The benefits of adding carfilzomib to dexamethasone, compared with adding bortezomib – seen in the ENDEAVOR study among patients with relapsed and refractory multiple myeloma – persist regardless of age, cytogenetic risk status or number of prior therapy lines. The study, together with the three prospective planned subgroup analyses, was presented at the 57th annual meeting of the American Society of Hematology, held in Orlando, FL, December 5th-8th 2015.

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Multiple myeloma is a cancer of the bone marrow, which is the spongy tissue found at the center of some bones.

“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 coauthors in The Lancet Oncology.

Carfilzomib (Kyprolis), the first irreversible proteasome inhibitor, was approved by the European Medicines Agency (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 leads to an excessive build-up of proteins within cells, which can cause cell death. The irreversibility of carfilzomib’s binding, it is believed, may offer more sustained inhibition of targeted enzymes.

In the phase 3 open label multicenter ENDEAVOR study, published simultaneously online in The Lancet Oncology to coincide with the meeting, 929 adult patients with relapsed multiple myeloma, with up to 3 prior lines of therapy, were randomized 1:1 to intravenous carfilzomib and oral dexamethasone (Kd, n=464) or intravenous bortezomib (Velcade) and oral dexamethasone (Vd, n=465).

Cycles were 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). 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).

In abstract 1844, Antonio Palumbo, from the University of Torino, Italy, and colleagues undertook a post-hoc subgroup analysis categorizing ENDEAVOR participants into three groups according to age: less than 65, 65-74, and 75 years and older.

Results show that the HR for median progression-free survival for Kd vs. Vd was 0.58 for patients aged less than 65 years, 0.53 for patients aged 65-74 years, and 0.38 for patients aged 75 years and older.

Furthermore, for patients receiving Kd, the overall response rate (complete response or better plus very good partial response or better) was 74% for those aged under 65 years, 77% for those aged 65-74 years, and 84% for those aged over 75 years.

Rates of grade 2> peripheral neuropathy were lower in the Kd arm than the 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, adding the perfect dose for this population has yet to be defined. “I’m 100 % sure of the 36/m2 dose and 70% sure for the 56 mg/m2 dose,” he said.

In abstract 30, Dimopoulos and colleagues assessed the cytogenetic risk status of patients in the ENDEAVOR study with Fluorescence in situ hybridization. The high-risk group was defined as those with genetic subtypes t[4;14) or t(14;16) in more than 10% of screened plasma cells or deletion 17p in more than 20% of screened plasma cells, based on central review of bone marrow samples at study entry.

Results show that for high-risk patients, carfilzomib benefits persisted, with median progression-free survival at 8.8 months for Kd versus 6 months for Vd (HR 0.646, 95% CI: 0.453-0.921). Overall response rates in high-risk groups were 72.2% for carfilzomib and 58.4% for bortezomib.

Dimopoulos says:

As expected, median progression-free survival for patients with high-risk cytogenetics was lower compared with the overall population. However, patients treated with carfilzomib had a clinically meaningful improvement in progression-free survival compared with bortezomib with high or stand-risk cytogenetics.”

In abstract 729, Philippe Moreau, from the University of Nantes, France, and colleagues undertook a post-hoc subgroup analysis categorizing ENDEAVOR study participants into two groups according to number of prior treatment one or more than two lines.

Results showed in patients receiving one line of prior therapy, disease progression or death occurred in 30.2% (70) receiving Kd versus 47 % (109) receiving Vd. Furthermore, median progression-free survival was 22.2 months for those receiving Kd versus 10.1 months for those receiving Vd (HR =0.45; 95 % CI, 0.33-0.61).

For those receiving more than two prior lines of therapy, disease progression and death occurred in 43.5% (101) receiving Kd versus 57.5% (134) receiving Vd. The median progression-free survivals for patients with more than two prior lines were 14.9 months and 8.4 months, respectively (HR=0.60; 95% CI, 0.47-0.78).

“Carfilzomib had a favorable benefit-risk profile in relapsed multiple myeloma, irrespective of prior treatment. Carfilzomib should be considered in patients who have progressed on lenalidomide maintenance,” Moreau concluded.

Amgen announced the submission to the EMA for a 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. The FDA are scheduled to make a decision by January 22nd 2016.