Carfilzomib, daratumumab and dexamethasone

Recently, a subgroup analysis of the MMY1001 study (phase IB) was published, in which daratumumab (anti-CD38) was combined with carfilzomib and dexamethasone in lenalidomide-refractory patients with RRMM. A total of 51 lenalidomide-refractory patients were treated and showed an ORR of 81%, with 8 patients achieving maximum recommended dose-negative status. The ORR for all patients was 86%. The most common grade 3 or 4 AEs were thrombocytopenia (37%), anemia (29%), neutropenia (28%), and lymphopenia (26%).37 In the CANDOR study, the addition of daratumumab to carfilzomib and dexamethasone is being investigated in a phase III randomized study in RRMM patients with one to three prior lines of treatment.

Selinexor, carfilzomib and dexamethasone


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Currently, a phase I study in which selinexor, carfilzomib, and dexamethasone are to be combined is enrolling patients to determine the MTD and recommended phase II dose. Treatment with carfilzomib-based regimens can be quite intensive for patients, coming to the hospital twice weekly for 3 weeks in a row in a 4-week cycle. This burden has led to a phase I/II study investigating the possibility of a once-weekly dosing schedule of carfilzomib combined with dexamethasone.

Carfilzomib in once-weekly administration schedules

In the phase I part of the CHAMPION-1 study, the MTD was established at 70 mg/m2 weekly with 30-minute infusions on days 1, 8, and 15 of a 28-day cycle. In the phase II part of the study, 89 patients were treated with carfilzomib 70 mg/m2 in combination with dexamethasone 40 mg once weekly. In total, 104 patients received carfilzomib at 70 mg/m2 once weekly. The median duration of treatment was 7.7 months, ORR was 77%, 13% of patients achieved a complete response, and CBR was 84%. The ORR for bortezomib-exposed and -refractory and lenalidomide-refractory patients was 73%, 63%, and 71% respectively. Median PFS was 12.6 months.

In total, 62% of patients experienced grade 3 or higher AEs: thrombocytopenia (6%), anemia (6%), neutropenia (4%), fatigue (11%), hypertension (7%), pneumonia (6%), and acute kidney injury (6%). Grade 3 cardiac failure was seen in 2% of patients, and grade 3 PNP in only 1%. Five patients died during the study, one due to disease progression and four due to AEs. Two of these – acute respiratory distress syndrome and cardiopulmonary arrest – were possibly carfilzomib-related. This schedule might be beneficial, considering the lower burden for patients and caregivers, with comparable toxicity to the twice-weekly administration schedule.38

This study led to a phase III study (ARROW), published in 2018, in which RRMM patients with two or three previous lines of treatments, including a PI (carfilzomib or oprozomib excluded) and an IMiD, were treated with once- (20/70 mg/m2) or twice-weekly carfilzomib (20/27 mg/m2), with weekly dexamethasone dosed at 40 mg. A total of 478 patients were included in the study. Median PFS was 11.2 months for the once-weekly group and 7.6 months for the twice-weekly group (P=0.0029), with time to progression of 12.4 months and 8.5 months, respectively. ORR was 62.9% in the once-weekly group vs 40.8% in the twice-weekly group, with median DOR of 15.0 and 13.8 months and median time to response of 1.1 and 1.9 months. Median OS was not reached. At 12 months, OS was 76.6% for the once-weekly group vs 71.9% for the twice-weekly group.

AEs of grade 3 or higher occurred in 68% of patients in the once-weekly group vs 62% in the twice-weekly group. Hematologic grade 3 or higher AEs were anemia (18% vs 18%), thrombocytopenia (7% vs 7%), and neutropenia (6% vs 7%). Nonhematologic AEs of grade 3 or higher included pneumonia (10% vs 7%), hypertension (6% vs 5%), and sepsis (3% vs 1%). No grade 3 or higher PNP occurred in the once-weekly group and in only one person in the twice-weekly group, 3% of patients in the once-weekly group had grade 3 or higher cardiac failure vs 4% in the twice-weekly group, and 13% of patients in the once-weekly group and 12% of patients in the twice-weekly group had to discontinue carfilzomib due to a treatment-emergent AE.13 Based on the results of the ARROW study, recently the once-weekly administration of carfilzomib has been approved by the FDA for patients with RRMM.

TOXICTY OF CARFILZOMIB

Single agent

Siegel et al reviewed the safety profile of carfilzomib as a single agent where data from four phase II studies (PX-171–003-A0 and A1, PX-171–004, and PX-171–005) were combined. In total, 526 patients were included in the analysis: 14.6% of patients required a dose reduction and 22.6% required a dose delay due to an AE, while 14.8% of patients discontinued therapy due to an AE. Reasons to discontinue therapy were congestive heart failure (1.5%), dyspnea (1.3%), acute renal failure/increased blood creatinine (both 1.1%), and cardiac arrest (1.0%). In the following sections, the most important AEs are described. Cardiac AEs are discussed separately. The AEs of any grade most reported overall were fatigue (55%), anemia (46.8%), and nausea (44.9%).

Hematologic

The most reported grade 3 or higher AEs were thrombocytopenia (23.4%), anemia (22.4%), lymphopenia (18.1%), and pneumonia (10.5%).

Renal

In sum, 23.8% of patients had creatinine clearance <50 mL/min, 39.4% had clearance of 50–80 mL/min at baseline, and 13.2% had at least one episode of decrease in renal function of any grade. In half of these patients, the decline in renal function was transient, and the median duration of worsening of renal clearance was 1.4 weeks. In the other 37 patients, renal function decline was nontransient, and 8 of these 37 discontinued treatment due these renal side effects.

Peripheral neuropathy

At baseline, 71.9% of patients experienced PNP grade 1 or grade 2. In this pooled analysis, 1.3% of carfilzomib-treated patients experienced deterioration to grade 3 PNP. All these patients had grade 1 or 2 PNP at baseline. No grade 4 PNP was reported. Only one patient had to discontinue treatment due to neuropathic pain.

Pulmonary

In sum, 42.2% of patients reported dyspnea and 26.0% cough. Most were grade 1 or 2. Grade 3 AEs were reported by 4.8% of patients. There were no grade 4 pulmonary AEs. One patient died due to congestive heart failure, and 1.3% of patients discontinued treatment due to a pulmonary AE. Other AEs were pleural effusion (4%), pulmonary hypertension (2%), pulmonary embolism (1%), hemoptysis (0.6%), and pneumonitis (0.4%), while 18.8% of patients had at least one respiratory infection. Two patients died due to respiratory infection.

Tumor-lysis syndrome

In total, five patients experienced TLS. After prophylactic guidelines were implemented, only one patient experienced TLS (of five in total).39 In the pooled analysis of 526 patients receiving carfilzomib monotherapy 7.2% experienced cardiac failure during treatment and 22.1% reported any cardiac AE, including 14.3% hypertension. The cardiovascular event rate described was higher than previously described with treatment with bortezomib. The exact underlying mechanism of cardiac AEs is still unknown. In the following section, some pathophysiological background is discussed.39

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