Carfilzomib Versus Bortezomib: Comparing Proteasome Inhibitors in Newly Diagnosed Myeloma

Carfilzomib plus melphalan and prednisone (KMP) failed to improve survival outcomes for patients with newly diagnosed multiple myeloma (MM) compared with bortezomib plus melphalan and prednisone (VMP), according to results from the phase III CLARION trial published in Blood.

In this randomized, open-label, international trial, Thierry Facon, MD, from the Hôpital Claude Huriez in Lille, France, enrolled adults with previously untreated MM who were considered ineligible for autologous hematopoietic cell transplantation. Eligible patients had measurable disease and an Eastern Cooperative Oncology Group performance score of 0 to 2.

A total of 955 patients were randomized 1:1 to receive either:

  • KMP: carfilzomib 20 mg/m2 administered as a 30-minute intravenous infusion on days 1 and 2 of cycle 1 and 36 mg/m2 thereafter (n=478)
  • VMP: bortezomib 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 (n=477)

In addition, patients received melphalan 9 mg/m2 and prednisone 60 mg/m2 on days one through four of each cycle with both regimens.

Patients were treated for a maximum of nine 42-day cycles or until disease progression, unacceptable toxicity, withdrawal of consent, or death. No crossover between treatment arms was permitted.

The median age was 72 years in both arms (range not provided), and the authors noted that “there were no major imbalances in terms of baseline characteristics between the two treatment groups.”

At a median follow-up of 22 months (range not reported), the median progression-free survival (PFS) was comparable between the two treatment groups: 22.3 months in the KMP group versus 22.1 months in the VMP group (hazard ratio [HR] = 0.906; 95% CI 0.746-1.101; p=0.16).

Median overall survival also was similar and not reached in either group. In the KMP and VMP groups, 107 patients (22.4%) and 95 patients (19.9%) died (HR=1.08; 95% CI 0.82-1.43; p=0.7).

However, in exploratory analyses, the authors found that patients treated with KMP appeared to have a longer median time to progression than those treated with VMP: 27.5 months (range = 22.4 months to not estimable) versus 23.5 months (range = 21.0-27.7 months; HR=0.841; 95% CI 0.679-1.041; p=0.05).

As seen in the TABLE on page 22, response rates appeared to be higher in the KMP group, with a higher rate of very good partial response or better, though a similar proportion of patients in the KMP and VMP groups achieved a complete response. Also, the median duration of response was similar between both groups: 25.2 months (range = 21.3 months to not estimable) versus 22.8 months (range = 20.2-25.8 months; p value not reported).

Rates of minimal residual disease (MRD)–negativity, another secondary endpoint, were again similar between the KMP and VMP groups among the 327 evaluable patients (15.7% and 15.5%, respectively). Achieving MRD-negative disease was associated with higher rates of PFS at two years compared with MRD-positive patients, irrespective of treatment received, the authors noted. “Identical MRD-negative rates between treatment arms anticipated the lack of significant differences in PFS between arms, demonstrating the potential role of MRD as a surrogate endpoint in clinical trials,” they added.

The incidence of grade ≥3 adverse events (AEs) was 74.7 percent and 76.2 percent. Grade ≥3 AEs that were at least 5-percent more frequent in KMP-treated patients than VMP-treated patients included:

  • anemia
  • pyrexia
  • nausea
  • vomiting
  • hypertension
  • peripheral edema
  • dyspnea
  • chills

In addition, the incidence of AEs leading to treatment discontinuation (16.7% and 14.7%), serious AEs (49.6% and 42.1%), and treatment-emergent, grade 5 AEs (6.5% and 4.3%) was higher with carfilzomib than with bortezomib.

“Increased toxicity in the carfilzomib group of CLARION may explain clinical outcomes, and melphalan may not be an ideal drug to combine with carfilzomib in this setting,” the researchers concluded. “Alternative carfilzomib-based regimens merit further evaluation in [patients with newly diagnosed MM].”

The study’s findings are limited by the fixed treatment duration used in the CLARION protocol, as well as by its open-label design, which may have introduced bias.

The authors report relationships with Amgen, which sponsored the study.

Reference

Facon T, Lee JH, Moreau P, et al. Randomized phase 3 study of carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible, NDMM patients. Blood. 2019 February 28. [Epub ahead of print]

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