ATLANTA (FRONTLINE MEDICAL NEWS) – Adding the anti-CD38 monoclonal antibody daratumumab (Darzalex) to the standard VMP regimen as first-line therapy for patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease (MRD) negativity, investigators in the ALCYONE trial reported.

Among 706 patients with newly diagnosed transplant-ineligible multiple myeloma randomized to receive bortezomib (Velcade), melphalan, and prednisone (VMP) with or without daratumumab followed for a median of 16.5 months, the median progression-free survival (PFS) for patients assigned to daratumumab plus VMP (D-VMP) had not been reached, compared with 18.1 months for patients treated with VMP alone.

This difference translated into a hazard ratio for progression or death with D-VMP of 0.50 (P less than .0001), said Jesus San-Miguel, MD , from the Clinical University of Navarra in Pamplona, Spain. ­

“This result clearly indicated for the first time that, in a phase 3 randomized study conducted with a monoclonal antibody in newly diagnosed myeloma patients, the addition of daratumumab to the standard of care reduced the risk of progression or death by 50%, and this is associated with significantly deeper responses, including a threefold higher MRD negativity rate,” he said at a media briefing prior to presentation of the data in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

The VMP regimen is used more commonly in Europe than the United States as first-line therapy for patients with previously untreated multiple myeloma who are aged 65 years or older or are otherwise not suitable candidates for autologous stem cell transplants (ASCT).

In the ALCYONE trial, patients who met this definition were enrolled and stratified by International Staging System scores, region, and age (younger or older than 75 years) and were then randomized to 6-week cycles of VMP, with or without daratumumab. In the experimental arm, daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2-9, and every 4 weeks for cycles 10 and beyond (post VMP-treatment phase) until disease progression.

As noted before, the primary endpoint of investigator-assessed PFS significantly favored the addition of daratumumab. Dr. San-Miguel attributed this difference to the overall response rates, which were 91%, including 43% complete responses with daratumumab, vs. 74% ORR with 24% CR, without the monoclonal antibody.

The rate of MRD negativity, measured with a threshold sensitivity of 10–5, was also significantly higher with daratumumab at 22% vs. 6% (P less than .0001).

Among all patients who achieved MRD negativity, regardless of treatment, there was a lower risk of progression or death, Dr. San-Miguel said.

The rate of treatment discontinuation because of infection was higher with VMP (1.4%) than with D-VMP (0.9%). One patient in each trial arm discontinued therapy because of pneumonia. Rates of any serious adverse event were higher with D-VMP (42%, compared with 33%). Infusion-related reactions occurred in 27.7% of patients assigned to daratumumab.

Rates of grade 3 or 4 hematologic and nonhematologic toxicities were generally similar between the treatment arms, and there were no new safety signals with daratumumab, Dr. San-Miguel said.

The ALCYONE trial is one of several ongoing studies looking at the addition of daratumumab to standard therapies in the frontline, including the phase 3 MAIA trial (with daratumumab added to lenalidomide and dexamethasone), the phase 3 CASSIOPEIA trial (with the antibody added to bortezomib, thalidomide, and dexamethasone), the phase 2 GRIFFIN trial (with daratumumab plus lenalidomide, bortezomib, and dexamethasone), and the phase 2 LYRA trial (with the antibody added to cyclophosphamide, bortezomib, and dexamethasone).

The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.

SOURCE: Mateos MV et al. ASH Abstract LBA-4 .