SAN DIEGO – Data mined from several phase II studies of carfilzomib monotherapy confirm previous observations, but also raise new questions and insights into the use of the investigational proteasome inhibitor in relapsed and/or refractory multiple myeloma.
The first of three posters simultaneously presented at the American Society of Hematology used multivariate modeling to confirm a dose-response relationship for carfilzomib in bortezomib (Velcade)-naive and bortezomib-treated patients.
After study effect was adjusted for, the odds of achieving a partial response or better for a patient treated with 27 mg/m2 were 4.08-fold higher than for a patient receiving only 20 mg/m2 (P less than .001).
When using the average dose as a continuous variable and again adjusting for study effect, the odds of a response increased by 1.28-fold for each 1-mg/m2 increase in average carfilzomib dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m2 to 27 mg/m2 (P less than .001), reported Sunhee Ro, Ph.D., an employee of San Francisco–based Onyx Pharmaceuticals, which is developing the drug. Statistician Pierre Squifflet of the International Drug Development Institute in Belgium was the lead author.
The dose-effect relationship was observed not only on the primary end point of overall response rate, but also time to progression, progression-free survival, and overall survival.
The analysis included three study populations: 266 heavily pretreated patients who had received at least two prior therapies including bortezomib and either thalidomide or lenalidomide and who received carfilzomib 20 mg/m2 in cycle one with escalation to 27 mg/m2 if tolerable, 35 patients pretreated with one to three prior therapies including bortezomib who received carfilzomib 20 mg/m2, and 129 bortezomib-naive patients treated at 20 mg/m2 or the same dose with escalation to 27 mg/m2 if tolerable.
A corresponding toxicity analysis is underway, as are clinical trials assessing higher-dose regimens. The analysis raises the obvious question of whether the 20- to-27-mg/m2 dose schedule Onyx used in its recent accelerated review filing for carfilzomib is possibly too low.
Dr. Ro and other Onyx employees milling about the poster were hesitant to comment, with Ruben Sanchez, the associate director of publications at Onyx, saying only that the maximum tolerated dose of carfilzomib is 20-70 mg/m2 and that studies are ongoing at an "experimental dose" of 20-56 mg/m2.
Unfavorable Cytogenetics
The second poster confirmed that unfavorable cytogenetics did not significantly impact overall response rates or response duration, but found that median overall survival was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities at 11.9 months vs. 19.2 months.
A similar trend was observed for median progression-free survival at 3.6 months vs. 4.6 months, reported Dr. Andrzej J. Jakubowiak of the University of Michigan Comprehensive Cancer Center in Ann Arbor.
When the researchers looked at specific cytogenetic abnormalities in the 234 evaluable patients dosed using the 20- to 27-mg/m2 schedule, median overall survival was the lowest among those with deletion 17p3 at 7 months vs. 10.6 months with deletion 13, 10.4 months with hypodiploidy, and 11.8 months with translocation t(4:14).
Dr. Sundar Jagannath
Progression-free survival and time to progression also tended to be longer for patients with hypoploidy and translocation t(4:14) than for patients with deletion 13 and deletion 17p13. This observation is compatible with current thinking highlighted in an educational multiple myeloma program at the meeting, that cytogenetic abnormalities are becoming something of a moving target, coauthor Dr. Sundar Jagannath, director of the multiple myeloma program at Mt. Sinai Medical Center in New York, said in an interview.
"One area, 17p13 deletion, is still a challenge, but t4;14 translocation, hypodiploidy, and deletion 13 ... are all no longer considered as high risk in the presence of protease inhibitors," he said. "It is nothing unique to carfilzomib; it’s just the class of protease inhibitors."
Dr. Jagannath said that even in patients with the problematic 17p13 deletion, researchers have used gene expression profiling to further delineate those at high and low risk, and that data clearly show that outcomes are improved in low-risk 17p13 deletion patients with the inclusion of the protease inhibitor bortezomib therapy.
Safety Data
The third poster features integrated safety data from 526 heavily pretreated patients receiving carfilzomib 20 mg/m2 or 20-27 mg/m2, showing that grade 3/4 treatment adverse events occurred in 80% of patients, but were characterized as mostly reversible and primarily hematologic in nature.
The most common grade 3 adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). There were no fatal hematologic events and no grade 4 or 5 bleeding reactions associated with thrombocytopenia, reported Dr. Seema Singhal, professor of medicine and director of the multiple myeloma program at Northwestern Memorial Hospital in Chicago, and her associates.