Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Abstract

Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomide-refractory patients were eligible. Carfilzomib- and daratumumab-naïve patients (n = 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 initial dose, escalated to 70 mg/m2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide. The trial was registered at www.clinicaltrials.gov as #NCT01998971.

Conflict of interest statement

Conflict-of-interest disclosures: A.C. has acted as a consultant for Array BioPharma, Celgene, Novartis, Millennium, Amgen, Janssen Oncology, and Bristol-Myers Squibb; received travel expenses from Takeda, Celgene, Novartis, Amgen, Janssen Oncology, and Bristol-Myers Squibb; and received research funding from Array BioPharma, Celgene, Millennium, Novartis, Onyx, Janssen, Pharmacyclics, Acetylon Pharmaceuticals, Biotest, and Bristol-Myers Squibb. J.M.-L. has received research funding from Bristol-Myers Squibb, Janssen, Novartis, Pfizer, and Celgene; received honoraria from/participated in speakers bureaus for Bristol-Myers Squibb, Janssen, Celgene, Novartis, Incyte, and Takeda; and reports ownership interest in Vivia Biotech. M.-V.M. has served on advisory boards for and received honoraria from Janssen, Amgen, Takeda, Celgene, GlaxoSmithKline, EDO, and Pharmamar. J.B. has received honoraria for lectures from Janssen, Amgen, Celgene, Takeda, and Binding Site. L.B. has received honoraria from and acted as a consultant for Celgene, Takeda, Janssen, and Amgen. A.O. has served on advisory boards or sponsored symposia for Amgen, Celgene, Janssen, and Takeda. B.A. has received honoraria from Janssen, Amgen, and Celgene and has served on advisory committees for Amgen. P.R.-O. has served on advisory boards for and received honoraria for lectures from Janssen, Celgene, Takeda, Sanofi, Merck Sharp & Dohme, and Bristol-Myers Squibb. L.P. has participated in speakers bureaus for Alexion Pharmaceuticals and Seattle Genetics. A.J. has served on advisory boards or as a consultant for and has received honoraria from AbbVie, Amgen, Adaptive, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Takeda, and SkylineDx. C.d.B., J.W., P.L.C., J.U., and J.S. are employees of Janssen Research & Development. S.L. has acted as a consultant for or served in an advisory role for Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Millennium, Novartis, and Onyx. P.M. has served on advisory boards and received honoraria from Janssen, Amgen, Takeda, AbbVie, and Celgene.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Response rates in patients treated with daratumumab plus Kd. Data are based on a computerized algorithm. Len, lenalidomide; sCR, stringent complete response.

Figure 2.

PFS and OS in patients treated with daratumumab plus Kd. Median PFS in the all treated population and across subgroups (A), median PFS by cytogenetic risk group at baseline (B), and median OS in the all treated population and across subgroups (C) at a median follow-up of 16.6 months. Bort, bortezomib; Len, lenalidomide; NE, not evaluable.