Studies support carfilzomib’s approval

Bone marrow aspirate
showing multiple myeloma

Results from 3 multicenter clinical trials indicate that carfilzomib elicits good responses and manageable toxicities in both newly diagnosed and pretreated patients with multiple myeloma (MM).

Carfilzomib is a novel, highly selective proteasome inhibitor that was recently approved by the FDA to treat relapsed or refractory MM. 

The new drug application for carfilzomib was based primarily on a study published July 25 in Blood. Results of another recent study also seem to support the drug’s approval. And a third study suggests the drug may be appropriate for newly diagnosed MM.

Phase 2b trial in relapsed/refractory MM

This trial included 266 heavily pretreated patients with relapsed or refractory MM who had received at least 2 prior therapies, including bortezomib and either thalidomide or lenalidomide.

Patients went on to receive single-agent carfilzomib at 20 mg/m² twice weekly for 3 out of 4 weeks in cycle 1. They then received the drug at 27 mg/m² for a maximum of 12 cycles.

The overall response rate, which included patients who achieved a partial response or better, was 23.7%. The median duration of response was 7.8 months, and the median overall survival was 15.6 months.

Adverse events were manageable, without cumulative toxicities, the researchers said. The most common events were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 and 2, and 33 patients withdrew due to an adverse event. 

“[C]arfilzomib produced clinically significant responses with an acceptable safety profile in heavily pretreated patients with relapsed and refractory multiple myeloma,” said lead study author David S. Siegel, MD, PhD, of the John Theurer Cancer Center in Hackensack, New Jersey.

“Given the limited number of treatment options available to patients with advanced-stage multiple myeloma and the diminished prospects for retreatment once an agent has been utilized, we believe there is a significant need in this patient population.”

Phase 2 trial in advanced MM

This trial evaluated carfilzomib in 129 MM patients who had relapsed following 1 to 3 courses of treatment. Patients previously treated with bortezomib were excluded from the study, as the use of bortezomib might make carfilzomib’s effects more difficult to determine.

The researchers separated patients into 2 treatment arms. Cohort 1 was scheduled to receive intravenous carfilzomib at 20 mg/m² for all treatment cycles. Cohort 2 was scheduled to receive 20 mg/m² for cycle 1 and then 27 mg/m² for all subsequent cycles.

The overall response rate was 42.4% in cohort 1 and 52.2% in cohort 2. The clinical benefit response—the overall response rate plus the minimal response—was 59.3% in cohort 1 and 64.2% in cohort 2.

The median duration of response was 13.1 months in cohort 1 and not reached in cohort 2. The median time to progression was 8.3 months in cohort 1 and not reached in cohort 2.

The most common adverse events were fatigue (62.0%) and nausea (48.8%). Patients also experienced peripheral neuropathy (17.1%), mostly grades 1 and 2, but 1 patient developed grade 3. 

“We saw significant responses in patients considered more difficult to treat, including those with more advanced disease and poor prognoses,” Dr Siegel said. “Our results support the potential use of carfilzomib in this patient population.”

Phase 1/2 trial in newly diagnosed MM

This study evaluated carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) as a frontline treatment for MM.

“Triple-agent regimens with bortezomib, lenalidomide, and/or thalidomide are currently the preferred frontline strategy for newly diagnosed multiple myeloma,” said study author David H. Vesole, MD, PhD, also of the John Theurer Cancer Center.

“However, maintaining dose levels over time can be limited by the treatments’ emerging toxicities. This study demonstrated that the combination of carfilzomib, lenalidomide, and dexamethasone is well-tolerated and highly active for these patients.”

The researchers enrolled 53 patients with newly diagnosed MM who had symptomatic disease. Patients received CRd induction therapy in 28-day cycles for up to 8 cycles, until disease progression, or until they developed unacceptable toxicity. After that, patients received maintenance CRd for up to 24 cycles and then moved to single-agent lenalidomide.

Of the 49 patients who completed 4 treatment cycles, 67% achieved at least a near complete response (nCR). Forty-five percent were in stringent complete response (sCR), defined as no detectable tumor cells or myeloma protein in the blood or bone marrow.

Of the 36 patients who completed 8 or more treatment cycles, 78% achieved nCR, with 61% in sCR. Overall, 62% of trial participants achieved at least nCR, with 42% achieving sCR.

Progression-free survival was 97% at 12 months and 92% at 24 months. All patients who achieved sCR continued to respond to therapy for a median of 9 months.

Grades 3 and 4 toxicities included hypophosphatemia (25%), hyperglycemia (23%), anemia (21%), thrombocytopenia (17%), and neutropenia (17%). Twenty-three percent of patients experienced grade 1 or 2 peripheral neuropathy.

Discussion

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