Based on these studies, Stewart et al performed a phase III study (ASPIRE) in which the effect of adding carfilzomib to lenalidomide and dexamethasone was investigated in RRMM patients with one to three prior lines of therapy. In this study, carfilzomib dosed at 20 mg/m2 on days 1 and 2 of the first cycle and 27 mg/m2 thereafter was used (28-day cycles, carfilzomib given on days 1, 2, 8, 9, 15, and 16) with 2–10 minutes’ infusion. A total of 792 patients were included in the study, equally divided over the two groups. Median PFS was 26.1 months in the carfilzomib group compared to 16.6 months in the control group (P<0.001). Median OS was 48.3 months vs 40.4 months, respectively (P=0.0045). The difference in OS was more pronounced in patients treated with one prior line of therapy (11.4 months) compared to those treated with two or more prior lines of therapy (6.5 months).
The 24-month OS was 73.3% in the carfilzomib group compared to 65.0% in the control group, and ORR 87.1% and 66.7% (P<0.0001) with a complete response rate of 31.8% and 9.3% (P<0.0001), respectively. Median time to response was 1.6 months for the carfilzomib group and 2.3 months in the control group, with median DOR of 28.6 months vs 21.2 months, respectively. Also, quality of life improved significantly more in the carfilzomib group. Adding carfilzomib to lenalidomide–dexamethasone did not cause an increase in PNP incidence (17.1% vs 17.0%). In the carfilzomib group, any grade 3 AE was reported in 83.7% of patients compared to 80.7% in the control group: cardiac failure happened in 3.8% vs 1.8%, ischemic heart disease in 3.3% vs 2.1%, hypertension in 4.3% vs 1.8%, dyspnea in 2.8% vs 1.8%, and acute renal failure in 3.3% vs 3.1%, respectively. In both groups, 6.9% of patients died as a result of an AE. Adding carfilzomib to lenalidomide and dexamethasone has led to a significantly improved PFS of 7.9 months, with improved quality of life and an acceptable toxicity profile.27,28
OTHER NEW, NON-FDA-APPROVED COMBINATIONS WITH CARFILZOMIB
Carfilzomib and deacetylase inhibitors
Deacetylase inhibitors like panobinostat and vorinostat have shown synergy with PIs like bortezomib. The mechanism of synergy is likely multifactorial, including disruption of protein degradation and inhibition of the interaction of MM cells with their microenvironment.29 In 2015, a phase I/II trial was published investigating the MTD of carfilzomib in combination with the deacetylase inhibitor panobinostat in patients with RRMM. A total of 44 patients participated: 13 in phase I and 31 in phase II. Panobinostat was administered on days 1, 3, 5, 15, 17, and 19 of a 28-day cycle, carfilzomib on days 1, 2, 8, 9, 15, and 16. No dose-limiting toxicity (DLT) was observed, and thus the MTD in this study was defined as panobinostat 30 mg and carfilzomib 20/45 mg/m2.
The ORR was 67% and CBR 79% for all patients. For patients treated at the MTD, ORR was 72% and CBR 88%. Median PFS was 7.7 months, with a median time to progression of 7.7 months. Median OS was not reached: at 24 months, OS was 67%. Grade 3/4 hematologic AEs were thrombocytopenia (38%), neutropenia (21%), and anemia (9%). Nonhematologic grade 3 and 4 AEs were fatigue (11%) and hypertension (9%). Neuropathy grade 3 or 4 did not occur. In total, 14 serious treatment-related AEs occurred in 12 patients. One patient died due to treatment-related heart failure. Three patients discontinued treatment due to toxicity of treatment: anemia, decreased left ventricular ejection fraction, and supraventricular tachycardia.30
Another phase I dose-finding study was performed by Kaufman et al, combining panobinostat and carfilzomib. Panobinostat was administered three times a week in the first 3 weeks of a 4-week cycle at a dose ranging from 15 mg to 20 mg. Carfilzomib was administered twice weekly during the first 3 weeks at doses ranging from 20/27 mg/m2 to 20/45 mg/m2. The MTD was panobinostat 20 mg in combination with carfilzomib 20/36 mg/m2. In this study, three DLTs occurred: grade 4 thrombocytopenia with grade 3 acute kidney injury, persistent grade 4 thrombocytopenia and grade 3 diarrhea. Grade 3 or higher anemia (35%), thrombocytopenia (35%), neutropenia (20%), fatigue (15%), anorexia (10%), hyponatremia (10%), and nausea (10%) occurred. The ORR was 50%, with a median PFS of 14.3 months.31
Vesole et al investigated the combination of carfilzomib (15 mg, 20 mg, or 20/27 mg/m2 on days 1, 2, 8, 9, 15, and 22), lenalidomide (15 or 25 mg from day 1 until day 21), vorinostat (300 or 400 mg, days 1–7 and 15–21), and dexamethasone 40 mg weekly. A total of 17 patients were treated in this phase I study, in which no DLT was reported and the MTD not reached. Grade 3 or higher AEs were anemia (41%), thrombocytopenia (53%), neutropenia (53%), infection (18%), hyperglycemia (18%), electrolyte imbalance (12%), fatigue (6%), and constipation (6%). There were no cardiac AEs. Muscle cramping occurred in 59% of patients, though all grade 2 or lower. The ORR was 53%, with 12% achieving a very good PR and 41% a PR. Median time to response for these patients was 2 months, with median DOR of 15 months and 29% of patients achieving stable disease. Median PFS was 12 months where median OS was not reached.32
Carfilzomib, pomalidomide and dexamethasone
Shah et al investigated the MTD of carfilzomib, pomalidomide, and dexamethasone in a phase I study in RRMM patients with a median six prior lines of therapy. In total, 32 patients were enrolled. Initial doses were carfilzomib 20/27 mg/m2, with pomalidomide once daily from day 1 till day 21 starting at 4 mg and dexamethasone 40 mg/week. All patients were refractory to lenalidomide. A total of 32 of 33 patients received bortezomib, of which 30 were refractory to bortezomib. The MTD was determined at dose level 1, as described earlier. ORR was 50%, CBR 66%, and 16% of patients reached a very good PR. Median PFS was 7.2 months and median OS 20.6 months. Grade 3 or higher AEs were, among others, acute renal failure (three patients), congestive heart failure (one patient), pneumonia (four patients), and dyspnea (one patient). Two patients experienced pulmonary embolism, even though they used aspirin prophylaxis. There was no grade 3 or higher PNP.33
Carfilzomib, ibrutinib and dexamethasone
Chari et al conducted a phase I trial investigating ibrutinib–carfilzomib–dexamethasone combination therapy in patients with RRMM. The primary objective was to determine the MTD. Secondary objectives were to determine ORR and DOR. Ibrutinib was prescribed at 560 mg or 840 mg once daily from day 8 in the first cycle in a 28-day cycle. Carfilzomib was administered twice weekly in the first 3 weeks, starting at 20 mg/m2 and increased to 27 or 36 mg/m2. Dexamethasone was used orally at 20 mg/day twice weekly. A total of 43 patients participated, and no DLT was observed. AEs of grade 3 or higher occurred in 86% of patients, including hematologic toxicities (thrombocytopenia 12%, neutropenia 7%, anemia 19%) and nonhematologic AEs (hypertension 23%, pneumonia 19%, fatigue 16%, diarrhea 14%). Two patients experienced grade 3 PNP. A total of 13 patients discontinued treatment, of which 4 experienced a cardiac event (1 heart failure, 2 atrial fibrillation, 1 atrial flutter). The ORR was 67% and CBR 76%. Median DOR was 12.9 months. Even in bortezomib-refractory patients, ORR was 73%, with median DOR 9.1 months. Comparable ORR of 78% and DOR were measured in patients with high-risk cytogenetics (del17p and/or t[4;14]).
Median PFS was 7.2 months at a median follow-up of 20.5 months. In high-risk patients, PFS was 8.1 months. The authors concluded that the combination of ibrutinib and carfilzomib with dexamethasone is a possible treatment modality, with promising responses rates that are durable.34 The initial results of the phase II part of the study were recently published, in which 40 patients were treated at the recommended phase II dose, with ORR of 72% and median PFS of 11.6 months. For high-risk and non-high-risk patients, ORR and PFS were 75% and 8.1 months vs 71% and 9.4 months, respectively, suggesting that this treatment combination might overcome the adverse prognosis of high-risk cytogenetic MM. Grade 3 or higher AEs that occurred were anemia (15%), thrombocytopenia (13%), neutropenia (8%), hypertension (18%), pneumonia (13%), diarrhea (10%), and hyperglycemia (10%).35
Carfilzomib, isatuximab and dexamethasone
In a phase IB study, isatuximab was combined with carfilzomib in RRMM. In total, 33 patients were treated in the dose-escalation and dose-expansion cohort, with 29 evaluable patients. ORR was 61% and CBR 86%. Median PFS was not reached, and there was no DLT or severe toxicity. Based on these promising results, the phase III IKEMA study was initiated, which randomized patients with RRMM between carfilzomib and dexamethasone vs carfilzomib and dexamethasone combined with isatuximab (anti-CD38). Estimated study completion is April 2019.36
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