Role of Frontline Kyprolis Unclear in Multiple Myeloma Care

Topline findings from the phase 3 CLARION study reported that progression-free survival (PFS) was not imporved with Kyprolis (carfilzomib) when compared with Velcade (bortezomib) when used in combination with melphalan and prednisone as a treatment for transplant ineligible patients with newly diagnosed multiple myeloma.

Median PFS with Kyprolis, melphalan, and prednisone was 22.3 months compared with 22.1 months with Velcade, melphalan, and prednisone. Additionally, the rate of fatal treatment-emergent adverse events was higher with Kyprolis versus Velcade (6.5 percent vs 4.3 percent, respectively).

Amgen, the developer of Kyprolis, 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, M.D., 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 3 CLARION study, which was initiated in 2013, randomized 955 patients with newly diagnosed multiple myeloma to receive melphalan and prednisone plus Velcade or Kyprolis. 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 one to four of each 42-day cycle, melphalan was administered at 9 mg/m² and prednisone was given at 60 mg/m². Kyprolis was administered intravenously (IV) on days one, two, eight, nine, 22, 23, 29 and 30. On days one and two of the first cycle, the agent was administered at a lower 20-mg/m² dose. For subsequent cycles, Kyprolis was given at 36 mg/m². Velcade could be administered either by IV or subcutaneous (SQ) injection. The treatment was given at 1.3 mg/m² on days one, four, eight, 11, 22, 25, 29 and 32 for cycles one to four and on days one, eight, 22 and 29 for cycles five to nine. In both groups, treatment was administered for 54 weeks.

An early assessment of overall survival also demonstrated a lack of superiority for Kyprolis versus Velcade. 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 Kyprolis versus Velcade for was 1.21.

Grade 3 or higher adverse events were experienced by 74.7 percent of patients treated with Kyprolis compared with 76.2 percent with Velcade. Grade 2 or higher peripheral neuropathy was experienced by 2.5 percent of patients treated with Kyprolis compared with 35.1 percent with Velcade. The exact numbers for patients treated with IV versus SQ Velcade 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 Kyprolis regimen but also called out the increased rate of deaths and a lack of convenience for the Kyprolis administration schedule. Ultimately, Stewart noted, economics would also be a factor when determining treatment.

Findings from the CLARION study are added to the ENDEAVOR trial, which compared Kyprolis and Velcade for patients with relapsed/refractory multiple myeloma. In this phase 3 study, both drugs were given with dexamethasone. A larger, less frequent dose of Kyprolis was administered in this study. The majority of patients received Velcade subcutaneously (75 percent).

Median PFS with Kyprolis plus dexamethasone was 18.7 versus 9.4 months with Velcade plus dexamethasone. The objective response rate was 77 percent with Kyprolis versus 29 percent with Velcade. The proportion of patients with grade 2 or higher peripheral neuropathy was significantly higher with Velcade (32 percent versus 6 percent).

"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.

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

Several additional studies continue to compare Kyprolis with Velcade in various combinations for patients with multiple myeloma. The phase 3 ENDURANCE study is currently looking at lenalidomide plus dexamethasone with Kyprolis or Velcade 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).