Background: The second revision of the International Staging System (R2-ISS) is a new and simple tool to risk stratify newly diagnosed multiple myeloma (NDMM) patients. Our aim in this study was to evaluate the utility of R2-ISS in NDMM patients who received upfront autologous hematopoietic stem cell transplantation (auto-HCT).

Methods: We conducted a retrospective analysis of all NDMM patients who underwent upfront auto-HCT between 1988 and 2021 at MD Anderson Cancer Center and had available data for calculation of R2-ISS, including albumin, β-2 microglobulin, LDH, and fluorescence in-situ hybridization (FISH) analysis at diagnosis. High-risk cytogenetic abnormalities (HRCA) were t(4;14), del(17p), and 1q21 gain or amplification, as detected by FISH. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was hematological response after auto-HCT.

Results: A total of 1291 patients were included, with a median age of 62 years (range 29 - 83) and 60% were male. Four hundred-and-nineteen patients (32%) had HRCA. Most patients received either bortezomib, lenalidomide, and dexamethasone (VRD) (34%) or carfilzomib, lenalidomide, and dexamethasone (KRD) (25%) induction regimens, and most patients (95%) received melphalan based conditioning. The distribution of R2-ISS stages in our cohort was as follows: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III, and 131 (10%) stage IV. A total of 1027 (80%) patients received post auto-HCT maintenance, mostly lenalidomide with or without dexamethasone (n = 785, 61%) (Table 1).

With a median follow-up of 42.2 months (range 0.3 - 181.0) for the entire cohort, the median PFS was 73.0, 65.2, 44.0, and 24.8 months ( P < .001) and the median OS was 130.8, 128.5, 94.2, and 61.4 months ( P < .001) for patients with R2-ISS stages I, II, III, and IV, respectively (Figure 1). On multivariable analysis (MVA) for PFS, using R2-ISS stage I as the reference group, there was no significant difference for R2-ISS stage II (hazard ratio [95% CI], 1.11 [0.76-1.63]; P = .59), but there was a significant worsening in PFS for R2-ISS stage III (1.55 [1.05-2.29]; P = .028) and R2-ISS stage IV (2.04 [1.24-3.36]; P = .005). On MVA for OS, again using R2-ISS stage I as the reference group, there was no significant difference for R2-ISS stage II (1.33 [0.74-2.40]; P = .34) or R2-ISS stage III (1.75 [0.97-3.17]; P = .06), but there was a significant worsening in OS for R2-ISS stage IV (2.43 [1.18-5.01]; P = .017).

On MVA, other measures significantly associated with worsening PFS were year of auto-HCT < 2010, lambda light chain disease subtype, presence of HRCA, prior MRD/response other than negative/≥CR, and not achieving MRD negative/≥ CR post auto-HCT. For OS, other measures significantly associated with worsening survival on MVA were presence of HRCA, HCT-CI > 3, having at least one bone lesion, not achieving CR at best response, and not receiving post auto-HCT maintenance therapy.

Conclusion: Our study demonstrates that R2-ISS is a reliable prognostic tool for NDMM in a large cohort of patients who received standard anti-myeloma treatment, including modern induction regimens, upfront auto-HCT, and post-transplant maintenance.

Bashir:Stemline: Research Funding; Acrotech: Research Funding; GSK: Research Funding; Pfizer: Research Funding. Srour:Orca Bio: Research Funding. Saini:Panbela Theraputics: Research Funding; GSK: Research Funding. Lin:Takeda: Patents & Royalties, Research Funding. Nieto:Secura Bio: Research Funding; Affimed: Research Funding; Astra Zeneca: Research Funding. Lee:Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Pfizer: Consultancy; Monte Rosa Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Allogene Thereapeutics: Consultancy; Regeneron: Consultancy, Research Funding; Amgen: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Patel:AbbVie; Allogene Therapeutics, Inc.; Arcellx; Bristol Myers Squibb/Celgene Corporation; Cellectis; Janssen Pharmaceuticals, Inc.; Nektar Therapeutic; Poseida Therapeutics; Precision BioSciences, Inc.; and Takeda Pharmaceuticals U.S.A., Inc.: Research Funding; AbbVie; Arcellx, AstraZeneca; Bristol Myers Squibb/Celgene Corporation; Caribou Science; Cellectis; Curio Bioscience; Genentech; Janssen Pharmaceuticals, Inc.; Karyopharm; Legend Biotech; Merck & Co., Inc.; Oncopeptides; Pfizer; Precision BioSciences: Consultancy; Takeda: Consultancy. Manasanch:Pfizer: Honoraria; Telo Genomics: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria. Kebriaei:Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Thomas:Bristol Myers Squibb, Janssen Pharma Genentech, X4 pharma, Cellectar Biosciences, Ascentage Pharma: Research Funding; Genentech: Research Funding; Abbvie, Cellectar Biosciences: Consultancy; X4 pharma: Research Funding; Cellectar Biosciences: Consultancy; Cellectar Biosciences: Research Funding; Janssen Pharma: Research Funding; Ascentage Pharma: Research Funding. Orlowski:Asylia Therapeutics: Current equity holder in private company, Patents & Royalties; 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. Shpall:Affimed: Other: License agreement; Axio: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: License agreement; NY Blood Center: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Navan: Membership on an entity's Board of Directors or advisory committees; Fibrobiologics: Membership on an entity's Board of Directors or advisory committees; Celaid Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syena: Other: License agreement. Champlin:Johnson & Johnson/Janssen: Consultancy; Omeros: Consultancy; Actinium Pharmaceuticals: Consultancy; Kadmon: Consultancy; Arog: Consultancy; Cell Source: Research Funding; Orca Bio: Consultancy; Takeda Corporation: Patents & Royalties. Qazilbash:Amgen: Research Funding; NexImmune: Research Funding; Janssen: Research Funding; Bioline: Other: Advisory board; Angiocrine: Research Funding.

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2023
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