Early Relapse in Patients with Newly-Diagnosed Multiple Myeloma: A European Myeloma Network/Harmony Alliance Analysis Including 10843 Patients

EKM, AM and MD contributed equally to this work.

BACKGROUND. Despite major advances in the treatment of multiple myeloma (MM) in the past two decades, outcomes remain heterogenous, with some patients being primary refractory and others being long-term non-progressors. There is still an unmet need to identify patients at risk for early relapse/progression (ER) upfront to tailor new treatment strategies and improve outcomes in this population.

METHODS. This analysis included data from 10843 patients with newly diagnosed (ND)MM treated in 16 international, multicenter clinical trials from 2005 to 2016. Data were collected by the European Myeloma Network (EMN) within the HARMONY Platform (www.harmony-alliance.eu) supported by the European Hematology Association (EHA).

The primary endpoint was a landmark analysis of overall survival (OS) starting from 18 months after randomization in patients with and without ER within 18 months from MM diagnosis (ER<18). ER<18 as an independent factor and baseline factors associated with ER<18 were analyzed in multivariable models. An additive scoring system to predict ER<18 was developed based on a clinical and statistical selection of MM disease parameters. High-risk cytogenetic abnormalities (HRCA) were defined as either del(17p), t(4;14), t(14;16) or +1q21. Patients who were censored (n=442) or died without progressive disease within the first 18 months (n=661) were excluded from the analyses.

RESULTS. A total of 9740 patients were available for the landmark analyses at 18 months from MM diagnosis (median follow-up: 72 months, IQR 58-87), 1970 of whom had an ER<18 (1254 deaths), 7051 had no ER<18 (2392 deaths) and 719 had died with progressive disease within the first 18 months. OS at 18 months from MM diagnosis was significantly shorter in patients with ER<18 vs those without ER<18 (median OS: 48 [95% CI 46-51] vs 115 months [95% CI 109-122], HR 3.32, 95% CI 3.10-3.56, p<0.0001). In a multivariable model including 2768 complete patient cases, ER<18 was an independent prognostic factor (HR 2.79, 95% CI 2.60-3.00, p<0.0001), along with established prognostic factors such as International Staging System (ISS) stage III (vs I: HR 1.83, 95% CI 1.65-2.02, p<0.0001), HRCA (vs standard risk: HR 1.77, 95% CI 1.58-1.99, p<0.0001) and elevated lactate dehydrogenase (LDH; yes vs no: HR 1.31, 95% CI 1.20-1.43, p<0.0001).

ER<18 was significantly associated with single-hit HRCA (OR 1.53, 95% CI 1.27-1.83, p<0.0001) and double-hit HRCA (OR 2.87, 95% CI 2.24-3.68, p<0.0001). Other factors associated with ER<18 were ISS stages II and III (II: OR 1.52, 95% CI 1.35-1.72, p<0.0001; III: OR 2.06, 95% CI 1.79-2.37, p<0.0001) and elevated LDH (OR 1.37, 95% CI 1.21-1.56, p<0.0001). Treatment with a proteasome inhibitor plus an immunomodulatory agent vs only one of the two drug classes significantly reduced the risk of ER<18 (OR 0.48, 95% CI 0.42-0.53, p<0.0001). The dissection of HRCA in a similar multivariable model revealed that double-hit HRCA involving del(17p) had the overall strongest association with ER<18 (OR 3.32, 95% CI 2.29-4.81, p<0.0001), followed by single-hit del(17p) (OR 2.25, 95% CI 1.59-3.17, p<0.0001).

An additive scoring system for ER<18 identified single-hit HRCA (1 point), double-hit HRCA (2), ISS II (1), ISS III (2) and elevated LDH (1) as significant MM disease-specific parameters. Patients with low (0-1 points, 47% of patients), intermediate (2-3, 44%) and high (4-5, 9%) counts had gradually increasing and statistically significant different risks for ER<18 of respectively 18% (reference), 33% (OR 2.31, 95% CI 1.92-2.78, p<0.0001) and 49% (OR 4.51, 95% CI 3.37-6.04, p<0.0001). Among patients with ER<18, the three risk categories retained their prognostic impact, with a median OS at 18 months from MM diagnosis of 68 (95% CI 56-89), 41 (95% CI 37-46) and 29 months (95% CI 25-34) in the low-, intermediate- and high-risk groups, suggesting OS heterogeneity even among functional high-risk MM patients.

CONCLUSIONS. Our unique, large dataset of NDMM patients confirmed the unmet need for patients with ER<18 and brought to light the adverse prognostic impact of del(17p) as single- or double-hit HRCA. Although it did not account for all patients with ER<18, the accumulation of established MM-specific risk factors was associated with an increasing risk for ER<18, and MM-specific risk factors retained their prognostic significance among functional high-risk patients.

Mai:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding; Stemline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding; GlaxoSmithKline (GSK): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. D'Agostino:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: 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. Wester:Janssen: Honoraria; Sanofi: Honoraria. Zamagni:Bristol Myers Squibb: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini Stemline: 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. Mateos:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Pfizer: 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; Celgene - Bristol Myers Squibb: Honoraria; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Salamanca University: Current Employment. van de Donk:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Novartis: 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; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jackson:Bristol Myers Squibb: Other: Honoraria for advisory boards/speaking, Research Funding; Onyx: Research Funding; Sanofi: Other: Honoraria for advisory boards/speaking; Amgen: Other: Honoraria for advisory boards/speaking; Johnson & Johnson: Other: Honoraria for advisory boards/speaking; Pfizer: Other: Honoraria for advisory boards/speaking; Menarini: Other: Honoraria for advisory boards/speaking; Takeda: Other: Honoraria for advisory boards/speaking, Research Funding. Rocchi:Pfizer: Other: Speaker honoraria; GlaxoSmithKline: Other: Speaker honoraria; Sanofi: Other: Speaker honoraria; Bristol Myers Squibb: Other: Speaker honoraria; Amgen: Other: Speaker honoraria. Salwender:GlaxoSmithKline: Honoraria; Bristol Myers Squibb/Celgene: Honoraria, Other: Travel grant; Janssen: Honoraria, Other: Travel grant; Oncopeptides: Honoraria; Pfizer: Honoraria; Stemline: Honoraria; Sanofi: Honoraria, Other: Travel grant; Amgen: Honoraria, Other: Travel grant; AbbVie: Honoraria; Roche: Honoraria; Takeda: Honoraria; Chugai: Honoraria; Sebia: Honoraria. Bladé:Celgene/Bristol Myers Squibb: Other: Honoraria for lectures; Sanofi: Other: Honoraria for lectures; Janssen: Other: Honoraria for lectures; Amgen: Other: Honoraria for lectures. van der Holt:Intergroupe Francophone du Myelome (IFM): Other: Honoraria for data safety monitoring board membership. Weisel:GlaxoSmithKline: Consultancy, Honoraria, Other: Research grant to institution; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Other: Research grant to institution; Amgen: Consultancy, Honoraria, Other: Research grant to institution; Janssen: Consultancy, Honoraria, Other: Research grant to institution; Sanofi: Consultancy, Honoraria, Other: Research grant to institution; Adaptive Biotechnologies: Consultancy, Honoraria; AstraZeneca: Honoraria; BeiGene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Novartis: Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche Pharma: Consultancy, Honoraria; Stemline: Honoraria; Takeda: Consultancy, Honoraria; Regeneron: Consultancy; AbbVie: Other: Research grant to institution. Gay:GlaxoSmithKline: 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; Bristol Myers Squibb/Celgene: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Zweegman:Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Hernandez Rivas:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cook:Celgene: Research Funding; Janssen-Cilag: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Research Funding. Kaiser:GSK: Consultancy; Poolbeg: Consultancy, Honoraria; Roche: Consultancy; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy; J&J/Janssen: Consultancy, Honoraria, Research Funding; Regeneron: Consultancy; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding. Goldschmidt:Incyte Corporation: Research Funding; Karyopharm: Research Funding; Merck Sharp and Dohme (MSD): Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Molecular Partners: Research Funding; Novartis: Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Pfizer: Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Hoffmann-La Roche: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product; support for attending meetings and/or travel, Research Funding; GlycoMimetics Inc.: Research Funding; Heidelberg Pharma: Research Funding; GlaxoSmithKline (GSK): Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product; support for attending meetings and/or travel, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product; Takeda: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; grants and/or provision of Investigational Medicinal Product, Research Funding; MorphoSys AG: Research Funding; Array Biopharma/Pfizer: Other: Grants and/or provision of Investigational Medicinal Product; Bristol Myers Squibb/Celgene: Other: Grants and/or provision of Investigational Medicinal Product; Dietmar Hopp Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Mundipharma GmbH: Other: Grants and/or provision of Investigational Medicinal Product. Boccadoro:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding. San-Miguel:Regeneron: Other: Advisory board; Sanofi: Other: Advisory board; Roche: Other: Advisory board; Takeda: Other: Advisory board; Abbvie: Consultancy, Other: Advisory Board; MSD: Other: Advisory board; Amgen: Consultancy, Other: Advisory Board ; Karyopharm: Other: Advisory board; Novartis: Other; Janssen-Cilag: Other: Advisory board; Haemalogix: Other: Advisory board; GlaxoSmithKline: Other: Advisory board; Celgene: Other: Advisory board; Bristol Myers Squibb: Other: Advisory board; SecuraBio: Other: Advisory board. Sonneveld:Oncopeptides: Patents & Royalties; European Myeloma Network: Other: President; Pfizer: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: 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.