As reported in The Lancet Oncology by Thierry Facon, MD, of the Centre Hospitalier Universitaire de Lille, and colleagues, a prespecified interim analysis of overall survival in the pivotal phase III MAIA trial has shown a significant benefit with the addition of daratumumab to lenalidomide/dexamethasone in patients with newly diagnosed transplant-ineligible multiple myeloma.¹

The primary analysis of the MAIA trial supported the June 2019 FDA approval (November 2019 EC approval by EMA) of daratumumab in combination with lenalidomide/dexamethasone in this setting, showing superior progression-free survival with the regimen after a median follow-up of 28 months.²

Thierry Facon, MD

Study Details

In the open-label trial, 737 transplant-ineligible patients from sites in 14 countries were randomly assigned between March 2015 and January 2017 to receive 28-day cycles of intravenous daratumumab (16 mg/kg once per week during cycles 1–2, once every 2 weeks in cycles 3–6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1–21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group, n = 368) or lenalidomide/dexamethasone alone (control group, n = 369). Treatment was continued until disease progression or unacceptable toxicity. Randomization was stratified by International Staging System (ISS) disease stage, geographic region, and age. Centrally assessed progression-free survival was the primary endpoint. Overall survival was a key secondary endpoint. For the prespecified interim analysis of overall survival, the prespecified stopping boundary was P = .0414.

Demographic and baseline disease characteristics for the daratumumab vs the control group were as follows: median age was 73 years vs 74 years (1% vs 1% of patients < 65 years, 20% vs 20% of patients 65 to < 70 years, 35% vs 36% of patients 70 to < 75 years, and 43% vs 44% of patients ≥ 75 years); 91% vs 92% of patients were white; 17% vs 16% of patients had Eastern Cooperative Oncology Group performance status score of 2 (all others 0 or 1); ISS stage was I in 27% vs 28% of patients, II in 44% vs 42% of patients, and III in 29% vs 30% of patients; the most common types of measurable disease were IgG in 61% vs 63% of patients and IgA in 18% vs 18% of patients; cytogenetic risk was standard in 85% vs 86% of patients and high in 15% vs 14% of 642 patients with available cytogenetic data; and median time since initial diagnosis was 0.95 months (interquartile range [IQR] = 0.53-1.46 months) vs 0.89 months (IQR = 0.59-1.45 months).

Overall Survival and Updated Efficacy Results

Median follow-up was 56.2 months (IQR = 52.7–59.9 months) at the time of overall survival interim analysis. With extended follow-up, median progression-free survival was not reached (95% confidence interval [CI] = 54.8 months to not reached) in the daratumumab group vs 34.4 months (95% CI = 29.6–39.2 months) in the control group (hazard ratio [HR] = 0.53, 95% CI = 0.43–0.66, P < .0001); the estimated progression-free survival rate at 60 months was 52.5% (95% CI = 46.7%–58.0%) vs 28.7% (95% CI = 23.1%–34.6%). 

Subsequent therapy had been received by 31% of patients in the daratumumab group and 51% of patients in the control group at clinical cutoff. Among those receiving subsequent therapy, the most common first subsequent therapy was a proteasome inhibitor–containing regimen without an immunomodulatory drug (53% vs 54%). A daratumumab-containing regimen was first subsequent therapy in 10% vs 21% of patients and any subsequent line of therapy in 15% vs 46% of patients.

At clinical cutoff, death had occurred in 32% of the daratumumab group and 42% of the control group. Median overall survival was not reached (95% CI = not reached to not reached) in the daratumumab group vs not reached (95% CI = 55.7 months to not reached) in the control group (HR = 0.68, 95% CI = 0.53–0.86, P = .0013). The estimated 60-month overall survival rate was 66.3% (95% CI = 60.8%–71.3%) in the daratumumab group vs 53.1% (95% CI = 47.2%–58.6%) in the control group.

Prespecified subgroup analyses of overall survival according to stratification factors showed hazard ratios favoring the daratumumab group over the control group: 0.79 (95% CI = 0.43–1.44) for ISS stage I, 0.61 (95% CI = 0.42–0.88)  for stage II, and 0.72 (95% CI = 0.49–1.04) for stage III; 0.63 (95% CI = 0.40–0.98) for North America (101 vs 102 patients) and 0.70 (95% CI = 0.53–0.93) for other regions; and 0.60 (95% CI = 0.42–0.85) for age younger than 75 and 0.76 (95% CI = 0.55–1.06) for age ≥75 years. The hazard ratios were 0.80 (95% CI = 0.46–1.39) for patients with high cytogenetic risk and 0.64 (95% CI = 0.48-0.85) for patients with standard cytogenetic risk.

Updated overall response rates were 92.9% vs 81.6% (odds ratio [OR] = 3.00, P < .0001), with complete response or better achieved in 51% vs 30% of patients (OR = 2.44, P < .0001). At a median follow-up of 47.9 months (IQR = 44.2-51.3), minimal residual disease-negative status was achieved in 31% of patients in the daratumumab group vs 10% of patients in the control group (OR = 3.91, P < .0001).

Adverse Events

The median duration of study treatment was 47.5 months (IQR = 20.0–56.4 months) in the daratumumab group and 22.6 months (IQR = 8.2–46.8 months) in the control group. The most common (> 15% in either group) grade ≥ 3 treatment-emergent adverse events were neutropenia (54% of patients in the daratumumab group vs 37% of patients in the control group), pneumonia (19% vs 11%), anemia (17% vs 22%), and lymphopenia (16% vs 11%). Grade ≥ 3 infections occurred in 41% vs 29% of patients. Serious adverse events occurred in 77% vs 70%, with the most common being pneumonia (18% vs 11%).

Treatment-emergent adverse events led to discontinuation of any component of study treatment in 13% vs 22% of patients. Second primary malignancies were reported in 20% vs 13% of patients. Treatment-related death occurred in 4% vs 3% of patients, with the most common cause being pneumonia (two patients in each group).

The investigators concluded: “Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the front-line use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation.” 

DISCLOSURE: The study was funded by Janssen Research & Development. For full disclosures of the study authors, visit thelancet.com.

REFERENCE

1. Facon T, Kumar SK, Plesner T, et al: Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): Overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 22:1582-1596, 2021.

2. Facon T, Kumar SK, Plesner T, et al: Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 380:2104-2115, 2019.