In November 2016, the U.S. Food and Drug Administration approved the anti-CD38 monoclonal antibody daratumumab in combination with two standard-of-care regimens (dexamethasone plus lenalidomide or bortezomib), after clinical trials showed that the addition of daratumumab prolonged progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (MM).
In an open-label, phase I study presented at the 2017 ASCO Annual Meeting, investigators evaluated whether adding the proteasome inhibitor carfilzomib to the daratumumab, lenalidomide, and dexamethasone combination could further improve response rates, without increasing toxicity, in patients with newly diagnosed MM.
Andrzej J. Jakubowiak, MD, PhD, director of the myeloma program at The University of Chicago Medicine in Illinois, and co-authors evaluated the quadruplet combination in 22 patients (median age = 60 years; range = 24-74 years) with newly diagnosed MM.
Treatment consisted of six 28-day cycles:
- daratumumab 16 mg/kg once weekly for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (the first dose of daratumumab was split over 2 days)
- carfilzomib on days 1, 8, and 15 of each cycle (initial dose of 20 mg/m2 and 36 mg/m2 or 70 mg/m2 thereafter, based on tolerability)
- lenalidomide 25 mg on days 1-21
- dexamethasone 20-40 mg once weekly
Per study protocol, patients were treated for a maximum of 13 cycles, or were allowed to discontinue treatment to undergo hematopoietic cell transplantation (HCT).
Patients received a median of 8 treatment cycles (range = 1-10), and 19 were able to tolerate the highest dose of carfilzomib (70 mg/m2) by day 15 of cycle 1.
Over a median follow-up of 7.4 months (range = 4.0-9.3 months), six patients (27%) discontinued treatment for the following reasons: pulmonary embolism (n=1), progressive disease (n=1), and HCT (n=4).
Serious adverse events (AEs) occurred in 46 percent of patients, and 14 percent of these were considered possibly related to daratumumab treatment. The majority of patients (n=18; 82%) experienced a grade 3/4 treatment-related AE, the most common (occurring in >10% of patients) were lymphopenia (50%) and neutropenia (23%). One of these patients experienced a grade 3 cardiac AE related to daratumumab treatment, but the episode resolved and “the patient quickly resumed study treatment with a reduced carfilzomib dose,” the authors noted. “No grade 5 treatment-emergent AE was reported.”
“The addition of daratumumab to carfilzomib, lenalidomide, and dexamethasone was well tolerated,” the authors wrote, adding that “the overall safety profile was consistent with that previously reported for carfilzomib, lenalidomide, and dexamethaonse alone.”
Twenty-one patients were evaluable for response at the time of presentation. All patients who received the daratumumab combination responded to treatment, for an overall response rate (defined as partial response or better) of 100 percent:
- complete response: 5%
- very good partial response: 86%
- partial response: 9%
The 6-month PFS rate was also 100 percent.
“These data support further investigation of [this daratumumab quadruplet combination] as a frontline treatment regimen,” the authors concluded. However, the study’s findings are limited by its small population, and future studies will need to compare the safety and efficacy of this combination with other standard-of-care regimens.
Jakubowiak AJ, Chari A, Lonial S, et al. Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study. Abstract #8000. Presented at the 2017 ASCO Annual Meeting, June 4, 2017; Chicago, Illinois.