Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma

Abstract

Background: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.

Methods: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.

Results: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 10⁵ white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).

Conclusions: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).

Figure 1.. Progression-free Survival.

Shown are the results of the Kaplan–Meier estimates of progression-free survival among patients in the intention-to-treat population. The daratumumab group received treatment with daratumumab, lenalidomide, and dexamethasone; the control group received treatment with lenalidomide and dexamethasone. The interim analysis of progression-free survival was performed after 240 events of disease progression or death had occurred (62% of the planned 390 events for the final analysis).

Figure 2.. Prespecified Subgroup Analysis of Progression-free Survival.

Shown are the results of an analysis of progression-free survival in prespecified subgroups in the intention-to-treat population. The daratumumab group received treatment with daratumumab, lenalidomide, and dexamethasone; the control group received treatment with lenalidomide and dexamethasone. The International Staging System (ISS) disease stage, which is derived on the basis of the combination of serum β₂-microglobulin and albumin levels, consists of three stages, with higher stages indicating more advanced disease. The subgroup analysis for the type of myeloma was performed on data from patients who had measurable disease in serum. A high-risk cytogenetic profile was defined by the detection of a del17p, t(14;16), or t(4;14) cytogenetic abnormality (or a combination of these) on fluorescence in situ hybridization or karyotype analysis. Impaired baseline hepatic function includes mild impairment (total bilirubin level less than or equal to the upper limit of the normal range [ULN] and aspartate aminotransferase level higher than the ULN, or total bilirubin level higher than the ULN and ≤1.5 times the ULN), moderate impairment (total bilirubin level >1.5 times and ≤3 times the ULN), and severe impairment (total bilirubin level >3 times the ULN). Eastern Cooperative Oncology Group (ECOG) performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. NE denotes could not be estimated.