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SAN DIEGO -- Patients with newly diagnosed multiple myeloma had almost a 60% improvement in progression-free survival (PFS) if they received the anti-CD38 daratumumab (Darzalex) in addition to standard therapy, a large randomized trial showed.

After a median follow-up of 47.5 months, the 4-year PFS rate was 67.7% with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) versus 84.3% with daratumumab (D) plus VRd. Almost 90% of patients allocated to D-VRd had complete response (CR) or better as compared with 70% of the VRd group, and patients treated with D-VRd were almost 50% more likely to meet stringent criteria for CR.

Significantly more patients achieved minimum residual disease (MRD)-negative status with the addition of the anti-CD38 antibody, regardless of the definition used to define MRD negativity, reported Pieter Sonneveld, MD, PhD, of Erasmus University in Rotterdam, the Netherlands, at the American Society of Hematology (ASH) annual meeting.

"We think that these randomized phase III results support D-VRd followed by D-VRd consolidation as a new standard of care for transplant-eligible patients with newly diagnosed multiple myeloma," Sonneveld concluded.

The results were published simultaneously in the .

New Results, New Questions

The outcome of the phase III trial poses a number of challenging questions about standard of care, cost, and sequencing, as members of the audience pointed out during a discussion that followed the presentation.

"We're going to be seeing in the coming years other trials of bringing highly effective agents into earlier lines of therapy in multiple myeloma and we need to be careful what endpoints really are going to be useful in what, in the end, are sequencing studies," said Dan Vogl, MD, of the University of Pennsylvania Abramson Cancer Center in Philadelphia. "Daratumumab has a single-agent response rate and a proven overall survival benefit in later lines of therapy for multiple myeloma."

"The real question is, should daratumumab be used in all patients?" he posed. "Is it the standard of care for newly diagnosed patients, as part of initial therapy and maintenance after transplant, during which time it does have higher rates of cytopenias, higher rates of infections, and a substantial cost burden? Or could daratumumab be used just as effectively as part of second- or third-line therapy without sacrificing truly beneficial long-term outcomes like overall survival?"

In response, Sonneveld said, "I think that daratumumab is one of the most effective agents right now. With the proven efficacy in this trial, but also in other trials, I think it should be part of a first-line regimen. We are also looking at new novel agents. For example, the European Myeloma Network is conducting a trial comparing CAR T-cell therapy with this PERSEUS schedule, and in time we will learn what is the best position, the best place for each of these effective novel agents."

A reported at ASH showed favorable preliminary results with another comparison of four versus three drugs upfront: carfilzomib (Xalkori), lenalidomide, and dexamethasone (KRd) with or with the anti-CD38 monoclonal antibody isatuximab (Sarclisa). The primary analysis showed an MRD-negative rate of 77% with isatuximab plus KRd (Isa-KRd) versus 67% with KRd. Data for PFS, a secondary endpoint, are not yet available, said Francesca Gay, MD, PhD, of the University of Torino in Italy.

Four Versus Three

The rationale for the PERSEUS trial included recognition of VRd induction, followed by autologous stem-cell transplant (ASCT) and lenalidomide maintenance, as standard of care for transplant-eligible patients with newly diagnosed myeloma. The phase II GRIFFIN study demonstrated the feasibility of adding daratumumab to the VRd regimen and showed with D-VRd induction and lenalidomide consolidation.

The trial included 709 patients with newly diagnosed myeloma who were eligible for ASCT. They were randomized to induction with VRd plus daratumumab or placebo, followed by ASCT and consolidation with daratumumab and lenalidomide, then up to 2 years of maintenance daratumumab. The primary endpoint was PFS, and overall survival was a key secondary endpoint.

Sonneveld noted that the addition of daratumumab to upfront therapy did not adversely affect ASCT or engraftment.

The results showed that D-VRd significantly increased 4-year PFS, achieving a 58% reduction in the hazard for progression or death (HR 0.42, 95% CI 0.30-0.59, P<0.001). The benefit in favor of D-VRd held up in an analysis of all prespecified subgroups.

The data also showed that patients allocated to D-VRd had more than a threefold improvement in the likelihood of achieving CR or better (OR 3.13, 95% CI 2.11-4.65, P<0.0001). Moreover, the proportion of patients achieving stringent CR was 69.3% with D-VRd versus 44.6% with VRd.

The addition of daratumumab increased MRD-negative rates whether defined by next-generation sequencing (NGS) as 10^-5 (75.2% vs 47.5%, P<0.0001) or 10^-6 (65.1% vs 32.2%, P<0.0001). The proportion of patients who sustained MRD-negative status (10^-5) for at least 12 months was 64.8% with D-VRd and 29.7% with VRd.

Overall survival data remain immature, but an interim analysis showed a trend in favor of D-VRd (HR 0.73), said Sonneveld.

Daratumumab did add to toxicity. Grade 3/4 adverse events included neutropenia (62.1% with D-VRd vs 51.0% with VRd), thrombocytopenia (29.1% vs 17.3%), and infections (35.3% vs 27.4%).

Gay reported results from the primary analysis of the phase III IsKia trial, which included 302 patients with transplant-eligible newly diagnosed myeloma. They were randomized to induction with KRd with or without isatuximab, followed by ASCT, and then to Isa-KRd or KRd.

Isa-KRd achieved a higher rate of post-consolidation MRD-negative status whether defined by NGS 10^-5 (77% vs 67%, P=0.049) or NGS 10^-6 (67% vs 48%, P<0.001). MRD-negative rates (10^-5) increased over time in both groups but favored Isa-KRd at post-induction, post-ASCT, and post-consolidation.

"The follow-up of this trial is short term. We will probably be able to analyze the 1-year sustained MRD in the coming year," said Gay. "With longer follow-up, the trial can offer the opportunity to explore correlation between depth of MRD negativity and survival endpoints."