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One Proteasome Inhibitor Tops Another in Relapsed Myeloma

— Progression-free survival doubled with carfilzomib versus bortezomib

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VIENNA -- Patients with relapsed myeloma lived twice as long without progression when treated with carfilzomib (Kyprolis) versus bortezomib (Velcade), a large randomized trial showed.

Carfilzomib plus dexamethasone resulted in a median progression-free survival (PFS) of 18.7 months versus 9.4 months with the bortezomib-dexamethasone combination. Overall response, complete response, and very good partial response all favored the carfilzomib arm in the trial, which enrolled more than 900 patients.

Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • Progression free survival in relapsed melanoma was twice as long with carfilzomib plus dexamethasone versus bortezomib plus dexamethasone.
  • While overall response, complete response, and very good partial response all favored carfilzomib, deaths and adverse event-related treatment discontinuation were similar with both drugs.

Although median treatment duration in the carfilzomib group was more than a year longer than in the bortezomib group, treatment discontinuation because of adverse events and the number of treatment-related deaths were similar in the two groups, as reported here at the European Hematology Association meeting.

"This is the first head-to-head study comparing two proteasome inhibitors," said , of the University of Athens in Greece. "The combination of carfilzomib and dexamethasone resulted in a twofold decrease in the risk of progression or death compared with bortezomib and dexamethasone."

"Carfilzomib-dexamethasone was superior to bortezomib-dexamethasone regardless of age or prior bortezomib exposure and represents a new standard of care," he added.

The has designated bortezomib-dexamethasone as a standard regimen for relapsed myeloma. Single-agent carfilzomib has demonstrated activity in relapsed/refractory myeloma with a 20/27 mg/m2 dosage infused over 2 to 10 minutes. A phase Ib/II trial showed a higher response rate in relapsed myeloma when carfilzomib was administered at a 2 infused over 30 minutes, along with dexamethasone, said Dimopoulos.

The superior results with the higher dose/longer infusion time for carfilzomib provided a rationale to compare the regimen against standard-of-care bortezomib-dexamethasone.

Investigators in the multicenter trial enrolled patients who had received as many as three prior regimens. Prior exposure to bortezomib or carfilzomib was allowed if the patient had achieved at least a partial response to the therapy, had at least a 6-month proteasome inhibitor-free interval, and had not discontinued treatment because of adverse events. Patients who had severe or symptomatic (painful) peripheral neuropathy within the previous 14 days were excluded from the trial.

The trial involved 929 randomized patients, who continued assigned therapy until disease progression or development of unacceptable toxicity. The study population had a median age of 65, and about 15% of patients were 75 or older. A majority (56%) of patients had International Staging System II-III disease, and 20% to 25% had high-risk cytogenetic profiles. About 30% of patients had grade I peripheral neuropathy at enrollment. Half of the patients had received two or more prior regimens, and 54% had prior exposure to bortezomib.

The primary endpoint was PFS by intention-to-treat analysis. The difference in median PFS translated into a 47% reduction in the hazard for progression or death in favor of the carfilzomib arm (HR 0.53, P<0.0001). Subgroup analysis revealed a consistent advantage for carfilzomib across all prespecified patient populations.

Treatment with carfilzomib resulted in an overall response rate of 77%, complete response or better in 13%, and very good partial response or better in 54%. Rates in the bortezomib arm were 63%, 6%, and 29%, respectively (P<0.0001 for all comparisons). Median duration of response was twice as long with carfilzomib (21.3 versus 10.4 months).

Overall survival data remain immature. A preliminary analysis showed a median overall survival of 24.3 months with bortezomib, whereas the median has yet to be reached in the carfilzomib arm. Follow-up will continue until the required number of events have accrued for a final analysis of overall survival, said Dimopoulos.

The carfilzomib arm had a median treatment duration of 40 weeks compared with 27 weeks in the bortezomib arm. Virtually all patients in both treatment arms had adverse events during the treatment period, including grade ≥3 adverse events in 77% of patients assigned to carfilzomib and 63% assigned to bortezomib. The proportion of patients requiring dose reduction because of adverse events was 23% in the carfilzomib arm and 48% in the bortezomib arm.

Discontinuation because of adverse events occurred in 14% of cases in the carfilzomib group and 16% of the bortezomib group. Four patients in the carfilzomib group and three in the bortezomib group died in association with adverse events.

The most common hematologic adverse events in both groups were anemia (39% with carfilzomib, 27% with bortezomib) and thrombocytopenia (21%, 17%). Grade ≥3 anemia occurred in 15% and 10% of the carfilzomib and bortezomib groups, respectively, and thrombocytopenia in 8% and 9%.

Both treatment groups had about a 30% incidence of infection, with upper respiratory infection and pneumonia accounting for all but a few cases. Grade ≥3 pneumonia occurred in 7% to 8% of both groups. No other type of infection occurred in as many as 2% of patients in either group.

In response to a question from the audience, Dimopoulos said analysis of response by cytogenetic risk is ongoing, but preliminary data suggest superiority of carfilzomib in both high-risk (>20% of the patients) and standard-risk patients. Another member of the audience asked about the effect of treatment on cardiac function, and Dimopoulos again said analysis is incomplete but suggests no between-group differences in left ventricular ejection fraction over the course of the study.

"To my knowledge, no more than 1% to 2% of patients have developed reversible cardiomyopathy, which disappears upon discontinuation of treatment," said Dimopoulos.

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined 鶹ý in 2007.

Disclosures

The study was supported by Onyx Pharmaceuticals.

Dimopoulos disclosed relevant relationships with Celgene, Janssen, Onyx, and Genesis.

Primary Source

European Hematology Association

Source Reference: Dimopoulos M, et al "Carfilzomib and dexamethasone improves progression-free survival and response rates vs bortezomib and dexamethasone in patients with relapsed multiple myeloma: the phase III study ENDEAVOR" EHA 2015; Abstract LB2071.