Daratumumab plus VMP a potential therapy for transplant-ineligible multiple myeloma
The addition of daratumumab to a bortezomib-melphalan-prednisone (VMP) regimen appears to improve progression-free survival (PFS) over VMP alone in individuals newly diagnosed with multiple myeloma who are ineligible for stem-cell transplantation, according to findings from the phase III ALCYONE* trial.
“In this first phase III randomized study with a monoclonal antibody in [newly diagnosed multiple myeloma], daratumumab plus VMP [D-VMP] reduced the risk of progression or death by 50 percent,” said senior study author Professor Jesus San-Miguel from the Clínica Universidad de Navarra, Pamplona, Spain, who presented the results at ASH 2017.
Researchers of this multinational, open-label trial randomized 706 patients (median age 71 years, median 0.8 months since diagnosis) with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive VMP (subcutaneous bortezomib [1.3 mg/m2 BIW on weeks 1, 2, 4, and 5 of cycle 1 and QW on weeks 1, 2, 4, and 5 of cycles 2–9], oral melphalan [9 mg/m2 QD on days 1–4 of each cycle], and oral prednisone [60 mg/m2 QD on days 1–4 of each cycle]), or D-VMP (with additional intravenous daratumumab [16 mg/kg at doses of 20 mg QW in cycle 1, Q3WK in cycles 2–9, and Q4WK until disease progression or toxicity]) for up to nine cycles (42 days per cycle).
After a 16.5-month median follow-up period, PFS was longer in patients in the D-VMP compared with the VMP arm (not reached vs 18.1 months), with a PFS rate of 71.6 percent vs 50.2 percent at 18 months (hazard ratio, 0.50, 95 percent confidence interval, 0.38–0.65; p<0.001). [ASH 2017, abstract LBA-4; New Engl J Med 2017;doi:10.1056/NEJMoa1714678]
Compared with patients in the VMP arm, those on D-VMP had a better overall response rate (90.9 percent vs 73.9 percent; p<0.001) with a better median duration of response (not reached vs 21.3 months) and a higher rate of complete response or better (42.6 percent vs 24.4 percent; p<0.001).
More patients on D-VMP than VMP tested negative for minimal residual disease (MRD**; 22.3 percent vs 6.2 percent; p<0.001).
“D-VMP induced significantly deeper responses including a more than threefold higher MRD-negative rate,” said San-Miguel.
“In this trial, negative status for [MRD] was associated with longer [PFS] than positive status, irrespective of trial treatment,” said San-Miguel and co-authors.
The most common grade 3–4 adverse events (AEs) were neutropenia (39.9 and 38.7 percent of patients on D-VMP and VMP, respectively), thrombocytopenia (34.4 and 37.6 percent, respectively), and anaemia (15.9 and 19.8 percent, respectively). Grade 3–4 infections occurred more frequently in patients on D-VMP compared with VMP (23.1 percent vs 14.7 percent), the most common being pneumonia (11.3 percent vs 4.0 percent).
Serious AEs occurred in 41.6 and 32.5 percent of patients on D-VMP and VMP, respectively, though treatment discontinuation due to AEs was less common with D-VMP than VMP (4.9 percent vs 9.0 percent).
“Monoclonal antibodies like daratumumab have already been approved for use in relapsed patients; here, we are showing that the benefits extend to newly diagnosed patients, as well,” said San-Miguel.
“Three phase III studies have now demonstrated a consistent doubling of PFS and more than threefold increase in MRD-negativity rate when combining [daratumumab] with [standard-of-care] regimens,” said San-Miguel and co-authors.
“ALCYONE strongly supports D-VMP as a standard of care in transplant-ineligible [newly diagnosed multiple myeloma],” he said.