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 >0, BMI ≥30, LDH >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%/<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 >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 <30 (66.4 mos vs NR, HR 1.86) and White pts with BMI <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.
Disclosures
Houde:Janssen: Research Funding; Alexion, AstraZeneca Rare Diseases: Research Funding; BMS: Consultancy, Research Funding; Alnylam, Amgen, CaelumBiosciences, Celgene, Intellia,Janssen, Prothena, Regeneron: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khan:Janssen: Honoraria; Secura Bio: Consultancy, Research Funding; BMS: Research Funding; Amgen, Sanofi: Speakers Bureau. Hassoun:Celgene, Takeda, and Janssen Pharmaceuticals: Research Funding. Anderson:Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Merz:Alexion Pharmaceuticals: Consultancy, Research Funding; X4 Pharmaceuticals: Honoraria. Zon:Amagma Therapeutics: Consultancy, Current equity holder in private company. Efebera:Pfizer: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Adaptive: Honoraria, Speakers Bureau. Hartley-Brown:Pfizer: Consultancy, Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria; GlaskoSmith Kline: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Lonial:Bristol-Myers Squibb Company, Janssen Biotech Inc, Novartis, Takeda Pharmaceuticals USA Inc.: Other: Contracted Research, Research Funding; Novartis: Research Funding; TG Therapeutics Inc: Other: Board of Directors with Stock; AbbVie Inc, Amgen Inc, Bristol-Myers Squibb Company, Celgene Corporation, Genentech, a member of the Roche Group, GlaxoSmithKline, Janssen Biotech Inc, Novartis, Pfizer Inc, Takeda Pharmaceuticals USA Inc: Consultancy, Other: Advisory Committee; Janssen: Research Funding. Voorhees:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Regeneron: Consultancy; Nervianos Medical Sciences: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety and Monitoring; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Orlowski:BMS/Celgene Corporation, CARsgen Therapeutics, Exelixis Inc., Heidelberg Pharma, Janssen Biotech Inc., Sanofi/Genzyme, Takeda Pharmaceuticals USA Inc.: Other: Clinical Research Funding, Research Funding; Asylia Therapeutics, BioTheryX Inc., Heidelberg Pharma: Other: Laboratory Research Funding, Research Funding; AbbVie, Adaptive Biotech, Asylia Therapeutics, Inc., BioTheryX, Bristol-Myers Squibb Pharmaceuticals, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Nanjing IASO Biotherapeutics, Neoleukin Corporation, Oncopeptides AB, Pfizer, In: Consultancy, Honoraria; Asylia Therapeutics: Current equity holder in private company, Patents & Royalties. Libby:Adaptive Biotechnologies: Consultancy. Hurd:BMS/Celgene: Current equity holder in publicly-traded company. Costello:BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Regeneron: Honoraria; Poseida, Ionis, Harpoon Therapeutics: Research Funding. Raje:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immuneel: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Caribou Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; K36 Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. McCarthy:BMS, Karyopharm: Honoraria, Other: DSMB; GSK: Honoraria. Milner:AstraZeneca, BeiGene, Blueprint Medicines, Bristol Myers Squibb: Speakers Bureau. Gasparetto:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Agha:GenCART, Inc.: Current equity holder in private company. Jagannath:Takeda: Consultancy; Legend Biotech: Consultancy; Genmab: Other: DMC chairman; ASH: Membership on an entity's Board of Directors or advisory committees; IMS: Membership on an entity's Board of Directors or advisory committees; SOHO: Membership on an entity's Board of Directors or advisory committees; Karyopharma: Consultancy; Sanofi: Consultancy, Other: DMC Chariman; Caribou: Consultancy; Regeneron: Consultancy; BMS: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria. Alsina:Genzyme: Consultancy, Honoraria; RevHealth LLC, Red Med LLC: Honoraria; Janssen Oncology: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding. Giralt:Amgen, Actinuum, Celgene/BMS, Kite Pharma, Janssen, Jazz Pharmaceuticals, Johnson & Johnson, Novartis, Spectrum Pharma, Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen, Actinuum, Celgene/BMS, Omeros, Johnson & Johnson, Miltenyi, Takeda: Research Funding. Laubach:Lignancies: Honoraria. Nadeem:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GPCR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:GlaxoSmithKline: Consultancy, Honoraria; Menarini Silicon Biosystems: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy; The Binding Site: Consultancy; Huron Consulting: Consultancy; Adaptive: Honoraria; Aptitude Health: Consultancy; 10x Genomics: Honoraria; Disc Medicine: Other: Spouse is Chief Medical Officer and holds equity in the company; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Vor Biopharma: Ended employment in the past 24 months, Honoraria, Speakers Bureau; Oncopeptides: Consultancy; Window Therapeutics: Consultancy. Mo:AbbVie, Janssen: Membership on an entity's Board of Directors or advisory committees; AbbVie, BioLine, GSK, Janssen, Karyopharm, Pfizer, Pharmacyclics, Sanofi, Spectrum, Takeda: Consultancy. Anderson:Window, Starton: Current equity holder in private company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; NextRNA: Current equity holder in private company; Oncopep: Current equity holder in private company, Current holder of stock options in a privately-held company; Dynamic Cell Therapies: Current equity holder in private company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics, Raqia, NextRNA,Dynamic Cell Therapy: Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pfizer, Janssen, Astrazeneca, Daewoong, Amgen, Starton, OncoPep, Precision Biosciences, Window Therapeutics, Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Richardson:Sanofi: Consultancy; GSK: Consultancy; Bristol Myers Squibb: Consultancy, Other: Contracted research, Research Funding; Oncopeptides: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Research Funding; AstraZeneca Pharmaceuticals LP, Bristol-Myers, Squibb Company, Celgene Corporation, GlaxoSmithKline, Janssen Biotech Inc, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda Pharmaceuticals USA Inc;: Consultancy.
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