Frontline Carfilzomib Not Superior to Bortezomib in Phase III Myeloma Study

Sean E. Harper, MD

Carfilzomib (Kyprolis) did not improve progression-free survival (PFS) compared with bortezomib (Velcade) when used in combination with melphalan and prednisone as a treatment for transplant ineligible patients with newly diagnosed multiple myeloma, according to topline findings from the phase III CLARION study.

Median PFS with carfilzomib, melphalan, and prednisone was 22.3 months compared with 22.1 months with bortezomib, melphalan, and prednisone (HR, 0.91; 95% CI, 0.75-1.10). Additionally, the rate of fatal treatment-emergent adverse events was higher with carfilzomib versus bortezomib (6.5% vs 4.3%, respectively).

Amgen, the developer of carfilzomib, released findings from the CLARION study. The company plans to submit full data for future presentation and publication, according to the company.

"The CLARION results, generated in the context of a melphalan-containing regimen, are disappointing, especially given the robust data we've seen in the second-line setting," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a statement. "However, the myeloma landscape has changed dramatically since the design of the CLARION study with very few newly diagnosed patients treated with melphalan-based regimens, particularly in the United States," he added. "We remain committed to exploring Kyprolis in combination with other agents to advance the treatment of multiple myeloma."

The phase III CLARION study, which was initiated in 2013, randomized 955 patients with newly diagnosed multiple myeloma to receive melphalan and prednisone plus bortezomib or carfilzomib. The study enrolled at 213 locations, with primary investigators located in the United States, South Korea, Spain, and France. The median age of patients was 72 years.

On days 1 to 4 of each 42-day cycle, melphalan was administered at 9 mg/m² and prednisone was given at 60 mg/m². Carfilzomib was administered intravenously (IV) on days 1, 2, 8, 9, 22, 23, 29, and 30. On days 1 and 2 of the first cycle, the agent was administered at a lower 20-mg/m² dose. For subsequent cycles, carfilzomib was given at 36 mg/m². Bortezomib could be administered either by IV or subcutaneous (SQ) injection. The treatment was given at 1.3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32 for cycles 1 to 4 and on days 1, 8, 22, and 29 for cycles 5 to 9. In both groups, treatment was administered for 54 weeks.

An early assessment of overall survival also demonstrated a lack of superiority for carfilzomib versus bortezomib. At this assessment, the lower end of the confidence interval was 0.90 and the higher end was 1.64. The overall survival hazard ratio for carfilzomib versus bortezomib for was 1.21.

Grade ≥3 adverse events were experienced by 74.7% of patients treated with carfilzomib compared with 76.2% with bortezomib. Grade ≥2 peripheral neuropathy was experienced by 2.5% of patients treated with carfilzomib compared with 35.1% with bortezomib. The exact numbers for patients treated with IV versus SQ bortezomib were not yet released.

Multiple myeloma expert Keith Stewart, MBChB, from the Mayo Clinic, noted on Twitter that CLARION was an important trial in multiple myeloma. He highlighted a near absence of peripheral neuropathy with the carfilzomib regimen but also called out the increased rate of deaths and a lack of convenience for the carfilzomib administration schedule. Ultimately, Stewart noted, economics would also be a factor when determining treatment.

Median PFS with carfilzomib plus dexamethasone was 18.7 versus 9.4 months with bortezomib plus dexamethasone (HR, 0.53, 95% CI, 0.44—0.65; P <.0001). The objective response rate was 77% with carfilzomib versus 29% with bortezomib. The proportion of patients with grade ≥2 peripheral neuropathy was significantly higher with bortezomib (32% versus 6%; P <.0001).

"Based on studies in the Kyprolis label, including the ENDEAVOR study, a head-to-head comparison of Kyprolis to Velcade in patients with relapsed or refractory multiple myeloma, we know Kyprolis to be a major advance in proteasome inhibitor therapy," said Harper.

Carfilzomib is currently approved as a monotherapy for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 or more lines of therapy. In January 2016, the FDA approved carfilzomib for use in combination with dexamethasone alone or with lenalidomide plus dexamethasone for patients with relapsed/refractory multiple myeloma following prior treatment with 1 to 3 lines of therapy, based partially on findings from the phase III ENDEAVOR trial.

Several additional studies continue to compare carfilzomib with bortezomib in various combinations for patients with multiple myeloma. The phase III ENDURANCE study is currently looking at lenalidomide plus dexamethasone with carfilzomib or bortezomib as treatments for patients with newly diagnosed multiple myeloma. The primary endpoint of the study, which is being conducted by the NCI and ECOG-ACRIN, is overall survival (NCT01863550).

Findings from the CLARION study are added to the ENDEAVOR trial, which compared carfilzomib and bortezomib for patients with relapsed/refractory multiple myeloma. In this phase III study, both drugs were given with dexamethasone. A larger, less frequent dose of carfilzomib was administered in this study. The majority of patients received bortezomib subcutaneously (75%).