Daratumumab/Carfilzomib Combo Effective in Lenalidomide-Refractory MM

Combining daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with lenalidomide-refractory relapsed multiple myeloma had promising efficacy and was generally well-tolerated, according to the results of a subgroup analysis of the MMY1001 trial.

“Daratumumab with carfilzomib/dexamethasone is a safe and efficacious regimen regardless of prior lenalidomide exposure or refractoriness,” said Ajai Chari, MD, of Mount Sinai School of Medicine, who presented the results of the study (abstract 8002) at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO), held June 1–5 in Chicago.

Daratumumab is currently approved as a monotherapy in combination with standard-of-care regimens in relapsed and refractory disease, and in combination with bortezomib, melphalan, and prednisone in nontransplant newly diagnosed myeloma.

Although there have been many studies of relapsed/refractory disease, many are lenalidomide-based. With increasing adoption of lenalidomide maintenance, there is a need for large studies of regimens in lenalidomide-refractory disease.

In the phase I MMY1001 study, 103 patients (89% of whom were lenalidomide-refractory) were treated with daratumumab plus pomalidomide, and dexamethasone. In this group, median progression-free survival (PFS) was 9.9 months, with a 66% response rate. These and other studies showed that the addition of daratumumab to standard care is effective in lenalidomide-refractory disease, but it remained unknown how daratumumab worked in combination with carfilzomib.

Chari presented the results of 85 patients enrolled in the study. All had received one to three prior lines of therapy but had never been treated with carfilzomib. Fifty-one of the patients were refractory to lenalidomide.

The first 10 patients on study received a single first dose of daratumumab at 16 mg/kg on cycle 1, day 1, and subsequent patients got a split dose of 8 mg/kg on days 1 and 2 of cycle 1. Carfilzomib was given at 20 mg/m² on day 1, cycle 1, and at 70 mg/m² thereafter. Dexamethasone was given at 40 mg once weekly.

The median follow-up was 12 months. Chari said 98% of patients escalated to 70 mg/m² carfilzomib within the first two cycles. Thirty-nine percent of patients have discontinued therapy, primarily due to disease progression.

Overall, the treatment was relatively well tolerated, Chari said. There was some occurrence of thrombocytopenia, anemia, and neutropenia, but rates of grade 3/4 neutropenia were relatively low (21%) for a pretreated population. Nonhematologic toxicities were primarily grades 1 and 2. Grade 3/4 events were mostly asthenia (12%) and hypertension (14%). The safety profile for patients with lenalidomide-refractory disease was similar to that of the entire cohort.

Looking specifically at cardiac function, there were no notable changes from baseline over time in median left ventricular ejection fraction. The median time to onset of cardiac events was 191 days. One patient had a grade 4 adverse event not related to daratumumab, five patients had grade 3 cardiac adverse events that resolved, and two had unresolved grade 3 cardiac events.

In his presentation, Chari compared infusion rates and reactions in patients who received split-dose daratumumab compared with single-infusion therapy. Among patients who had a single first infusion, 50% had infusion-related reactions; with a split first infusion, those rates decreased to 36% on day 1 and 4.0% on day 2.

“This study highlights the ability to do split dosing, particularly in community practice and to improve patient convenience,” Chari said.

Among all treated patients, the overall response rate was 84%, with 27% achieving complete response. In lenalidomide-refractory disease, the overall response rate was 79%, with 19% of patients achieving complete response.

Optional testing for minimal residual disease (MRD) in 11 patients with complete response revealed that 4 patients were MRD-negative; one of those patients was lenalidomide-refractory.

The median PFS and overall survival (OS) have not yet been reached in the entire population. In patients with lenalidomide-refractory disease, median PFS was 14.1 months and median OS was 21.1 months.