Treatment Outcomes By Duffy Genotype in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVd) Alone or Rvd Plus Autologous Stem Cell Transplantation (ASCT) in the Determination Phase 3 Trial

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Background Erythrocyte Duffy null phenotype, seen in ∼66% of African American (AA) and <1% of White pts, is associated with lower absolute neutrophil count (ANC) and has a key role in cytokine and chemokine homeostasis , which may influence MM pathobiology, response to proinflammatory stressors, and treatment effect. The DETERMINATION trial of RVd-alone vs RVd+ASCT in NDMM showed significantly improved progression-free survival (PFS; median 46.2 vs 67.5 mos; hazard ratio [HR] 1.53, 95% CI 1.23–1.91) with RVd+ASCT. PFS was improved with RVd+ASCT in White pts (n=540, 74.8%; median 44.3 vs 67.2 mos; HR 1.67, 95% CI 1.29–2.15), but in AA pts (n=132, 18.3%) median PFS was not reached (NR) vs 61.4 mos (HR 1.07, 95% CI 0.61–1.89). Race is an inadequate explanation for differences in outcomes; we hypothesized that Duffy null phenotype may influence outcomes and magnitude of benefit with these treatment modalities in NDMM . Methods Pts received RVd-alone or RVd+ASCT followed by R maintenance until progression. Peripheral blood samples underwent genomics analysis for SNP rs2814778 and were classified as C/C (Duffy null) or non-C/C (Duffy non-null). Results Duffy status is currently available for 295 pts (Fig 1). The cohort is broadly representative of the ITT population but has fewer AA pts, pts with ECOG PS >0, and pts with elevated LDH . Treatment duration was longer than in ITT pts: median duration from randomization (RVd-alone vs RVd+ASCT) was 62.2 vs 36.5 mos in Duffy null and 44.7 vs 45.5 mos in Duffy non-null pts; median duration of R maintenance was 55.2 vs 30.4 mos in Duffy null and 38.5 vs 42.9 mos in Duffy non-null pts. Median (IQR) baseline ANC was 2.8 (2.1–4.2) in Duffy null and 3.3 (2.5–4.7) x 10 9 /L in Duffy non-null pts. Rates of grade ≥3 hematologic adverse events (AEs) during all treatment (RVd-alone vs RVd+ASCT) were 69.2% vs 93.8% in Duffy null and 58.7% vs 96.6% in Duffy non-null pts; rates of grade ≥3 hematologic AEs during R maintenance were 23.1% vs 57.1% in Duffy null and 26.7% vs 44.3% in Duffy non-null pts. PFS in this cohort was similar to PFS in the ITT population (Fig 2). Fig 3 shows PFS by Duffy status. On univariate analysis in pts receiving RVd-alone, PFS was significantly longer in Duffy null vs Duffy non-null pts (HR 0.20, 95% CI 0.05–0.80), but in pts receiving RVd+ASCT the PFS HR was 1.73 (95% CI 0.89–3.39). Conclusions These exploratory analyses showed substantial differences in relative PFS by treatment arm and notably for RVd-alone between Duffy null (primarily AA) and Duffy non-null (primarily White/other race) pts, which were more pronounced than differences by race overall. Whilst race is considered a social construct, Duffy status provides a biologically plausible rationale for treatment effect. Although limited by sample size and near-complete concordance of Duffy null with race in current datasets, further exploration of Duffy status on outcomes is warranted, with additional analysis ongoing.

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