Introduction

Lenalidomide (len) is the standard maintenance therapy in multiple myeloma (MM) due to its proven survival benefits. Daratumumab (dara) single-agent maintenance when compared to observation has shown improved PFS. This investigator-initiated trial is the only randomized study (NCT04497961; n=89) that evaluated single-agent dara vs len maintenance. The final results of this fully accrued study with primary endpoint of difference in quality of life (QOL) global health status (GHS) and secondary endpoints of efficacy and toxicity are reported.

Methods

This was a single-center open-label, randomized study of maintenance dara compared to len. Patients (pts) with NDMM who achieved ≥VGPR after induction were randomized (1:1), stratified by age and ASCT status to receive either len or dara as maintenance. Pts were followed with monthly QOL surveys (EORTC QLQ-C30, MY20), quarterly serologic markers, and annual imaging and bone marrow biopsy. High-risk cytogenetics were defined as presence of t(4;14), t(14;16), t(14;20), del17p, gain/amp 1q or del1p. Survey responses were compared using a mixed-effects linear regression model with random intercept. Response including MRD negativity in the marrow by flow cytometry (10-5) was assessed per IMWG 2016 criteria, PFS was estimated using Kaplan–Meier approach, and toxicities were graded per CTCAE v5.0.

Results

89 pts were enrolled (44 in len arm, 45 in dara arm) with a median follow-up of 24.9 months as of July 2025. Median age was 64yrs with 48.3% ≥65yrs, 57.3% male; 71.9% White, 20.2% Black, 7.8 other races. High-risk cytogenetics were present in 25% in len arm and 26.7% in dara arm. In the len arm, 56.8% received quadruplets, 40.9% triplets, and 1 pt received infusional chemotherapy. In the dara arm, 57.8% and 42.2% received quadruplets and triplets, respectively. Dara during induction was received by 56.8% in len arm and 71.1% in dara arm. Len during induction was received by 93.2% in len arm and 100% in dara arm. ASCT was done in 79.5% in len arm and 77.8% in dara arm.

The mean baseline GHS for the overall study was 72 (95%CI 69, 75). There was a significant increase in GHS per cycle (mean increase 0.18; 95%CI 0.11, 0.25) on maintenance. There was no difference in the primary endpoint of GHS between two arms (p=0.9). The total QLQ score did not change with time on maintenance (p=0.47) and there was no difference between the arms (p=0.5).

Improvement in social functioning (p≤0.001), insomnia (p≤0.001), constipation (p=0.04), and worsening of nausea/vomiting (p≤0.001), diarrhea (p≤0.001) were noted with time on maintenance in the overall cohort. When compared to len, the dara arm showed improved diarrhea (p≤0.001) and dyspnea (p=0.04) but worse emotional functioning (p=0.004) and constipation (p=0.02). Changes in body image (p≤0.001) and future perspective (p=0.004) improved with time on treatment, with no difference between arms (p=0.45 and p=0.29, respectively).

At screening the len arm had 40.9% sCR, 18.2% CR and 40.9% VGPR and dara arm had 48.9% sCR, 6.7% CR and 44.4% VGPR. Best responses in len arm were 59.1% sCR, 9.1% CR (68.2% ≥CR), 29.5% VGPR, 2.3% POD, and in dara arm were 77.8% sCR, 4.4% CR (82.2% ≥CR) and 17.8% VGPR. MRD negativity rates at screening and deepest response post-baseline assessment were 50% (n=44) and 55.3% (n=38) in len arm and 48.9% (n=50) and 57.5% (n=40) in dara arm. PFS rates at 12m and 24m were 92.5% and 79.5% in len arm and 95.2% and 78.9% in dara arm. There were 13 serious adverse events (SAE) in len arm, notably 3 infections and 4 neoplasms (BCCx2, SCC, lung ca), and 22 SAE in dara arm, notably 9 infections and 2 neoplasms (BCC, prostate ca). Of 21 pts that came off study, 14 for POD (7 len arm; 7 dara arm), 4 for toxicity (2 len arm - neuropathy, urticaria; 2 dara arm - osteomyelitis, pneumonitis), 2 for secondary malignancies (MDS in len arm, CML in dara arm), and 1 in len arm for pt preference.

Conclusions

This is the only randomized trial that compared single-agent len to dara as maintenance, assessing QOL as well as efficacy and, toxicity. GHS improved with time on maintenance but was not different between arms. While ≥CR rates were numerically higher in dara arm, the study was not powered for efficacy comparison. These data add to ongoing maintenance trials utilizing anti-CD38 monoclonal antibodies. Given encouraging tolerability and efficacy, dara offers an effective maintenance option, especially in pts with len intolerance.

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2025
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