months

Safety

  • The most common adverse events (AEs) leading to carfilzomib dose reduction include: acute kidney injury (n = 1 vs n = 2), infections (n = 2 vs n = 2), and hypertension (n = 4 vs n = 0)
  • The incidence of hematological grade III-V treatment-related AEs: 24% vs 30%, P = 0.82
  • The incidence of non-hematological grade III-V treatment-related AEs: 38% vs 41%, P = 0.83

In conclusion, this pooled analysis of two phase I/II trials found that once-weekly 70 mg/m2 carfilzomib treatment has similar efficacy and tolerability compared to twice-weekly 36 mg/m2 carfilzomib therapy in patients with transplant-ineligible NDMM, as an induction combination and a single-agent maintenance therapy. Due to the non-randomized design of the two studies, these results should be further validated in the randomized trial setting.

References
  1. Bringhen S. et al. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2018 Apr; 32(4):979–985. DOI: 10.1038/leu.2017.327.
  2. Bringhen S. et al. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3; 124(1):63–69. DOI: 10.1182/blood-2014-03-563759.
  3. Bringhen S. et al. Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase 1/2 studies. Haematologica. 2019 Feb 7. DOI: 10.3324/haematol.2018.208272. [Epub ahead of print]
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