Filanesib Alone or in Combination Shows Promise for Refractory Myeloma

An early-phase study of filanesib, the highly selective inhibitor of kinesin spindle protein, showed that the drug had clinical activity and manageable toxicity when combined with prophylactic filgrastim in patients with heavily pretreated multiple myeloma. The results of the study were published in Cancer.

Filanesib “induces apoptosis preferentially in cells that depend on short-lived survival proteins during mitosis. Thus, multiple myeloma, which typically demonstrates an over-reliance on the survival protein Mcl-1, may be an appropriate target for filanesib,” wrote Jatin J. Shah, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

The phase I/II study established the maximum tolerated dose at 1.50 mg/m² per day administered as a 1-hour infusion. Patients received filanesib on days 1 and 2 of 14-day cycles. The study included cohorts of patients treated with and without dexamethasone.

For the phase II single-agent cohorts, patients had received prior bortezomib and prior thalidomide and/or lenalidomide. For the phase II filanesib-plus-dexamethasone cohort, patients had received prior alkylator therapy and had disease refractory to lenalidomide, bortezomib, and dexamethasone. Prophylactic filgrastim was incorporated during dose escalation and was used throughout phase II.

The median number of prior therapies was six. The most common dose-limiting toxicities of filanesib were febrile neutropenia and mucosal inflammation. During the phase II portion of the study, grade 3 and 4 cytopenias occurred in about one-half of patients.

In the phase II portion of the study, the response rate was 16% for single-agent filanesib in patients with prior bortezomib and immunomodulatory agent treatment. The researchers noted that this response was “comparable to the single-agent activity observed with recently approved pomalidomide (overall response rate, 16%–23%).”

“In addition to the response rates, the activity of filanesib is durable, with prolonged stable disease reported and approximately 30% of patients continuing therapy beyond 6 months,” the researchers wrote. They noted that overall survival was 19.0 months in the phase II filanesib cohort.

For patients with refractory disease treated with filanesib plus dexamethasone, the overall response rate was 15%. Responses in these patients were also durable, with an overall survival of 10.7 months. Again, the researchers noted that these response rates are similar to those “for pomalidomide/dexamethasone and carfilzomib regimens approved in the United States for the treatment of similar, if not less refractory, multiple myeloma patient populations.”

The researchers conducted a post-hoc exploratory analysis of baseline alpha-1–acid glycoprotein (AAG), an acute-phase reactant protein that may be elevated in individuals with cancer. They found that at a baseline AAG value of 110 mg/dL or above, no patients demonstrated a minimal response or better. Among patients with low AAG levels in the single-agent cohort, the overall response rate was 23%, and in the filanesib/dexamethasone cohort it was 20%.

“AAG levels vary considerably among patients with multiple myeloma and can fluctuate over time,” the researchers noted. “It is unclear whether this biomarker is predictive for response to filanesib or, instead, represents a prognostic biomarker.”