A Tale of Two Proteasome Inhibitors: Carfilzomib Versus Bortezomib in Multiple Myeloma

At the 16th International Myeloma Workshop (IMW), two clinical trials of patients with newly diagnosed and relapsed/refractory multiple myeloma (NDMM; RRMM) showed disparate results. In the phase III CLARION trial of patients with NDMM, carfilzomib failed to improve progression-free survival (PFS) compared with bortezomib when added to a combination of melphalan and prednisone; in the phase III ENDEAVOR trial of patients with RRMM, however, treatment with a combination of carfilzomib and dexamethasone improved overall survival (OS), compared with patients who received a combination of bortezomib and dexamethasone.

CLARION

This randomized, open-label, multicenter, phase III CLARION trial, presented by Thierry Facon, MD, from the Centre Hospitalier Régional Universitaire de Lille in France, enrolled 955 transplant-ineligible NDMM patients from 213 locations in the United States, South Korea, Spain, and France.1 All patients received melphalan 9 mg/m2 and prednisone 60 mg/m2 (administered on days 1-4 of each treatment cycle) and were randomized 1:1 to receive either:

  • carfilzomib (20 mg/m2 on days 1-2 and 36 mg/m2 thereafter; n=478)
  • bortezomib (1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32; n=477)

Median age was 72 years in both arms, and the authors noted that “there were no major imbalances in baseline characteristics between treatment arms.”

Fifty-nine percent of carfilzomib-treated patients and 61 percent of bortezomib-treated patients received the entire planned 54 weeks of treatment.
Response rates were higher in the carfilzomib group:

  • overall response rate = 84.3% vs. 78.8% (odds ratio [OR] = 1.41; 95% CI 1.01-1.97)
  • complete response rate = 25.9% vs. 23.1% (OR=1.18; 95% CI 0.88-1.59)

Median PFS was 22.3 months (95% CI 20.9-26.7) in the carfilzomib arm, compared with 22.1 months (95% CI 20.8-24.4) in the bortezomib arm, for a non-significant hazard ratio (HR) of 0.906 (95% CI 0.75-1.1; p=0.159). Time to progression (a secondary endpoint) was also similar between both groups (HR=0.84; 95% CI 0.68-1.04 for carfilzomib vs. bortezomib).

At the time of presentation, OS data were immature, but Dr. Facon reported 99 (20.7%) and 78 (16.4%) events in the carfilzomib and bortezomib arms, respectively (HR=1.21; 95% CI 0.89-1.64).

Treatment discontinuation because of an adverse event (AE) occurred in 16.7 percent of carfilzomib-treated patients and 14.7 percent of bortezomib-treated patients. The rate of fatal treatment-emergent AEs was higher in the carfilzomib group (6.5% and 4.3%), but the significance was not reported.

Grade ≥3 AEs occurred in 74.7 percent of carfilzomib-treated patients and 76.2 percent of bortezomib-treated patients. The most common grade ≥3 AEs included acute renal failure (7.4% and 2.1%), cardiac failure (8.2% and 2.8%), dyspnea (3.6% and 0.6%), and hypertension (10.1% and 3.6%). Prevalence of grade ≥2 peripheral neuropathy (a secondary endpoint) was lower in the carfilzomib group (2.5% and 35.1%).

“In a maximum of nine treatment cycles, carfilzomib did not improve PFS compared with bortezomib in transplant-ineligible NDMM patients,” Dr. Facon and colleagues concluded. “These results suggest that melphalan may not be an ideal drug to combine with carfilzomib in this setting.”

ENDEAVOR

According to updated results of the phase III ENDEAVOR trial, patients with RRMM who received carfilzomib and dexamethasone had longer OS than those who received a combination of bortezomib and dexamethasone.2

The ENDEAVOR trial is a head-to-head comparison of the two proteasome inhibitors, carfilzomib and bortezomib, in adult patients with RRMM who received one to three prior lines of therapy and had at least a partial response to at least one line of therapy. In an earlier analysis of the trial, carfilzomib was shown to lengthen median PFS, compared with bortezomib (18.7 months vs. 9.4 months; hazard ratio [HR] = 0.53; 95% CI 0.44-0.65; p <0.001).

At IMW, Meletios A. Dimopoulos, MD, from the National and Kapodistrian University of Athens School of Medicine in Greece, presented results from the planned second interim OS analysis.

A total of 929 patients were randomized 1:1 to receive:

  • carfilzomib (20 mg/m2 on days 1-2; escalated to 56 mg/m2 thereafter, if tolerated) and dexamethasone (20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23) in 28-day cycles (n=464)
  • bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11, administered intravenously or subcutaneously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) in 21-day cycles (n=465)

Patients were treated until progression or withdrawal.

Over a median follow-up of 38 months in the carfilzomib group and 37 months in the bortezomib group, the median OS was nearly eight months longer in the carfilzomib group: 47.6 months (95% CI 42.5 – not yet reached) versus 40 months (95% CI 32.6-42.3).

All-cause mortality was significantly lower with carfilzomib (HR=0.79; 95% CI 0.65-0.96; p=0.01), and this finding was consistent regardless of clinical factors, including prior bortezomib exposure, age, and performance status (TABLE).

Dr. Dimopoulos noted that safety results were comparable with those previously reported in the PFS interim analysis of the ENDEAVOR trial. The most frequent any-grade AEs in the carfilzomib and bortezomib cohorts included anemia (42.5% and 28.3%), diarrhea (36.3% and 40.6%), pyrexia (32.4% and 15.4%), dyspnea (32.2% and 13.6%), fatigue (32.2% and 30.7%), and hypertension (32.2% and 9.9%). Grade 3 AEs occurred more frequently in the carfilzomib cohort (81.4% vs. 71.1%). However, dose reductions occurred more frequently in the bortezomib plus dexamethasone cohort (48% vs. 23%).

Grade ≥3 hematologic AEs were similar between the two groups and included anemia, thrombocytopenia, neutropenia, upper respiratory infection, and pneumonia, while non-hematologic AEs included diarrhea, fatigue, dyspnea, pyrexia, constipation, and insomnia.

“Based on these data, we now know that carfilzomib not only significantly extended PFS compared with bortezomib, but also OS, making it a clinically meaningful advance in the treatment of RRMM,” Dr. Dimopoulos said during his presentation of the results.

However, the large portion of patients who had received prior bortezomib may have resulted in a bias in favor of carfilzomib, as it compared patients who were re-exposed to the same drug with those who were exposed to a new agent.


References

    1. 1. Facon T, Lee JH, Moreau P, et al. Phase 3 study (CLARION) of carfilzomib, melphalan, prednisone (KMP) v bortezomib, melphalan, prednisone (VMP) in newly diagnosed multiple myeloma (NDMM). Abstract #373. Presented at the 16th International Myeloma Workshop; New Delhi, India.
    2. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Overall survival of patients with relapsed or refractory multiple myeloma treated with carfilzomib and dexamethasone versus bortezomib and dexamethasone in the randomized phase 3 ENDEAVOR trial. Abstract #374. Presented at the 16th International Myeloma Workshop; New Delhi, India.

TABLE. Hazard Ratios for All-Cause Mortality by Subgroups
  Carfilzomib Versus Bortezomib
Prior bortezomib exposure
Yes 0.75
No 0.84
Age
<65 years 0.85
65-74 years 0.71
>75 years 0.84
Number of prior lines of therapy
1 0.83
2-3 0.76
Baseline ECOG performance status
ECOG 0 0.81
ECOG 1 0.80
ECOG 2 0.50
ECOG = Eastern Cooperative Oncology Group
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