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Carfilzomib regimen extends multiple myeloma survival, regardless of renal impairment
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The combination of carfilzomib and dexamethasone extended PFS and OS compared with bortezomib and dexamethasone among patients with relapsed or refractory multiple myeloma regardless of baseline renal function, according to a post-hoc exploratory subgroup analysis of a randomized phase 3 trial published in Blood.
“The present analysis is the first head-to-head comparison of carfilzomib [Kyprolis, Amgen] and dexamethasone vs. bortezomib [Velcade, Takeda[ and dexamethasone with regard to renal response and survival outcomes in [patients with] multiple myeloma with renal impairment,” Meletios Dimopoulos, MD, professor and chairman of the department of clinical therapeutics at National and Kapodistrian University of Athens School of Medicine, and colleagues wrote. “These results suggest that carfilzomib and dexamethasone may overcome poor prognosis of baseline advanced renal impairment.”
Renal impairment, a common complication of multiple myeloma, can complicate drug dosing and limit treatment options, leading to a higher incidence or severity of adverse events. Studies have shown median survival is less than half as long for patients with vs. without renal impairment (19.5 months vs. 40.4 months; P < .001).
However, many clinical trials exclude patients with multiple myeloma who have advanced renal impairment, researchers noted.
Dimopoulos and colleagues analyzed results of the prospective, open-label, multicenter phase 3 ENDEAVOR trial, which included 929 patients with relapsed/refractory multiple myeloma from 27 countries in North America, South America, Europe and the Asia-Pacific region.
Eligible patients were aged 18 years or older, received one to three previous treatments, had ECOG performance statuses of 0 to 2, had left ventricular ejection fraction of at least 40% and had creatinine clearance (CrCL) of at least 15 mL/min.
Researchers randomly assigned patients to carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) on days 1, 2, 8, 9, 15 and 16 and 20 mg oral or IV dexamethasone on days 1, 2, 8, 9, 15, 16, 22 and 23 of a 28-day cycle, or 1.3 mg/m2 IV or subcutaneous bortezomib on days 1, 4, 8 and 11 and dexamethasone on days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle.
The current analysis explored outcomes among patients grouped by baseline renal function:
- CrCL 15 to < 50 mL/min (carfilzomib group, n = 85; bortezomib group, n = 99);
- CrCL 50 to < 80 mL/min (carfilzomib group, n = 186; bortezomib group, n = 177); and
- CrCL 80 mL/min (carfilzomib group, n = 193; bortezomib group, n = 189).
Results showed consistent improvement in PFS and OS among those treated with the carfilzomib regimen compared with the bortezomib regimen, regardless of the number of prior treatments, across the renal function groups:
- CrCL 15 to < 50 mL/min — median PFS, 14.9 months vs. 6.5 months (HR = 0.49; 95% CI, 0.32-0.75); median OS, 42.1 months vs. 23.7 months (HR = 0.66; 95% CI, 0.44-0.98);
- CrCL 50 to < 80 mL/min — median PFS, 18.6 months vs. 9.4 months (HR = 0.48; 95% CI, 0.35-0.65); median OS, 42.5 months vs. 32.8 months (HR = 0.83; 95% CI, 0.62-1.1); and
- CrCL 80 mL/min — median PFS, not reached vs. 12.2 months (HR = 0.6; 95% CI, 0.43-0.82); median OS, not reached vs. 42.3 months (HR = 0.75; 95% CI, 0.55-1).
Results showed similar complete renal response rates in the carfilzomib group (15.3%; 95% CI, 8.4-24.7) and the bortezomib group (14.1%; 95% CI, 8-22.6) and rapid median time to complete renal response (1.9 months vs. 1.5 months).
In a combined analysis of the two treatments, patients with complete renal response achieved longer median PFS (14.1 months vs. 9.4 months) and longer median OS (35.3 months vs. 29.7 months) than nonresponders.
Rates of grade 3 or greater adverse events were higher among carfilzomib-treated patients across renal function subgroups. They included anemia, pneumonia, hypertension and thrombocytopenia.
Grade 3 or higher adverse events more common in the carfilzomib group included acute kidney injury, hypertension, cardiac failure and dyspnea, whereas grade 3 or higher peripheral neuropathy was more common in the bortezomib group.
Limitations included the fact that the post-hoc analysis did not include patients with relapsed/refractory multiple myeloma with end-stage renal disease on dialysis.
“These results confirm that improved renal response is associated with better survival outcomes in patients with baseline renal impairment,” Dimopoulos and colleagues wrote. “Overall, these data suggest that carfilzomib and dexamethasone has a favorable benefit-risk profile and should be considered a standard of care in patients with relapsed/refractory multiple myeloma, regardless of baseline renal function.” – by John DeRosier
Disclosures : Dimopoulos reports consultant or advisory roles with Celgene, Janssen, Amgen, Novartis and Takeda, as well as research funding from Genesis Pharma. Please see the study for all other authors’ relevant financial disclosures.
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