麻豆传媒

SAN DIEGO -- Older transplant-ineligible patients with newly diagnosed multiple myeloma had significant improvement in progression-free survival (PFS) with the addition of daratumumab (Darzalex) to lenalidomide (Revlimid), according to the randomized trial reported here.

Patients treated with lenalidomide alone had a median PFS of 31.9 months, whereas the median had yet to be reached in the group that received the anti-CD38 antibody in addition to lenalidomide. The estimated 30-month PFS was 71% with daratumumab and lenalidomide and 56% with lenalidomide alone. The difference translated into a 44% reduction in the hazard for disease progression or death.

The combination led to a significantly higher objective response rate and patients were more likely to attain negative minimal residual disease (MRD) status, as reported at the American Society of Hematology (ASH) meeting.

"Daratumumab and lenalidomide induced significantly deeper responses, including more than a threefold higher MRD-negative rate," Thierry Facon, MD, of Hôpital Claude Huriez in Lille, France, said during an ASH press briefing. "No new safety signals were observed using daratumumab and lenalidomide in patients with newly diagnosed multiple myeloma.

"These results support daratumumab and lenalidomide as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma.

But a U.S. myeloma specialist disagreed, saying the results from MAIA do not justify a change in the standard of care.

Single-agent lenalidomide is not the current North American standard for newly diagnosed multiple myeloma, said S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota. Instead, most patients receive the combination of bortezomib (Velcade), lenalidomide, and dexamethasone (VRd), which demonstrated an overall survival benefit versus Rd and is well tolerated.

"To change standard of care, we need a trial that compares the new regimen (DRd) head to head with the existing standard (VRd)," Rajkumar told 麻豆传媒 by email. "The MAIA trial is not such a trial."

"VRd is well tolerated and has demonstrated an overall survival benefit over Rd," he added. "We cannot compare PFS rates across trials. And particularly in this case because the duration of therapy was different. Bortezomib was given only for eight cycles with VRd in the SWOG trial. In the MAIA trial daratumumab was given until progression (median >4 years).

"So the PFS of the two trials cannot be compared with each other. By giving the third drug in the triplet for years, the PFS will of course be longer. That's to be expected. Further, DRd is much more expensive. It will probably add a million dollars in cost extra per patient. For that kind of cost difference we need better proof of benefit -- a survival advantage."

Thacon acknowledged that VRd is considered a standard of care, but said daratumumab appears to achieve deeper responses.

Interest in evaluating DRd evolved from results of previous randomized trials showing that the addition of daratumumab to lenalidomide and dexamethasone or to bortezomib (Velcade) and dexamethasone significantly improved PFS in patients with relapsed/refractory myeloma and in transplant-ineligible patients with newly diagnosed disease.

The largest benefit among the previous trials came from the randomized , which showed that DRd reduced the risk of disease progression or death by 63% versus lenalidomide monotherapy in patients with relapsed/refractory myeloma.

The MAIA trial included 737 patients with newly diagnosed multiple myeloma and who were not considered suitable candidates for stem-cell transplant because of advanced age or significant comorbid conditions. Investigators in the United States, Canada, Europe, and Australia randomized the patients 1:1 to receive lenalidomide and dexamethasone with or without daratumumab. Randomized treatment continued until disease progression or development of unacceptable toxicity.

The MAIA trial had a primary endpoint of PFS. Key secondary endpoints included complete response rate, very good partial response (VGPR), the rate of negative MRD, overall response rate, overall survival, and safety.

Median patient age was 73, with 44% of patients 75 or older. More than 80% had ECOG performance status 0-1. Cytogenetic profiling for 642 patients showed that 86% had standard-risk disease and 14% had high-risk disease.

A prespecified interim analysis after 28 months of follow-up revealed a statistically significant 44% reduction in the risk of disease progression or death in the DRd arm (95% CI 27%-57%, P<0.0001). Data for overall survival remained immature, but analysis of other secondary endpoints showed a consistent advantage for DRd.

• Overall response rate: 93% vs 81% (P<0.0001)
• Complete response or better: 47% vs 24%
• VGPR or better: 79% vs 53%
• MRD negativity: 24% vs 7% (P<0.001)

With regard to safety, the DRd regimen was associated with more neutropenia (57% vs 42%), diarrhea (57% vs 46%), fatigue (40% vs 28%), and pneumonia (23% vs 13%). The most common grade 3/4 treatment-emergent adverse events (TEAEs) in the DRd arm were neutropenia (50%), lymphopenia (15%), pneumonia (14%), and anemia (12%). Infusion-related reactions occurred in 41% of patients in the DRd arm.

Incidence of secondary malignancy was 3%-4% in both arms. Rates of TEAE associated with death were 6%-7% in the two groups.

"The safety profile is consistent with findings from the POLLUX trial for DRd," said Facon.

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