First-in-Class Targeted Agent Shows Activity in Refractory Multiple Myeloma

Jonathan Kaufman, MD

According to data presented at the 55th Annual Meeting of the American Society of Hematology in New Orleans, a first-in-class targeted agent demonstrated activity in patients with relapsed and refractory multiple myeloma.

One group of heavily pretreated patients had an objective response rate of 16% with single-agent filanesib (ARRY-520), a kinesin spindle protein (KSP) inhibitor. In a second cohort of patients with relapsed/refractory disease, the combination of filanesib and dexamethasone resulted in an objective response rate of 16%.

Duration of response was 8.6 months with filanesib monotherapy and 5.1 months in patients who received dexamethasone in addition to filanesib. Overall survival was 19 months with filanesib alone and between10 and 11 months with the dexamethasone regimen, Jonathan Kaufman, MD, reported during the meeting.

“This is a new medication that has a new mechanism of action and has significant activity in an otherwise relapsed/refractory population,” said Kaufman, associate professor of Hematology and Medical Oncology at the Winship Cancer Institute of Emory University in Atlanta. “We need new classes of drugs to offer options to patients who have failed three or more drugs.”

“The other important aspect of this study is that we found a new predictive biomarker,” Kaufman continued. “What this means is that, in the future, we can potentially save patients from ever being exposed to medications that have no chance of being efficacious.”

KSP plays a key role in mitosis, and laboratory studies have shown that inhibition of KSP leads to cell-cycle arrest, followed by cell death. Preliminary clinical studies suggested that filanesib has activity against multiple myeloma.

Kaufman reported mature data from a phase II trial that enrolled patients with heavily pretreated myeloma. Patients were accrued to two cohorts, one treated with single-agent filanesib (n=32) and the other treated with the KSP inhibitor and dexamethasone (n=50).

Investigators obtained baseline measurements of the acute-phase protein alpha-1 acidic glycoprotein (AAG), which studies have shown can bind filanesib, reducing free drug and possibly dampening the drug’s activity in patients with high levels of the protein.

Patients in the monotherapy group had received a median of six prior regimens, and those in the dexamethasone group had a median of nine prior regimens. Entry criteria specified failure of at least two prior regimens, including bortezomib and an IMiD compound (lenalidomide, thalidomide, pomalidomide).

In the monotherapy group, 41% of patients exhibited resistance to bortezomib and lenalidomide, and most patients in the dexamethasone group were refractory to three drugs. Time to progression on the most recent therapy was 7.5 months in the monotherapy group and 2.9 months in the dexamethasone group.

Among patients with AAG measurement data, six of 27 evaluable patients in the filanesib monotherapy group had elevated levels of AAG, as did 13 of 44 evaluable patients in the dexamethasone group.

In both groups, filanesib was administered intravenously every 2 weeks with growth factor support.

Although participants in the combination group were more refractory, the overall response rate was the same in both groups.

No patient with elevated baseline AAG attained an objective response to filanesib. Moreover, no patient with elevated AAG obtained a clinical benefit (including major response).

Exclusion of patients with elevated AAG at baseline increased the overall response rate to 24% in the monotherapy group and 19% in the patients who received dexamethasone and filanesib.

In the monotherapy group, overall survival was 19.0 months in the total population, 4.5 months in patients with elevated AAG, and 23.3 months in patients who had normal AAG levels at baseline. The more refractory group of patients treated with filanesib and dexamethasone had an overall survival of 10.7 months, including 2.4 months in the high-AAG subgroup and 10.8 months in the normal-AAG subgroup.

The KSP inhibitor had a similar safety profile in both treatment groups, Kaufman reported. The most frequent grade 3/4 adverse events were thrombocytopenia (44% of the monotherapy group and 42% of the dexamethasone group), anemia (38% and 50%), neutropenia (38% in both groups), fatigue (16% and 8%), leukopenia (13% and 4%), and pneumonia (3% and 12%). Both groups had a low incidence of febrile neutropenia (3% and 6%).

Lonial S, Shah JJ, Zonder J, et al. Prolonged Survival and Improved Response Rates With ARRY-520 In Relapsed/Refractory Multiple Myeloma (RRMM) Patients With Low α-1 Acid Glycoprotein (AAG) Levels: Results From a Phase 2 Study. Presented at: the ASH 55^thAnnual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 285.

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