Carfilzomib
Carfilzomib is a highly selective epoxyketone proteasome inhibitor with minimal affinity for nontarget proteases. In a recent phase II trial in patients with relapsed/refractory MM, reported at the 2010 American Society of Hematology (ASH) meeting, carfilzomib produced durable responses and was well tolerated.2 An ongoing phase I/II trial assessing carfilzomib, lenalidomide, and dexamethasone in newly diagnosed MM, also reported at the 2010 ASH meeting, has shown good activity and tolerability of the regimen.3 A phase III trial comparing carfilzomib plus lenalidomide and low-dose dexamethasone versus lenalidomide and low-dose dexamethasone in relapsed MM has been initiated.
Relapsed/refractory MM
In the trial in patients with relapsed/refractory MM, 266 patients with multiply relapsed MM who had disease refractory to their last treatment received carfilzomib (20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16) every 28 days for the first cycle, with the dose then being escalated to 27 mg/m2 on the same schedule for up to 12 cycles.2 Prior therapies included bortezomib, either lenalidomide or thalidomide, and an alkylating agent. Patients had a median duration of MM of 5.4 years and had received a median of 5 prior lines of chemotherapy and a median of 13 antimyeloma treatments; prior treatments included bortezomib in 99.6% of patients (a median of two prior regimens containing bortezomib), lenalidomide in 94%, thalidomide in 74%, corticosteroids in 98%, alkylating agents in 91%, and stem cell transplantation in 74%. Overall, 65% of patients were refractory to bortezomib prior to study entry.
At the time of reporting, 79 patients (30%) had completed at least 6 cycles of study treatment, approximately 11% had completed 12 cycles (with most entering an extension phase of the study), and 15 patients remained on study (all with more than 10 cycles of study treatment). Among 257 patients evaluable for response, 0.4% (one patient) had a complete response, 4.7% had a very good partial response, and 19% had a partial response, for an overall response rate of 24%; an additional 12% of patients had a minimal response, yielding an overall clinical benefit rate of 36%. Stable disease for at least 6 weeks was achieved in 32%. Among patients with a partial response or better, the median duration of response was 7.4 months. Among patients with a minimal response, the median duration of response was 6.3 months, indicating durable minor responses.
Toxicity consisted mainly of myelosuppression. Grade 3/4 hematologic toxicities consisted of thrombocytopenia in 18% of patients, lymphopenia in 11%, neutropenia in 8%, and anemia in 7%.4 Grade 3/4 nonhematologic toxicities included fatigue in 6% of patients; pneumonia and congestive cardiac failure in 3% each; nausea, dyspnea, increased blood creatinine levels, and increased blood uric acid levels in 1% each; and diarrhea in 0.4%. Grade 1/2 peripheral neuropathy was present in 77% of patients at baseline; new-onset neuropathy was infrequent, with grade 3 or lower neuropathy occurring in less than 1% of patients.2
Newly diagnosed MM
In an ongoing phase I/II trial, patients with newly diagnosed MM are receiving carfilzomib, lenalidomide, and dexamethasone.3 Carfilzomib is started at 20 mg/m2 (dose level 1) and increased to 27 mg/m2 (dose level 2) and 36 mg/m2 (dose level 3) given IV on days 1, 2, 8, 9, 15, and 16 in 28-day cycles. Lenalidomide is given at 25 mg/d on days 1−21 in each cycle, and dexamethasone is given weekly at 40 mg during cycles 1−4 and at 20 mg during cycles 5−8. Patients with a partial response or better are eligible to proceed to stem cell collection and autologous stem cell transplantation after at least 4 cycles and can continue study treatment after transplantation. After completion of 8 cycles, patients are to receive maintenance cycles consisting of carfilzomib on days 1, 2, 15, and 16; lenalidomide on days 1−21; and weekly dexamethasone at doses tolerated at the end of 8 cycles. A planned 36 patients are to be treated at the carfilzomib maximum tolerated dose.
At the time of reporting, 24 patients had been enrolled, 4 at dose level 1, 14 at dose level 2, and 6 at dose level 3. Toxicity data were available for 21 patients, including 19 who completed at least 1 cycle of treatment. A single dose-limiting toxicity event was observed, consisting of nonfebrile neutropenia in a patient at dose level 2. The maximum tolerated dose had not yet been reached. Grade 3/4 hematologic toxicities consisted of neutropenia in three patients, thrombocytopenia in three patients, and anemia in one patient. Grade 3 nonhematologic toxicities included five cases of elevated blood glucose levels, deep vein thrombosis during aspirin prophylaxis in one patient, and fatigue in one patient. Emergent peripheral neuropathy was observed in two patients, who developed grade 1 neuropathy.