Early Study of Bendamustine, Carfilzomib Shows Encouraging Results

A recent early study examined whether combining bendamustine with carfilzomib will create a safe and effective induction regimen for patients with myeloma as measured by the maximum tolerated dose (MTD). Secondary endpoints included overall response rate (ORR), time to response, progression-free survival, overall survival, toxicity, and stem cell yield.

The authors, writing in Blood Cancer Journal, noted the similarity of this approach, that it is currently used in other combinations. Carfilzomib is a second-generation proteasome inhibitor (PI). Current PI regimens, when combined with immunomodulatory drugs (IMIDs), are standard for patients with newly diagnosed myeloma.

PIs can also be combined with alkylating agents, allowing IMIDs to be saved for relapse cases. Combinations include bortezomib—bendamustine–prednisone, as well as bortezomib–cyclophosphamide–dexamethasone.

Bendamustine has synergistic activity with bortezomib, said the authors, who conducted a single-arm, single-center, open-label, phase 1/2 study of carfilzomib, bendamustine, and dexamethasone (CBD) in adults with newly diagnosed myeloma. Each treatment cycle was 28 days. Carfilzomib was started at 20 mg/m² (days 1, 2; cycle 1), after which it was escalated to 36 mg/ m² in patients 3 and 4 and to 56 mg/m² in patients 5 and beyond.

Patients eligible for autologous stem cell transplant (SCT) received 4 cycles of CBD, underwent stem cell harvest (SCH), and then received 4 more cycles of CBD followed by SCT. SCT-ineligible patients received 8 cycles of CBD.

Whether SCT-eligible or -ineligible, maintenance with carfilzomib 36 mg/m² on days 1, 2, 15, and 16 for up to 2 years was recommended, although the protocol was later amended to allow for investigator and patient changes.

An adverse event was considered a dose-limiting toxicity (DLT) if it occurred in cycle 1, was deemed related to study treatment, and was one of peripheral neuropathy ≥grade 2, any nonhematologic AE ≥ grade 3, neutropenia grade 4 lasting ≥7 days or with fever, thrombocytopenia grade 4 lasting ≥7 days or with bleeding, or any AE requiring a dose reduction during cycle 1 or a delay to the start of cycle 2.

Only patients who received ≥2 cycles of treatment were considered evaluable for response. Responses were determined by the treating physician according to the International Myeloma Working Group. All complete responses (CRs) were confirmed by bone marrow aspiration. MRD status was determined by flow cytometry.

The trial targeted 34 patients for enrollment; due to slow accrual and loss of funding, the trial was closed after 20 patients enrolled. The researchers evaluated the probability to observe a DLT by the Clopper—Pearson method, and survival was evaluated by Kaplan–Meier analysis.

Of the 20 patients, the median age was 65; 4 (20%) were male; 7 (35%) were Hispanic. All patients were evaluable for safety, and 19 were evaluable for response. Sixteen patients completed 8 cycles.

Of the 19 patients receiving ≥2 cycles, 15 (79%) were eligible for SCT, 13 (68%) underwent SCT, and 2 declined. SCH was not impacted by CBD.

For maintenance, 10 of 19 (53%) received carfilzomib; 5, lenalidomide; 2 were lost to follow-up; and 2 declined. Of the 10 patients receiving carfilzomib, the median duration of use was 15 months. In addition, the median duration on study treatment was 9.7 months. None of the patients discontinued study treatment due to disease progression.

The authors did not observe any DLTs. Although the study recruited fewer patients than planned, the authors said based on their 95% confidence interval for observing 1 DLT at the highest dose level, they can establish the highest dose as the MTD. The researchers said CBD was highly effective, with an ORR (≥partial response [PR]) of 100%. The best responses were 2 (11%) PRs, 5 very good PRs (26%), and 12 CRs (63%).

Among the CRs, 4 were MRD-positive and 5 were MRD-negative; 3 did not have testing.

Limitations of the study included a small sample size, failure to complete planned accrual, and a lack of high-cytogenetic-risk patients.

Reference

Leng S, Bhutani D, Raza S, et al. Phase I/II study of carfilzomib, bendamustine, and dexamethasone (CBD) in patients with newly diagnosed multiple myeloma [published online February 3., 2020] Blood Cancer J.

doi: 10.1038/s41408-020-0278-5