The primary end point was OS, with PFS, ORR, DOR, CBR, and disease-control rate as secondary end points. A total of 157 patients participated in the carfilzomib group vs 158 in the control group. The ORR was 19.1% and 11.4%, respectively, which was significant (P=0.0305), but this was not translated into superior median PFS (3.7 months in the carfilzomib group vs 3.3 months in the control group, P=0.2479) or median DOR (7.2 months and 9.5 months, respectively). Median OS was comparable, with 10.2 months in the carfilzomib group vs 10.0 months in the control group; therefore, the study did not meet the expected primary objective of carfilzomib superiority in OS over the control arm. Not meeting the primary end point of this study was most probably due to not adding dexamethasone to carfilzomib and the high efficacy of additional cyclophosphamide in the control group, which enhanced expected ORR and PFS in the control arm.

Grade 3 or higher AEs were comparable in both groups, except for acute renal failure (carfilzomib 8%, control 3%) and pneumonia (carfilzomib 6%, control 12%). Furthermore, cardiac failure of any grade was seen in seven patients in the carfilzomib group vs one patient in the control group. There was no difference in reported PNP between the groups.20


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It is generally known that combination therapy has a stronger antimyeloma effect compared to monotherapy. However, combination therapies might lead to higher toxicity rates. In this section, we describe the studies that led to the approval of two combination therapies with carfilzomib (carfilzomib plus dexamethasone and carfilzomib combined with lenalidomide and dexamethasone).

Carfilzomib and dexamethasone

In 2014, Papadopoulos et al conducted a phase I study in which the infusion time of carfilzomib was extended from 2 to 10 to 30 minutes, allowing higher doses of carfilzomib. Dosing started at 20 mg/m2 again, though with dose escalation to 36, 45, 56, and 70 mg/m2. The study was amended to investigate the safety and efficacy of carfilzomib combined with low-dose dexamethasone (40 mg weekly). The MTD was established at 56 mg/m2. The ORR for carfilzomib monotherapy was 48%, with a CBR of 52%. Adding dexamethasone resulted in an ORR of 55% and CBR of 64%. The safety profile in this study was comparable to previous phase I/II trials with carfilzomib.21

In 2014, a single-arm/single-center phase II study was published by Lendvai et al in which patients received carfilzomib (20/56 mg/m2). After two cycles of carfilzomib monotherapy, dexamethasone 20 mg could be added if response was less than PR. Dexamethasone could also be added at the time of progression. A total of 44 patients participated, with 42 evaluable for response: 17 patients achieved a PR or better with single-agent carfilzomib, while 6 of these 17 patients progressed later in treatment and received additional dexamethasone. A total of 23 of the 42 patients achieved a PR or better (55% ORR), with a median time to best response of two cycles and median DOR of 11.7 months. Median PFS and OS were 4.1 months and 20.3 months, respectively. There was no difference in outcome between cytogenetic high-risk and non-high-risk patients. Grade 3 or 4 AEs were lymphopenia (43%), thrombocytopenia (32%), leukopenia (18%), anemia (18%), and neutropenia (18%). Grade three or four non-hematologic AEs were hypertension (25%), pneumonia (18%) and heart failure (11%). PNP occurred in six patients, all grade 1, with two experiencing a worsening of preexisting PNP. Adding dexamethasone did not seem to have an effect on type or rate of AEs.22

Based on these promising results, the phase III ENDEAVOR study was initiated, which evaluated carfilzomib and dexamethasone vs bortezomib and dexamethasone in 929 RRMM patients with one to three prior lines of therapy. Importantly, bortezomib-refractory patients were excluded from trial participation. Carfilzomib was started at a dose of 20 mg/m2 for the first 2 days in cycle 1, and 56 mg/m2 thereafter. Bortezomib was given twice weekly subcutaneously or intravenously.

Dimopoulos et al wrote an interim analysis of the primary end point of this study. There was a significant benefit in terms of PFS for the carfilzomib-treated patients when compared to the control group (median PFS 18.7 vs 9.4 months, P<0.0001). The objective ORR was 77% in the carfilzomib group vs 63% in the bortezomib group (P<0.0001), with DOR 21.3 months vs 10.4 months, respectively. The median time to response was 1.1 months in both groups. Although there was an improvement in PFS in both high-risk and standard-risk patients, carfilzomib could not totally overcome the negative impact of high-risk cytogenetics on PFS in this study.

In this analysis, OS data were not yet mature. However, in 2017 an updated analysis with prolonged follow-up showed a marked improvement in median OS of 47.6 months in the carfilzomib group vs 40.0 months in the bortezomib group (P=0.010).23 The most common AEs (grade 3 or higher) were anemia (14% vs 10%), hypertension (9% vs 3%), thrombocytopenia (8% vs 9%), and pneumonia (7% vs 8%). PNP (grade 2 or higher) was seen in 6% of patients in the carfilzomib group compared to 32% in the bortezomib group. In both groups, 5% of patients died during treatment within 30 days of last administration. In 151 patients, divided over both groups, serial echocardiography performed, which showed two patients in both groups with reduction in their left ventricular ejection fraction.24

In conclusion, the ENDEAVOR study showed a benefit for carfilzomib–dexamethasone compared to bortezomib–dexamethasone in patients with one to three prior lines of therapy, with an important reduction in PNP. In this study, there was no benefit of serial echocardiography in preventing cardiovascular events.24 These data led to both FDA and EMA approval of this regimen.

Carfilzomib, lenalidomide and dexamethasone

In the PX-171–006 study, carfilzomib was combined with lenalidomide and low-dose dexamethasone, assessing safety and tolerability in 40 patients. Carfilzomib was given twice weekly starting at a dose of 15 mg/m2, which was gradually enhanced to 27 mg/m2. Lenalidomide was given in the first 21 days of a 28-day cycle, ranging from 10 mg a day to 25 mg a day. Dexamethasone was given at a dose of 40 mg weekly. The MTD was not reached, and thus the maximum planned dose (MPD) of the phase I study was used in the phase II study. Grade 3 or 4 hematologic toxicities were neutropenia (42.5%), anemia (20%), thrombocytopenia (32.5%), lymphopenia (27.5%), and nonhematologic toxicities of grade 3 or 4 were fatigue (7.5%), diarrhea (5.0%), hyperglycemia (22.5%), hypokalemia (10.0%), hyponatremia (15%), and hypophosphatemia (20%). Neuropathic events were reported in only 10% of patients, all grade 1 or 2, and all these patients had a history of neuropathy. The ORR was 62.5%, with a CBR of 75%. Median DOR was 11.8 months for patients who achieved at least a PR. Median PFS was 10.2 months.25

This led to the phase II dose-expansion study (PX-171–006) investigating safety and secondary end points as ORR and DOR, with 52 patients treated at the MPD. The ORR was 76.9%, with a median DOR of 22.1 months. Median time to response was 0.95 month, and median PFS 15.4 months. Median DOR was also 22.1 months for patients refractory to bortezomib (13 patients), with ORR of 69.2% and median PFS of 15.4 months. In lenalidomide-refractory patients, the ORR was 69.9%, with median DOR of 10.8 months and median PFS of 7.9 months. In the MPD cohort, 94.2% of patients experienced a grade 3 or 4 AE, including neutropenia (32.7%), thrombocytopenia (19.2%), anemia (19.2%), and lymphopenia (48.1%). The most common AEs of any grade were fatigue (69.2%) and diarrhea (57.7%), both mostly grade 1 or 2. Only one patient experienced grade 3 neuropathy. A total of 19.2% of patients had a cardiac AE of any grade, with three patients experiencing a grade 3 or higher AE.26

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