Carfilzomib is a selective, irreversible proteasome inhibitor which results in more sustained inhibition of the proteasome than the first-generation agent bortezomib.
Evidence supporting this protocol is provided by a randomised, phase 3, open-label, multi-centre trial (ENDEAVOR), involving 929 patients, which compared the combination of carfilzomib and dexamethasone to bortezomib and dexamethasone for the treatment of relapsed or refractory multiple myeloma (rrMM).rr
Between 2012 and 2014, 464 patients were randomised to receive intravenous carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1, 56 mg/m2 thereafter) on days 1-2, 8-9 and 15-16 of a 28-day cycle, together with dexamethasone 20 mg on days 1-2, 8-9, 15-16 and 22-23. The control group of 465 patients were randomised to receive bortezomib 1.3 mg/m2 by intravenous (IV) or subcutaneous (SC) route on days 1, 4, 8 and 11 of a 21-day cycle, together with dexamethasone 20 mg on days 1-2, 4-5, 8-9 and 11-12. In both arms, cycles were continued until disease progression or unacceptable toxicity.
The primary endpoint was progression free survival (PFS). Overall survival (OS), overall response rate (ORR), duration of response, incidence of grade 2 or higher neuropathy and safety were secondary endpoint/s.
At the first interim PFS analysis, the primary endpoint was met, with significantly higher PFS seen in the carfilzomib compared to the bortezomib group. ORR was also improved for patients receiving carfilzomib. At the time of interim analysis, there was no difference in OS between the two treatment arms.r A subsequent interim OS analysis has demonstrated an improvement in survival with the use of carfilzomib.r
Carfilzomib has also been investigated in randomised studies as a single-agent,r as a weekly 70 mg/m2 dose on day 1, 8 and 15 in combination with dexamethasone 40 mg on day 1, 8, 15 and 22 (where from cycle 9 onwards the dexamethasone was omitted on day 22) every 28 days,r and in combination with lenalidomide and dexamethasone.r Single-agent therapy is not currently a TGA-approved indication for carfilzomib. Dexamethasone dose and schedule can be adjusted at clinician’s discretion.r
Efficacy
After a median follow up of 11.9 months in the carfilzomib and 11.1 months in the bortezomib groups, the median PFS was 18.7 months compared to 9.4 months (HR 0.53, CI 95% 0.44 to 0.65; p<0.0001).
The ORR was also higher in the carfilzomib group at 77% vs 63% (OR 2.03, CI 95% 1.52 to 2.72; p<0.0001). Median treatment durations were 39.9 weeks for carfilzomib and 26.8 weeks for bortezomib with median response duration 21.3 months vs 10.4 months. Quality of life (QOL) data was not reported.r
A subsequent interim OS analysis on the same study group in 2017 demonstrated improved outcomes in the carfilzomib-treated group, with median OS 47.6 months (CI 95% 42.5-not evaluable) versus 40.0 months (CI 95% 32.6-42.3) in the bortezomib-treated group (HR 0.791, CI 95% 0.648 to 0.964; p0.010).r
Treatment responses in the intention-to-treat populationr
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Progression-free survival by independent review committeer
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Overall survivalr
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Furthermore, a secondary analysis of the phase 3 ENDEAVOR study comparing rrMM patients receiving carfilzomib-dexamethasone or bortezomib-dexamethsone in a 1:1 ratio. Patients in the bortezomib arm received either SC or IV bortezomib on days 1,4,8 and 11. A change in the route of bortezomib administration was allowed in the study, but these patients were not included in the secondary analysis. Patient demographics were balanced as per the table below.r
Baseline demographicsr
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PFS was longer for patients treated with carfilzomib-dexamethasone compared with SC or IV bortezomib. The final conclusion was that carfilzomib-dexamethasone was superior therapy to bortezomib-dexamethasone in rrMM regardless of the route of administration of bortezomib or if the patients had received prior bortezomib therapy.r
Kaplan-Meier progression-free survival curves for bortezomib-naive patientsr
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Toxicity
In the 2016 Dimopoulos paper, though more serious adverse events were reported in the carfilzomib-treated group (48.4% vs 35.5%), the rate of treatment discontinuation due to adverse events were similar between the two groups (14.0% vs 15.7%).
The main non-haematological adverse events included diarrhea, fatigue, dyspnea, fevers, insomnia, cough and hypertension. The rate of dyspnea, fevers and hypertension was reported as occurring twice as much in the carfilzomib arm.
Significantly fewer patients in the carfilzomib group experienced grade ≥ 2 peripheral neuropathy compared to those treated with bortezomib (6% vs 32%, p<0.0001), which was the most common adverse effect leading to treatment discontinuation.r
A meta-analysis indicates higher than expected rates of cardiovascular events associated with carfilzomib exposure. These include hypertension (12.2%), heart failure (4.1%) and ischaemic heart disease 1.8%. Dyspnoea (not necessarily cardiac in aetiology) - is also seen at a high frequency (23.9%).r
Tables 3 and 4 - Adverse eventsr
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