Multiple myeloma quadruplet prolongs survival, induces deeper responses

Adding subcutaneous daratumumab to the three-drug regimen containing bortezomib, lenalidomide, and dexamethasone (VRd) appears to improve outcomes for transplant-eligible patients with newly diagnosed multiple myeloma (MM), with extended disease-free periods and increased depth of response, according to the phase III PERSEUS trial.

Over a median follow-up of 47.5 months, progression-free survival (PFS) was significantly better with daratumumab plus VRd (D-VRd) than with VRd alone (hazard ratio [HR], 0.42, 95 percent confidence interval [CI], 0.30–0.59; p<0.0001). [ASH 2023, abstract LBA-1]

While the median PFS was not reached in either treatment arm, the estimated 48-month PFS rates were 84.3 percent with D-VRd versus 67.7 percent with VRd, reported lead study investigator Dr Pieter Sonneveld of Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

“Prespecified subgroup analyses showed a consistent PFS improvement with D-VRd versus VRd across clinically relevant subgroups, including patients with ISS stage III disease and patients with high cytogenetic risk,” Sonneveld added.

In addition, D-VRd amplified the depth of response. There were 87.9 percent and 75.2 percent of patients in the D-VRd arm who achieved complete response or better (≥CR) and minimal residual disease (MRD) negativity, respectively, as opposed to only 70.1 percent (p<0.0001) and 47.5 percent (p<0.0001) of patients in the VRd arm. Meanwhile, the data for overall survival remained immature.

“We were not surprised to see the difference with the addition of daratumumab, but we were very surprised by the magnitude of the difference between the two arms. This difference is of major clinical significance to the patient in terms of their well-being and [remaining] disease-free,” Sonneveld said in a statement.

PERSEUS included 709 patients (median age 60 years, 14.8 percent had ISS stage III disease, 21.7 percent had high cytogenetic risk) newly diagnosed with MM across multiple European countries who were considered eligible for autologous stem cell transplantation. Of these, 355 were assigned to the D-VRd arm and 354 to the VRd arm.

All patients received up to six cycles of VRd induction therapy in 28-day cycles, subsequently underwent a stem cell transplant if possible, and then continued taking lenalidomide thereafter as maintenance therapy. Patients who were in the D-VRd arm also received subcutaneous injections of daratumumab during both the induction and maintenance phases. At the time of data cutoff, 314 patients in the D-VRd arm and 299 in the VRd arm had completed the induction/consolidation phase of treatment.

Safety data were consistent with the known safety profiles of subcutaneous daratumumab and VRd. Serious treatment-emergent adverse events (TEAEs) occurred with slightly greater frequency in the D-VRd arm than in the VRd arm (57.0 percent vs 49.3 percent). However, Sonneveld noted that that TEAEs led to treatment discontinuation significantly less often in the D-VRd arm (8.8 percent vs 21.3 percent).

The most common grade ≥3 treatment-emergent adverse events (TEAEs) in the D-VRd and VRd arms were neutropenia (62.1 percent and 51.0 percent), thrombocytopenia (29.1 percent and 17.3 percent), diarrhoea (10.5 percent and 7.8 percent), pneumonia (10.5 percent and 6.1 percent), and febrile neutropenia (9.4 percent and 10.1 percent). Overall, seven deaths due to COVID-19 were recorded, including four in the D-VRd arm and three in the VRd arm.

“These data, together with results from the phase II GRIFFIN study, demonstrate the consistent and clinically meaningful benefit of quadruplet D-VRd followed by daratumumab–lenalidomide maintenance versus triplet VRd followed by lenalidomide maintenance, [as well as] support the combination of D-VRd followed by daratumumab–lenalidomide maintenance as a new standard of care for transplant-eligible newly diagnosed MM,” Sonneveld said.