Carfilzomib Shows Promise as Alternative to Bortezomib in Multiple Myeloma

James R. Berenson, MD

Two separate clinical trials presented at ASCO 2012 suggest that carfilzomib (Kyprolis) would be a safe and effective alternative to bortezomib (Velcade) for the treatment of multiple myeloma.

For patients with multiple myeloma who progressed while on treatment with bortezomib-containing regimens, carfilzomib is a potentially safe and effective replacement for bortezomib in those regimens, according to the conclusion of a phase I/II study.¹ Responses to carfilzomib were robust, achieved rapidly, and were durable when carfilzomib was combined with a wide variety of drugs and drug classes, including alkylating agents, anthracyclines, immunomodulators, and glucocorticoids, according to lead author, James R. Berenson, MD, Oncotherapeutics, Institute for Myeloma & Bone Cancer Research, Los Angeles, California.

Results were presented for the first 22 evaluable patients of a planned enrollment of 45. The trial is ongoing and currently enrolling patients. All patients had multiple myeloma with measureable disease and had progressed while receiving their most recent bortezomibcontaining regimens, or relapsed within 12 weeks of the last dose of the most recent bortezomib- containing regimen. Patients received at least 4 doses of bortezomib at ≥1.0 mg/m².

For all patients, carfilzomib was substituted for bortezomib, with the remainder of the patient’s regimen remaining unchanged. Response was observed in 63.6% of patients. At a median treatment duration of 3 months, 22.7% achieved complete response. Median time to progression and median progression-free survival were both 9.8 months. Median duration of response was 8.2 months.

The most common hematological events of all grades were thrombocytopenia (59.1%), lymphopenia (40.9%), hyperglycemia (36.4%), leukopenia (27.3%), and anemia (27.3%). Adverse events grade >2 included thrombocytopenia (31.8%), lymphopenia (22.7%), anemia (9.1%), decreased red blood cell count (4.5%), and leukopenia (4.5%).

Nonhematologic adverse events included headache (31.8%), fever (27.3%) insomnia (27.3%), and nausea (22.7%). Nonhematologic adverse events grade >2 included fever (9.1%), pneumonia (9.1%), sepsis (9.1%), chills (4.5%), peripheral neuropathy (4.5%) and urinary tract infection (4.5%).

Two of the six serious adverse events occurred in the same patient. The study will establish the maximal tolerated doses for the regimens.

A separate study in patients with multiple myeloma who were refractory or intolerant to both bortezomib and immunomodulators (thalidomide or lenalidomide) showed that single-agent carfilzomib had clinically meaningful and durable responses in these patients, who have a poor prognosis.²

David S. Siegel, MD, PhD

“This study strengthens the conclusion that carfilzomib has significant activity in patients who have no remaining treatment options, and thus have a critically important unmet need,” according to lead author David Siegel, MD, PhD, John Theurer Cancer Center, Hackensack, New Jersey.

The phase IIb study enrolled 266 heavily pretreated patients with multiple myeloma who were refractory to bortezomib in any other prior regimen, refractory/ intolerant to bortezomib and at least one immunomodulator, or disease-refractory to all five approved classes of treatment. Of these, 257 were evaluable for response and 266 for safety. Patients could receive up to 12 cycles of carfilzomib.

Overall response rate (ORR) was 22.9%. In patients with disease refractory to bortezomib (n =194), ORR was 16.5%; ORR was 22.2% in patients with disease refractory to lenalidomide (n = 221). ORR was 15.4% in patients with disease refractory to both bortezomib and lenalidomide (n = 169). ORR was 20.1% in patients with disease refractory to/and intolerant to both bortezomib and lenalidomide (n = 214). For the entire population, duration of response was a median of 7.8 months.

Overall survival (OS) for the entire study population was a median of 15.4 months. In patients with disease refractory to/and intolerant to both bortezomib and lenalidomide, median OS was 13.2 months. In patients refractory to all five approved classes of treatment, median OS was 15.0 months.

1. Berenson JR, Yellin O, Dichmann R, et al. A phase I/II study of carfilzomib (CFZ) as a replacement for bortezomib (BTZ) for multiple myeloma (MM) patients (Pts) progressing while receiving a BTZ-containing combination regimen J Clin Oncol. 2012;30(suppl; abstr 8098).
2. Siegel DSD, Martin T, Singhal S, et al. Response rates to single-agent carfilzomib in patients refractory or intolerant to both bortezomib and immunomodulators in trial PX-171-003-A1. J Clin Oncol. 2012;30(suppl; abstr 8035).