From the Journals

With RRMM and renal impairment, carfilzomib improves survival



Patients with renal failure and relapsed or refractory multiple myeloma fared better with the selective proteasome inhibitor carfilzomib, compared with bortezomib, according to a post hoc subgroup analysis of a large clinical trial.

Dr. Meletios A. Dimopoulos, National and Kapodistrian University of Athens (Greece) Neil Osterweil/MDedge News

Dr. Meletios A. Dimopoulos

In addition, patients who had a complete renal response had longer progression-free survival (PFS) and overall survival (OS), regardless of treatment group.

Many aspects of the disease state and treatment can contribute to renal failure in multiple myeloma, but cast nephropathy from precipitation of monoclonal light chains certainly contributes to persistent renal failure, Meletios Dimopoulos, MD, professor and chair of clinical therapeutics at the University of Athens, Greece, and his coauthors wrote in Blood.

The investigators wanted to see how individuals with varying levels of renal function fared in the ENDEAVOR trial, which compared carfilzomib (56 mg/m2) plus dexamethasone (Kd56) with bortezomib plus dexamethasone (Vd) for patients with relapsed or refractory multiple myeloma.

In an intent-to-treat population of 929 patients, 85 Kd56 and 99 Vd patients had creatinine clearance (CrCL) of at least 15 but less than 50 mL/min. Of patients with mild renal failure (CrCL of at least 50 but less than 80 mL/min), 186 were in the Kd56 and 177 in the Vd group. One hundred ninety-three patients receiving Kd56 and 189 Vd patients had CrCL of 80 mL/min or greater.

For ENDEAVOR patients with the lowest CrCL, median PFS was 14.9 months with Kd56 and 6.5 months with Vd (hazard ratio [HR], 0.49). For patients with intermediate CrCL, median PFS was 18.6 versus 9.4 months with Kd56 and Vd, respectively (HR, 0.48). For patients with the highest CrCL, PFS was not reached with Kd56; with Vd, median PFS was 12.2 months (HR, 0.60).

Patterns for OS mirrored the advantage seen with Kd56. Median OS was 42.1 versus 23.7 months for those with the worst renal function in the Kd56 arm and the Vd arm, respectively (HR, 0.66). Those with intermediate renal function saw median OS of 42.5 versus 32.8 months on Kd56 and Vd, respectively (HR, 0.83). Median OS for those with the highest CrCL was not reached on Kd56 and 42.3 months on Vd (HR, 0.75).

The investigators also tracked kidney function over the course of the study, with complete renal response defined as improvement of CrCL to at least 60 mL/min in any two consecutive study visits. By this yardstick, complete renal response was 15.3% for the Kd56 arm and 14.1% for those receiving Vd.

Looking across participants regardless of therapy, those with CrCL of at least 15 but less than 50 mL/min who also had complete renal response had longer PFS, compared with nonresponders (median 14.1 versus 9.4 months, HR, .805). OS also was longer in this group of patients (median 35.3 versus 29.7 months, HR, 0.91).

“Patients with complete renal response had superior overall outcomes compared with renal nonresponders across treatment groups ... highlighting the association between improved renal function and greater survival rates,” Dr. Dimopoulos and his colleagues wrote.

Kd56 therapy was associated with a higher number of grade 3 or higher adverse events, seen in 77.1%-87.1% of Kd56 patients and 65.9%-79.4% of Vd patients.

Renal failure, common in multiple myeloma, is associated with poor prognosis. Also, therapeutic options can be limited and dosing adjustments must often be made when patients have poor renal function, Dr. Dimopoulos and his coauthors noted.

However, previous studies showed that carfilzomib clearance, exposure, and overall pharmacokinetics were similar between multiple myeloma patients with and without renal impairment, including end-stage renal disease, the investigators wrote.

The subgroup analysis from ENDEAVOR suggested that “Kd56 may overcome the poor prognosis of baseline advanced renal impairment,” Dr. Dimopoulos and his colleagues wrote. “Furthermore, patients in the Kd56 arm had deeper responses compared with the Vd arm, regardless of baseline renal impairment.”

These data suggest that Kd56 should be considered a “standard of care” in patients with relapsed or refractory multiple myeloma, regardless of a patient’s baseline renal function.

The investigators reported multiple financial relationships with pharmaceutical companies, including Amgen, which markets carfilzomib and supported the study.

SOURCE: Dimopoulos M et al. Blood. 2019;133(2):147-55.

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