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    Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

    Category: Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

    Exploratory analyses of progression-free survival (PFS) with lenalidomide-bortezomib-dexamethasone (RVd) alone/RVd+ASCT by Duffy genotype in patients (pts) with newly diagnosed multiple myeloma (NDMM)

    (PA-432) Exploratory Analyses of Progression-free Survival (PFS) with Lenalidomide-bortezomib-dexamethasone (RVd) Alone/RVd+ASCT by Duffy Genotype in Patients (pts) with Newly Diagnosed Multiple Myeloma (NDMM)

    Thursday, September 18, 2025

    Introduction:      In the DETERMINATION phase 3 trial, relative PFS with RVd-alone vs RVd+ASCT differed between White (n=540/722, 74.8%; median 44.3 vs 67.2 months [mos]; hazard ratio [HR] 1.67, 95%CI 1.29–2.15) and African American (AA) pts (n=132/722, 18.3%; median not reached [NR] vs 61.4 mos; HR 1.07, 95%CI 0.61–1.89). Given that access to care was enhanced in DETERMINATION and race is a social construct, a pathobiological explanation was sought; high prevalence of Duffy null phenotype among AA pts and its known impact on the inflammasome was proposed as an alternative hypothesis for the observed differential treatment effect by race.

    Methods:   Genomics analysis of baseline peripheral blood samples for SNP rs2814778 classified pts as C/C (Duffy null) or non-C/C (Duffy non-null). Duffy status is currently available for 295 pts (40.9% of intent-to-treat [ITT] population); this cohort is broadly representative but contains fewer AA pts, pts with ECOG PS >0, and pts with elevated LDH, and also had longer treatment duration. Impact of Duffy status on PFS was evaluated with Cox proportional hazards regression in univariate and multivariable models. Heterogeneity of treatment effect was assessed by a test for interaction.

    Results:   Of 295 pts, 37 (12.5%) were AA, of whom 27 (73.0%) were Duffy null; 256 (86.8%) were White/other race, of whom 1 (0.4%) was Duffy null. In all pts in our cohort, PFS with RVd-alone vs RVd+ASCT (median 52.2 vs 82.3 mos; HR 1.41, 95%CI 1.01–1.96) was consistent with the ITT population; PFS data in AA pts (median NR vs NR; HR 0.76, 95%CI 0.23–2.50) and White/other race pts (median 49.4 vs 66.5 mos; HR 1.52, 95%CI 1.06–2.17) (interaction p-value 0.130) were similar to ITT findings in AA and White pts. PFS (pooled across treatment) was similar in Duffy null vs Duffy non-null pts (12/29 vs 132/266 events/pts; median NR vs 61.9 mos; HR 0.78, 95%CI 0.43–1.41). PFS with RVd-alone vs RVd+ASCT was substantially different in Duffy null pts (2/13 vs 10/16 events/pts; median NR vs 44.0 mos; HR 0.21, 95%CI 0.04–1.02) compared to Duffy non-null pts (73/121 vs 59/145 events/pts; median 48.4 mos vs NR; HR 1.73, 95%CI 1.21–2.46) (interaction p-value 0.002). On multivariable analysis, PFS was significantly longer in Duffy null vs Duffy non-null pts with RVd-alone (HR 0.15, 95%CI 0.04–0.63), but PFS HR was 1.69 (95%CI 0.85–3.37) with RVd+ASCT.

    Conclusions:   

    Treatment effect was substantially different according to Duffy status and more pronounced than that observed by race. The Duffy antigen has a key role in cytokine/chemokine homeostasis, potentially affecting MM pathobiology and inflammatory stressor responses, thereby providing a biologically plausible rationale for differential treatment effect. Current analyses are limited by sample size, near-complete concordance of Duffy status with race, and absence of Duffy null White/other race patients, with additional analysis therefore ongoing.

     
    Encore abstract, previously presented at EBMT 2025, poster A352.