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ASH 2015: Carfilzomib superior to bortezomib in relapsed and refractory multiple myeloma

by ecancer reporter Janet Fricker

In relapsed or refractory multiple myeloma progression free survival was significantly better for patients randomised to carfilzomib and dexamethasone than bortezomib and dexamethasone, found the ENDEAVOR study.

The Phase 3 open label study was presented at the 57th ASH, Annual Meeting and Exposition, held in Orlando, Florida, December 5-8, 2015, and published simultaneously online in The Lancet Oncology.

“Taken together, the results from the ENDEAVOR study suggest an important role for carfilzomib-based regimens for patients with relapsed or refractory multiple myeloma,” wrote Meletios Dimopoulos from the National and Kapodistrian University of Athens, Greece, and co-authors in The Lancet Oncology.

Carfilzomib, the first irreversible proteasome inhibitor, was approved by the EMA in November 2015 for use in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma who have received at least one prior therapy.

Blockade of proteasomes results in an excessive build-up of proteins in cells, which can lead to cell death.
Irreversibility of binding, it is believed, offers more sustained inhibition of target enzymes.
In the study, 929 adult patients with relapsed multiple myeloma, and up to 3 prior lines of therapy, were randomised 1:1 to intravenous carfilzomib and oral dexamethasone (Kd, n=464) or intravenous bortezomib and oral dexamethasone (Vd, n=465), with cycles repeated until disease progression or unacceptable toxicity.

Results showed that median progression free survival was 18.7 months for the Kd group versus 9.4 months for the Vd group (HR 0.53; 95 % CI, 0.44-0.65; P<0.001); and median overall survival was 24.3 months in the Vd arm, but had yet to be reached in the Kd arm (HR, 0.79; P=.066).

Ina separate study (abstract no 1844) Antonio Palumbo, from the University of Torino, Italy, and colleagues, undertook a post-hoc analysis categorizing ENDEAVOR participants into three subgroups according to age: < 65; 65-74; and > 75 years.

Results show the HR for median progression free survival for Kd versus Vd was 0.58 for patients aged <65 years; 0.53 for patients aged 65to 74 years; and 0.38 for patients aged > 75 years.

Furthermore, for patients receiving Kd the overall response rate (complete response or better very good partial response or better) was 74% for those aged <65 years; 77% for those aged 65 to 74 years; and 84% for those aged > 75 years.

Rates of grade 2> peripheral neuropathy were lower in the Kd arm than Vd arm across all age groups.
While rates of other select adverse events (grade >3) including hypertension, dyspnoea, and cardiac failure were higher in the Kd arm.

“The take-home message is that we have a second generation proteasome inhibitor that is more potent and better tolerated than bortezomib in the elderly,” said Palumbo.

On the back of ENDEAVOR Amgen announced submission to the European Medicines Agency (EMA) for variation to the Marketing Authorization Application to expand the indication for carfilzomib in combination with dexamethasone for the treatment of adult patients with multiple myeloma to those who have received at least one prior therapy.

References:

Dimopoulos M, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR: a randomised, phase 3, open label, multicentre study. The Lancet Oncology. http://dx.doi.org/10.1016/S1470-2045(15)00464-7 Published online 05 December 2015

Palumbo A, Dimopoulos M, Moreau P, et al. Carfilzomib and Dexamethasone Vs bortezomib and dexamethasone in patients with relapsed multiple myeloma: results of the phase 3 study Endeavor. According to age subgroup. Abstract 1844.

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