Significant overall survival benefit with daratumumab, lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma

Previous studies have established the progression-free survival benefit of daratumumab for newly diagnosed multiple myeloma. In the last update of the phase III MAIA trial, which investigated daratumumab combined with lenalidomide and dexamethasone (D-Rd) versus Rd alone, overall survival (OS) data were not yet mature. After almost five years of follow-up, D-Rd now demonstrates a significant OS benefit versus Rd alone, with a 32% reduction in the risk of death.

The phase III ALCYONE, MAIA and CASSIOPEIA studies have established the progression-free survival (PFS) benefit of daratumumab (DARA), when added to standard of care (SoC) regimens for newly diagnosed multiple myeloma (NDMM). Conversely, the phase III SWOG S0777 study has established VRd (bortezomib, lenalidomide and dexamethasone) as the SoC regimen for elderly patients with NDMM without intent for immediate transplant. Despite this, a statistically significant overall survival (OS) benefit in these elderly patients (≥65 years) was not observed, when compared to Rd (HR: 0.769; p= 0.168), representing an unmet clinical need. Furthermore, real-world data indicate that at least 50% of non-transplant elderly NDMM patients do not receive subsequent therapy, suggesting that the most effective therapy should be used in the first-line setting and not saved for relapse. In this light, an update of the phase III MAIA trial, which investigated DARA with a SoC regimen in a predominantly elderly cohort, was presented at the EHA 2021 meeting.

MAIA study design

The phase III MAIA trial is a multicentre, randomised, open-label, active-controlled study that enrolled 737 NDMM patients who were ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 or comorbidities. Patients were randomised in a 1:1 ratio to receive Rd (R: 25mg orally once daily, days 1-21; d: 40mg orally, days 1, 8, 15 and 22) with or without DARA in 28-day cycles (16mg/kg intravenously once weekly for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter). Patients received treatment until disease progression or unacceptable toxicity. The primary endpoint was PFS, with key secondary endpoints of overall response rate (ORR), OS and safety.

Strongly reduced risk of death with D-Rd

Baseline characteristics were well balanced between treatment arms. Of note, approximately 44% of participants were ≥75 years old, with only 1% being <65. At a median follow-up of 56.2 months, D-Rd induced deeper responses with significantly higher rates of complete responses (CR) and very good partial responses (VGPR), compared to Rd alone. With more than 28 months of additional follow-up, responses deepened with continued DARA therapy (primary analysis stringent CR [sCR]: 30%; 56.2 month analysis sCR: 35%). In this updated analysis, D-Rd continued to demonstrate a significant PFS benefit, when compared to Rd alone (median PFS: not reached [NR] vs. 34.4 months; HR [95%CI]: 0.53 [0.43-0.66], p< 0.0001). This PFS benefit also translated into an OS benefit. D-Rd reduced the risk of death by 32%, when compared to Rd alone (median OS NR in either arm; HR [95%CI]: 0.68 [0.53-0.86], p= 0.0013). The estimated 60-month OS rate was 66.3% with D-Rd and 53.1% with Rd. The reported OS benefit was observed across all pre-specified subgroups, except in those with impaired hepatic function at baseline (HR [95%CI]: 1.05 [0.48-2.30]). Of note, this OS benefit also included patients with high cytogenetic risk (HR [95%CI]: 0.80 [0.46-1.39]), although standard risk patients received a greater benefit (HR [95%CI]: 0.64 [0.48-0.85]).

At the time of this extended follow-up, 42% remained on D-Rd treatment, whilst 18% remained on Rd, respectively. The most common reasons for treatment discontinuation included progressive disease (27% vs. 34%) and adverse events (13% vs. 23%). The median time to next treatment was not reached with D-Rd, compared to 42.4 months with Rd alone (HR [95%CI]: 0.47 [0.37-0.59], p <0.0001). Overall, 46% of Rd patients received daratumumab as subsequent therapy. Comparing D-Rd to Rd, the most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (54% vs. 37%), anaemia (17% vs. 22%), lymphopenia (16% vs. 11%) and pneumonia (19% vs. 11%). Additionally, a lower percentage of grade 3-4 and serious TEAEs occurred after 24 months, compared to the first 24 months of treatment in both arms, and no new safety concerns were observed with longer follow-up.   

Conclusion

With a significant OS benefit and a PFS benchmark in patients with NDMM who are transplant ineligible, these results support upfront D-Rd as the new SoC for these patients. Additionally, these results have been achieved in a study population of predominantly elderly patients, with no new safety concerns observed with continuous therapy and extended follow-up.

Reference

Facon T et al., Overall survival results with daratumumab, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: phase 3 MAIA study. Presented at EHA 2021; abstract LB1901.