Elsevier

The Lancet Oncology

Volume 17, Issue 1, January 2016, Pages 27-38
The Lancet Oncology

Articles
Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study

https://doi.org/10.1016/S1470-2045(15)00464-7Get rights and content

Summary

Background

Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.

Methods

In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m2; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866.

Findings

Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3–16·1) in the carfilzomib group and 11·1 months (8·2–14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6–not estimable) in the carfilzomib group versus 9·4 months (8·4–10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44–0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]).

Interpretation

For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option.

Funding

Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Introduction

Multiple myeloma is a common and often fatal haematological malignancy. New treatment options, such as the first-in-class proteasome inhibitor bortezomib, have prolonged survival in patients with this disease.1, 2 Bortezomib was first approved in 2003 in the USA for the treatment of multiple myeloma and is given with dexamethasone as a standard treatment for relapsed or refractory disease worldwide.3, 4 Importantly, bortezomib given twice weekly as an intravenous infusion is associated with high rates of peripheral neuropathy (all grades, 34–54%; grade 3 or higher, 8–16%).3, 4, 5, 6 Furthermore, peripheral neuropathy is among the most common adverse events leading to treatment discontinuation (4–8% of patients) in phase 2 and 3 studies with bortezomib.3, 6, 7

When compared with intravenous administration, subcutaneous administration of bortezomib showed non-inferior efficacy (overall response in 42% of patients in both groups) and lower frequency grade 2 or higher (24% vs 39%) and grade 3 or higher peripheral neuropathy (6% vs 16%).5 Additionally, a once-weekly infusion of bortezomib in combination with melphalan and prednisone with or without thalidomide showed significantly reduced frequencies of grade 3–4 peripheral neuropathy compared with a twice-weekly schedule (8% vs 28%) without a reduction in efficacy.8 However, there are no published data from randomised trials that have compared the once-weekly schedule of bortezomib alone with the standard twice-weekly schedule, and the once-weekly schedule is not included in the bortezomib label. Although once-weekly and subcutaneous administration of bortezomib is associated with improved tolerability and convenience of this drug compared with twice-weekly administration, new anti-myeloma regimens are needed that are more effective and better tolerated.

Research in context

Evidence before this study

Bortezomib and dexamethasone is a standard treatment option worldwide for patients with multiple myeloma. We searched PubMed for clinical studies in multiple myeloma that have assessed carfilzomib with dexamethasone in patients with relapsed or refractory multiple myeloma. Specific search terms included “carfilzomib”, “dexamethasone”, “relapsed”, “refractory”, “second-line”, “third-line”, “salvage”, and “multiple myeloma”. We included all English language studies published until June 14, 2015.

We identified two studies that assessed the combination of carfilzomib and dexamethasone in patients with advanced multiple myeloma. In a phase 1b/2 study, carfilzomib showed promising activity and tolerability in combination with dexamethasone in patients with relapsed or refractory multiple myeloma or both. In a phase 2 study, treatment with carfilzomib with or without dexamethasone resulted in a high overall response and durable disease control in heavily pretreated patients with relapsed or refractory multiple myeloma, but was also associated with hypertension and heart failure. These studies suggested that carfilzomib with dexamethasone is a promising treatment option for patients with relapsed or refractory multiple myeloma.

Added value of this study

To our knowledge, ENDEAVOR is the first phase 3 head-to-head comparison between two proteasome inhibitors and is the largest phase 3 randomised trial to date in patients with relapsed or refractory multiple myeloma. In this study, patients treated with carfilzomib and dexamethasone had longer progression-free survival compared with those treated with bortezomib and dexamethasone. Overall, the results from ENDEAVOR suggest an important role for carfilzomib-based regimens for the treatment of patients with relapsed or refractory multiple myeloma.

Implications of all the available evidence

Compared with bortezomib and dexamethasone, carfilzomib with dexamethasone was associated with a significant and clinically meaningful improvement in progression-free survival. Furthermore, carfilzomib with dexamethasone had an acceptable adverse event profile. These results delineate the favourable benefit–risk profile of this regimen. Carfilzomib and dexamethasone should be considered as a treatment option for patients with multiple myeloma for whom bortezomib and dexamethasone could also be considered.

Carfilzomib is a selective proteasome inhibitor that is approved in the USA for use as a single agent in patients with relapsed and refractory multiple myeloma or in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma (one to three previous lines of therapy), at doses of 20 mg/m2 (starting dose) and 27 mg/m2 (target dose) infused over 10 min. Carfilzomib irreversibly binds to the proteasome, which results in more sustained proteasomal inhibition than that produced by bortezomib. In a phase 1b/2 study,9 carfilzomib given at higher doses (20 mg/m2 [starting dose] and 56 mg/m2 [target dose]) and for a longer infusion time (30 min) showed promising activity and tolerability in combination with dexamethasone in patients with relapsed or refractory multiple myeloma or both. We initiated this randomised, open-label, multicentre, phase 3 study (ENDEAVOR) to compare carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.

Section snippets

Study design and participants

In this randomised, open-label, phase 3 study patients were recruited from 198 sites in North America, Europe, South America, and the Asia-Pacific region (appendix pp 3–6). Patients aged 18 years or older with relapsed or refractory multiple myeloma, measurable disease (ie, serum M-protein of at least 5 g/L or urine M-protein of at least 200 mg/24 h; or in patients without detectable serum or urine M-protein, serum free light chain of at least 100 mg/L [involved light chain] and an abnormal

Results

Between June 20, 2012, and June 30, 2014, 929 patients from North America, Europe, South America, and the Asia-Pacific region were randomly assigned to treatment (464 to the carfilzomib group and 465 to the bortezomib group; figure 1). 360 (79%) patients in the bortezomib group received subcutaneous bortezomib throughout study treatment; all others received intravenous bortezomib at some point during treatment. Baseline characteristics were generally balanced between treatment groups (table 1;

Discussion

In this randomised, phase 3 study, patients treated with carfilzomib and dexamethasone had longer progression-free survival than those treated with bortezomib and dexamethasone. Progression-free survival in all subgroups, including bortezomib-naive patients and patients with high-risk or standard-risk cytogenetics, was longer in the carfilzomib group than in the bortezomib group. However, neither proteasome inhibitor appeared to significantly overcome the adverse prognostic effect of high-risk

References (23)

  • PG Richardson et al.

    Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib

    J Clin Oncol

    (2006)
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