Abstract
Introduction The recently reported DETERMINATION trial of RVd-alone vs RVd+ASCT and lenalidomide (R) maintenance to progression in pts with NDMM demonstrated a highly significant benefit in the primary endpoint of PFS (median 46.2 vs 67.5 months; hazard ratio [HR] 1.53, 95% CI 1.23-1.91) for RVd+ASCT, but no overall survival benefit after median follow-up of 76 months and despite only 28% of RVd-alone pts receiving subsequent ASCT to date (Richardson PG, et al. NEJM 2022). The trial was not specifically powered for subgroup comparisons, and in this context no statistically significant interactions (p<0.05) were seen. However, PFS HRs were clinically noteworthy and ranged from 0.96 to 3.40 in subgroups defined by race, body mass index (BMI), International Staging System (ISS) disease stage, and cytogenetics. Here we report univariate and multivariable analyses conducted to identify prognostic factors mediating differential outcomes with RVd-alone and RVd+ASCT.
Methods Pts aged 18-65 years received 3 21-day cycles of RVd triplet combination therapy, stem cell mobilization, and then either 5 more cycles of RVd (RVd-alone: n=357) or melphalan 200 mg/m2 + ASCT and 2 more cycles of RVd (RVd+ASCT: n=365), plus R maintenance until progression or intolerance (RVd-alone: n=291; RVd+ASCT: n=289; median duration 36.4 vs 41.5 months). We evaluated select pt and disease characteristics by race (white/Caucasian, black/African-American, other), BMI (<25, 25-<30, ≥30), and ISS stage (I, II, III) to identify factors with imbalances among subgroups. Univariate analysis was then conducted for PFS on all pts (N=722), using Cox proportional hazards regression. Factors with imbalances among subgroups and/or with univariate PFS association (p<0.20) were included in a multivariable model. These same factors were used in independent univariate and multivariable analyses of pts within each arm.
Results Analyses of baseline characteristics in subgroups defined by race showed notable imbalances, with black pts more likely to be female (p=0.001) and aged <60 years (p=0.024), and to have BMI ≥25 (p=0.024), ECOG performance status (PS) >0 (p=0.066), elevated lactate dehydrogenase (LDH) (p=0.042), hemogloblin ≤10 g/dL (p<0.001), and high-risk cytogenetics [t(4;14), t(14;16), del17p] (p=0.12). In BMI subgroups, pts with higher BMI were more likely to be male (p<0.001) and black (p=0.024). In ISS stage subgroups, pts with higher-stage disease were more likely to be aged ≥60 years (p=0.003) and to have ECOG PS >0 (p=0.018), elevated LDH (p<0.001), elevated calcium (p=0.009), and hemogloblin ≤10 g/dL (p<0.001).
From univariate analyses, the variables associated with poorer PFS among all 722 pts were ECOG PS >0, ISS stage II or III MM, high-risk cytogenetics, elevated LDH, and hemoglobin ≤10 g/dL. All except hemoglobin were independently associated with poorer PFS on multivariable analysis (Table). When multivariable models were evaluated by arm, white race, ECOG PS >0, high-risk cytogenetics, and LDH >ULN were all independent prognostic factors for poorer PFS with RVd-alone but not RVd+ASCT, suggesting that ASCT abrogates the poor prognosis associated with these factors. ISS stage II-III disease was associated with poorer PFS with RVd+ASCT but not RVd-alone, with ASCT offering greater PFS benefit in pts with stage I MM. Univariate/multivariable analyses for achievement of ≥CR also identified discrepancies in prognostic impact of pt and disease characteristics between treatment arms. Analyses of additional factors (e.g. revised ISS stage) and outcomes are ongoing, including correlative studies of minimal residual disease and whole-genome sequencing. Additional and updated data will be presented at the meeting.
Conclusions These data show a differential impact of prognostic factors between treatment approaches and may also reveal differences in MM pathobiology between subgroups. Further consideration of the significant associations among baseline clinicopathologic characteristics is warranted, as well as estimation of the differential impact of various risk factors. Pending validation, such models may help identify subgroups of NDMM pts for whom upfront ASCT could be more or less valuable. This will be especially important in the context of monoclonal antibody-based quadruplet induction therapies, which are showing increasingly high quality and durable responses with or without ASCT.
Disclosures
Hassoun:Celgene: Research Funding; Takeda: Research Funding; Janssen Pharmaceuticals: Research Funding. Richardson:Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy; Secura Bio: Consultancy; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Takeda: Research Funding; Takeda, Abbvie, GSK, and Celgene: Consultancy; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; Takeda, Celgene, and GSK: Honoraria; Takeda and GSK: Other: Travel expenses from Takeda and GSK; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding. Zonder:Janssen: Research Funding; Alexion, AstraZeneca Rare Diseas: Research Funding; BMS: Consultancy, Current Employment, Research Funding; Alnylam, Amgen, Caelum Biosciences, Celgene, Intellia, Janssen, Prothena, Regeneron: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Voorhees:Abbvie, BMS, GSK, Janssen Biotech, Karyopharm Therapeutics, Oncopeptides, Pfizer, Sanofi: Membership on an entity's Board of Directors or advisory committees. Kaufman:AbbVie, Genentech, and Bristol Myers Squibb: Consultancy; AbbVie: Other: Member of steering committee; Incyte: Other: Member of data safety monitoring committee . Yee:Regeneron: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Oncopeptides: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy. Scott:Janssen Oncology: Current Employment; GSK: Ended employment in the past 24 months. Torka:TG Therapeutics: Consultancy; Epizyme: Consultancy; Targeted Oncology, Physician Education Review: Honoraria; Lilly USA: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy. Libby:Adaptive Biotechnologies: Consultancy. Reeves:Incyte, BMS, PharmaEssentia, CTI Biopharma: Honoraria; Hemostasis & Thrombosis Research Society Mentored Research Award sponsored by CSL Behring: Research Funding. Wang:Physicians Education Resources (PER): Honoraria; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Practice Point Communications (PPC): Honoraria; Eastern Virginia Medical School: Honoraria; OncLive: Honoraria; MJH Life Sciences: Honoraria; Meeting Minds Experts: Honoraria; Dava Oncology: Honoraria; Medscape: Honoraria; Oncternal: Consultancy, Research Funding; IDEOlogy Health: Honoraria; Loxo Oncology: Research Funding; Studio ER Congressi: Honoraria; Vinverx: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Milken Institute: Consultancy; LLC TS Oncology: Honoraria; Moffit Cancer Center: Honoraria; Oncology Specialty Group: Honoraria; Molecular Templates: Research Funding; Genentech: Consultancy, Research Funding; Genmab: Research Funding; Pepromene Bio: Consultancy; Merck: Honoraria; Lilly: Consultancy, Research Funding; Leukemia & Lymphoma Society: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; InnoCare: Consultancy, Research Funding; Deciphera: Consultancy; BeiGene: Consultancy, Honoraria, Research Funding; BioInvent: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; AbbVie: Consultancy. Anderson:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Milner:AstraZeneca: Speakers Bureau; BeiGene USA, Inc.: Speakers Bureau; Blueprint Medicines Corporation: Speakers Bureau; Bristol Myers Squibb Company: Speakers Bureau; Incyte Corporation: Speakers Bureau. Gasparetto:AbbVie: Consultancy; Celgene Corporation: Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Karyopharm Therapeutics: Consultancy, Speakers Bureau; Pfizer Inc.: Consultancy; SANOFI US SERVICES INC.: Consultancy, Speakers Bureau. Agha:GenCART Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Khan:Secura Bio: Consultancy, Research Funding; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Honoraria. Hurd:Johnson & Johnson, BMS/Celgene, Merck, Pfizer: Current equity holder in publicly-traded company. Avigan:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd.: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Legend Bio Tech: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Partners Tx: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kowa: Consultancy; Sanofi: Consultancy; Kite: Consultancy; Takeda: Consultancy; Parexel: Consultancy; Janssen: Consultancy. Costello:BMS, Takeda, Janssen, Pfizer: Honoraria, Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Celgene, Janssen, Takeda: Research Funding; Novartis, BMS, GSK, Amgen, Merck, Janssen: Honoraria; AbbVie, Bluebird, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis Pharma, and Takeda.: Consultancy. Raje:Medscape: Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Research to Practice: Honoraria; Two Seventy Bio: Research Funding; Massachusetts General Hospita: Current Employment; Celgene: Honoraria; Janssen: Consultancy, Honoraria. McCarthy:Abbvie: Consultancy, Honoraria; Axios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Magenta Therapeutics: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Fate Therapeutics: Consultancy, Honoraria; Partner Therapeutics, Inc.: Consultancy, Honoraria; Bluebird Bio: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen Global Services, LLC: Consultancy, Honoraria; Starton Therapeutics: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Karyopharm Therapeutics Inc.: Consultancy, Honoraria; Takeda Pharmaceuticals America, Inc.: Consultancy, Honoraria; Sanofi: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Orlowski:CARsgen Therapeutics, Celgene/Bristol Myers Squibb, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Asylia Therapeutics, Inc.: Current equity holder in private company; Abbvie, BioTheryX, Inc., Bristol-Myers Squibb, Janssen Biotech, Karyopharm Therapeutics, Inc., Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda Pharmaceutic: Honoraria, Membership on an entity's Board of Directors or advisory committees; Asylia Therapeutics, Inc., BioTheryX, Inc., Heidelberg Pharma, Inc.: Research Funding. Nadeem:GPCR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Laubach:Lignancies: Honoraria. Pasquini:Janssen: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Kite: Research Funding. Giralt:TAKEDA: Membership on an entity's Board of Directors or advisory committees, Research Funding; MILTENYI: Research Funding; SPECTRUM Pharma: Membership on an entity's Board of Directors or advisory committees; OMEROS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Actinuum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Perrot:Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:AbbVie, Janssen, Celgene, Amgen, and Sanofi: Honoraria. Weller:Takeda: Research Funding. Munshi:Janssen: Consultancy; Takeda Oncology: Consultancy; Amgen: Consultancy; GSK: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Legend: Consultancy. Anderson:NextRNA: Other: Scientific founder ; Dynamic Cell Therapy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees; Raqia: Other: Scientific founder ; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Membership on an entity's Board of Directors or advisory committees; Window: Membership on an entity's Board of Directors or advisory committees; Starton: Membership on an entity's Board of Directors or advisory committees; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder .
