Treatment Outcomes and Prognostic Factors with Lenalidomide, Bortezomib, and Dexamethasone (RVd) Alone Versus Rvd Plus Autologous Stem Cell Transplantation (ASCT) in African American (AA) Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) in the Determination Phase 3 Trial
Authors: Houde Christiane A. , Khan Abdullah , Jacobus Susanna J. , Hassoun Hani , Anderson Larry D. , Merz Lauren E. , Zon Rebecca L. , Efebera Yvonne , Buck Tondre , Innis-Shelton Racquel D. , Hartley-Brown Monique A , Lonial Sagar , Campagnaro Erica L. , Voorhees Peter M. , Orlowski Robert Z. , Libby Edward , Hurd David Duane , Costello Caitlin L. , Raje Noopur S. , Medvedova Eva , McCarthy Philip L. , Milner Carter P. , Gasparetto Cristina , Agha Mounzer E , Gowin Krisstina , Kamble Rammurti T. , Jagannath Sundar , Nathwani Nitya , Alsina Melissa , Giralt Sergio A. , Laubach Jacob P. , Nadeem Omar , Ghobrial Irene M. , Mo Clifton C. , Samur Mehmet K. , Anderson Kenneth C. , Munshi Nikhil C , Richardson Paul G. 
Published: December 2023

Background

AA pts with NDMM have equal or longer overall survival (OS) vs White pts when treatment access is equal (Fillmore, Blood 2019; Dong, Blood Cancer J 2022). DETERMINATION included one of the largest cohorts of AA pts in prospective NDMM trials (n=132/722, 18.3%). The overall progression-free survival (PFS) difference (RVd-alone vs RVd+ASCT; median 46.2 vs 67.5 months [mos]; hazard ratio [HR] 1.53) was not seen in AA pts (HR 1.07; Richardson, N Engl J Med 2022). Multivariable PFS analyses, overall and by arm, showed that prognostic factors may vary according to treatment received, potentially indicating differences in MM pathobiology; PFS in AA vs White pts was longer with RVd-alone (HR 0.58) but similar with RVd+ASCT (HR 0.95) (Hassoun, EBMT 2023). We build upon this prior work with new analyses to explore outcomes with RVd-alone vs RVd+ASCT in AA and White pts.

Methods

Pts aged 18-65 y received RVd (3 cycles), stem cell mobilization, then 5 more RVd cycles (RVd-alone: n=357; 66 AA, 268 White) or ASCT and 2 more RVd cycles (RVd+ASCT: n=365; 66 AA, 272 White), and then R maintenance. We analyzed PFS (primary endpoint) by race, with exploration of potentially confounding effects of body mass index (BMI) and sex. Treatment exposure, response, event-free survival (EFS; events: progressive disease [PD], death, non-protocol therapy [NPT]), OS, and safety by race were evaluated. Exploratory genomic analyses in a subset of pts assessed frequency of Duffy-null genotype, a common variant in AA pts associated with lower circulating neutrophil count without increased infection risk that may have a key role in cytokine homeostasis (Jinna, Cells 2022).

Results

AA pts were younger and more commonly female than White pts, as seen in the GRIFFIN study (Nooka, Blood Cancer J 2022), with higher rates of ECOG PS &gt;0, BMI ≥30, LDH &gt;ULN, and low hemoglobin (panel A). Of 153 samples tested to date, 13 (8.5%) were Duffy-null: 11/17 (64.7%) AA and 2/136 (1.5%) non-AA pts. Median treatment duration from randomization (cycle 2) in AA and White pts, respectively, was 27.5 and 28.7 mos (RVd-alone) vs 36.1 and 36.2 mos (RVd+ASCT); 16% of AA and 13% of White pts discontinued within the first 3 RVd cycles due to adverse events (AEs; 5%/3% of AA/White pts), pt/investigator decision (5%/6%), PD (3%/3%), death (2%/&lt;1%), or other reasons (2%/1%). In the 79%/86% of AA/White pts (RVd+ASCT) who underwent ASCT on study, transplant parameters were similar. 77%/83% of AA/White pts on the RVd-alone arm and 74%/80% on RVd+ASCT started R maintenance; median duration was 43.3/35.8 mos and 45.2/40.4 mos, respectively. In AA/White pts, median % of cycles with mean R dose &gt;10 mg was 78%/88% (RVd-alone) and 83%/58% (RVd+ASCT). At data cut-off, of pts who started maintenance, 35%/25% of AA/White pts on the RVd-alone arm and 35%/29% on the RVd+ASCT arm were ongoing, and 65%/75% and 65%/71% had discontinued (including 37%/57% and 33%/37% due to PD), respectively. AE data are shown in panel B.

Odds of achieving ≥CR were greater with RVd-alone vs RVd+ASCT in AA pts and were lower for AA vs White pts on the RVd+ASCT arm (panel B). Median PFS (RVd-alone vs RVd+ASCT) was not reached (NR) vs 61.4 mos (HR 1.07) in AA pts and 44.3 vs 67.2 mos (HR 1.67) in White pts. PFS with RVd-alone vs RVd+ASCT was longer in AA pts with BMI ≥30 (median NR vs 58.6 mos, HR 0.74), but shorter in AA pts with BMI &lt;30 (66.4 mos vs NR, HR 1.86) and White pts with BMI &lt;30 (45.3 vs 82.3 mos, HR 1.78) or ≥30 (41.1 vs 64.4 mos, HR 1.58). The PFS with RVd-alone vs RVd+ASCT was similar in male (HR 1.28) and female (HR 0.90) AA pts but shorter in male (HR 1.47) and female (HR 1.85) White pts.

With RVd-alone vs RVd+ASCT, median EFS was 47.7 vs 48.2 mos (HR 0.99) in AA pts and 31.7 vs 46.7 mos (HR 1.30) in White pts; 5-y OS was 83.2% vs 78.7% (HR 0.99) in AA pts and 77.1% vs 80.3% (HR 1.08) in White pts. Among AA/White pts off study treatment, 64%/77% had received NPT; 27%/28% (RVd-alone arm) had received ASCT as NPT.

Conclusions

Our analyses suggest that PFS, EFS, and OS were similar with RVd-alone and RVd+ASCT in AA pts on this study. Importantly, while outcomes with RVd+ASCT were similar in AA and White pts, exploratory analyses suggest AA pts with high BMI and female AA pts may derive more PFS benefit from RVd-alone. Rates of starting maintenance/NPT use were lower in AA vs White pts, but maintenance duration proved longer in AA pts, with similar rates of grade ≥3 hematologic AEs, including neutropenia; analyses of outcomes by Duffy status are ongoing and will be presented.