Introduction: Daratumumab (Dara), an anti-CD38 antibody, is approved for the treatment of patients with multiple myeloma (MM) and recommended for approval in patients with high-risk smoldering MM (SMM). High-risk SMM (HR-SMM) exhibits tumor genomic features similar to MM, suggesting it could be too advanced for a single-drug intervention. We conducted a Phase II trial of single-agent daratumumab in patients of earlier stage, including high-risk monoclonal gammopathy of undetermined significance and low-risk SMM, to test if earlier treatment can lead to deep responses and prevent progression to MM.

Methods: Patients enrolled on this study met eligibility for either HR-MGUS or LR-SMM. HR-MGUS is defined as <10% bone marrow plasma cells and <3g/dL M protein and at least 2 of the following 3 high-risk criteria: Abnormal serum free light chain ratio (SFLC) of <0.26 or >1.65, M protein ≥ 1.5g/dL or non-IgG M protein. LR-SMM is defined by one of the following 3 criteria: M protein ≥3g/dL, ≥10% bone marrow plasma cells, SFLC ratio <0.125 or >8. Dara was administered weekly for cycles 1-2, every other week cycles 3-6, and monthly during cycles 7-20. The primary objective of this study was to determine the proportion of patients who achieve very good partial response (VGPR) or greater after 20 cycles of Dara. Secondary objectives included duration of response, safety, and rates of minimal residual disease (MRD)-negativity in VGPR or greater patients. Correlative studies included assessing changes in immune microenvironment, evaluating clonal heterogeneity using deep sequencing, and determining association of genomic aberrations correlating with either response to therapy or progression of disease.

Results: Between January 2018 and February 2020, 41 patients were enrolled on this study. Most patients (n=36/41; 88%) had LR-SMM, and 5 patients (12%) had HR-MGUS. Per the 2/20/20 Mayo 2018 criteria for patients with SMM (n=36), 22 patients had LR-SMM (54%), 12 had IR-SMM (29%), and 2 (5%) had HR-SMM. In total, 39/41 patients (95%) completed 20 cycles of therapy as per the protocol.

Grade 3 or higher toxicities included hypertension (n = 3/41; 7%), diarrhea (n = 1/41; 2%), flu-like symptoms (n = 1/41; 2%), and headache (n = 1/41; 2%). Upper respiratory infections (URI) occurred in 9 patients (22%), with 10% of patients developing grade 2 URIs. Neutropenia was seen in 12 patients (29%), with 7 (17%) experiencing grade 2 neutropenia. There were no grade 3 neutropenia or grade 3 infections. No patients developed secondary hematologic malignancies at a median follow-up of ~5 years

The overall response rate (ORR) was 54% (n=22/41; 90% CI: 40-67). Seven patients achieved a best overall response of VGPR or better (17%; 90% CI: 8-30%). Best overall responses were complete response (CR, n = 4/41; 10%; 90% CI: 3-21%), VGPR (n = 3/41; 7%; 90% CI: 2-18%), PR (n = 15/41; 37%; 90% CI: 24-51%), or minor response (MR, n = 12/41; 29%; 90% CI: 18-43%). The median follow-up for all 41 patients was 63.5 months (range, 6.7-79.8). Median OS was not reached (NR), and OS was 100% at 5 years of follow-up. Overall, two patients progressed to MM and in both cases, progression was diagnosed based on the SLiM criteria. Twenty-one patients (51%, 90% CI: 37-65) developed biochemical progression based on the IMWG criteria. The median biochemical PFS was 59.5 (range: 5.5-76.3) months. Biochemical PFS was significantly longer in patients who achieved VGPR or better (NR vs 52.2 months; two-sided log-rank, p=0.014) andduration of response was also longer (two-sided log-rank, p=0.075; one-sided, p=0.0375).

Correlative analyses leveraging whole-genome and single-cell RNA sequencing identified genomic and immune variables associated with biochemical progression.

Conclusions: This study demonstrates that daratumumab is safe and can lead to deep responses in certain early-stage patients, highlighting the importance of adopting genomic and immune profiling methods to improve patient selection and maximize the benefit/risk ratio in trials of early intervention.

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2025
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