Daratumumab Plus Standard of Care Well Tolerated in Multiple Myeloma

Adding daratumumab to carfilzomib, lenalidomide, and dexamethasone (KRd) is a feasible alternative to autologous stem cell transplantation (ASCT) with KRd and is a feasible component of induction therapy that did not adversely impact stem cell collection in patients with newly diagnosed multiple myeloma, according to findings from a phase Ib study (abstract 8000) presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.

“Daratumumab plus KRd was well tolerated; safety is consistent with previous reports,” said Andrzej J. Jakubowiak, MD, PhD, of the University of Chicago Medical Center. “Low infusion-related reaction rates were associated with split first dose.”

The combination was associated with a 100% overall response rate (ORR).

Standard treatment for multiple myeloma involves combination regimens that include a proteasome inhibitor and/or immunomodulatory drug with or without stem cell transplantation.

“Among triplet regimens, extended treatment with KRd emerged as highly active in newly diagnosed myeloma,” Jakubowiak noted. KRd outcomes “appear to be improved” by the addition of ASCT.

Daratumumab is a human immunoglobulin G1κ monoclonal antibody that targets CD38 directly and indirectly via immunomodulation. It induces “rapid, deep, and durable responses” in combination with bortezomib or lenalidomide and has been approved for use with standard of care for relapsed/refractory multiple myeloma after at least one prior treatment regimen.

Hypothesizing that daratumumab provides an alternative addition to KRd, the research team enrolled 22 patients in an open-label, multicenter, phase Ib study, regardless of participant eligibility for transplantation; patients with heart disease were ineligible for study participation.

On a dosing schedule of 28 days, patients received a split dose of daratumumab (8 mg/kg on days 1 and 2 of cycle 1, and 16 mg/kg once weekly on cycles 1 and 2; every 2 weeks on cycles 3–6; and then every 4 weeks), 20-mg/m² carfilzomib, 25-mg lenalidomide on days 1–21 of each cycle, and 40-mg dexamethasone per week. Patients were escalated from 20 to 70 mg/m² carfilzomib on days 1, 8, and 15. Patients received treatment until they chose to discontinue to undergo ASCT. All patients were on aspirin prophylaxis.

Most (68%) patients were men, had ECOG performance status scores of 0 (55%) or 1 (41%), and were white (86%). The primary study endpoints were safety and tolerability; the secondary endpoint was ORR.

At a median follow-up of 10.8 months, 8 patients (36%) discontinued treatment: 1 following disease progression, 1 following toxicity, and 6 (27%) for ASCT.

The most common hematologic adverse events were lymphopenia (68% all grades; 64% grades 3/4), thrombocytopenia (55%; 9%), anemia (46%; 9%), leukopenia (41%; 9%), and neutropenia (32%; 14%). Diarrhea (73%; 14%), upper respiratory infection (59%; 0%), cough (55%; 5%), constipation (50%; 0%), fatigue (50%; 0%), dyspnea (46%; 0%), and insomnia (46%; 5%) were also common.

Serious treatment-emergent adverse events affected 10 of the 22 patients (46%) and included pulmonary embolism (n = 3), pyrexia (2), influenza (2), and cardiac toxicities (1 patient each for tachycardia, congestive heart failure, and hypertension), Jakubowiak reported. One patient with pulmonary embolism not related to daratumumab or carfilzomib discontinued treatment.

Twenty-seven percent of patients experienced infusion-related reactions, including cough, throat irritation, nausea, and headache. None were grade 3 or 4 reactions.

At 12 months’ follow-up, the median progression-free survival rate was 94% and the overall survival rate was 100%.