Background: The neutrophil-to-lymphocyte ratio (NLR) is an independent prognostic marker in solid and hematological cancers. While the derived NLR (dNLR) was shown to be non-inferior to the NLR in large cohorts of patients with different cancer types, it has not been validated as a prognostic marker for multiple myeloma (MM) to date. Methods: Between May 22, 2011 and May 29, 2014, 176 patients with MM from 38 centers who were ineligible for autologous stem cell transplantation were analyzed. The dNLR was calculated using complete blood count differential data. The optimal dNLR cut-off value according to receiver operating characteristic analysis of overall survival (OS) was 1.51. All patients were treated with melphalan and prednisone combined with bortezomib. Results: The complete response rate was lower in the high dNLR group compared to the low dNLR group (7 vs. 26.1%, respectively; p = 0.0148); the corresponding 2-year OS rates were 72.2 and 84.7%, respectively (p = 0.0354). A high dNLR was an independent poor prognostic factor for OS (hazard ratio 2.217, 95% CI 1.015–4.842; p = 0.0458). Conclusion: The dNLR is a readily available and cheaply obtained parameter in clinical studies, and shows considerable potential as a new prognostic marker for transplantation-ineligible patients with MM.

Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J: International staging system for multiple myeloma. J Clin Oncol 2005; 23: 3412–3420.
Wuilleme S, Robillard N, Lodé L, Magrangeas F, Beris H, Harousseau JL, Proffitt J, Minvielle S, Avet-Loiseau H; Intergroupe Francophone de Myélome: Ploidy, as detected by fluorescence in situ hybridization, defines different subgroups in multiple myeloma. Leukemia 2005; 19: 275–278.
Romano A, Parrinello NL, Consoli ML, Marchionni L, Forte S, Conticello C, Pompa A, Corso A, Milone G, Di Raimondo F, Borrello I: Neutrophil to lymphocyte ratio (NLR) improves the risk assessment of ISS staging in newly diagnosed MM patients treated upfront with novel agents. Ann Hematol 2015; 94: 1875–1883.
Pessoa de Magalhães RJ, Vidriales MB, Paiva B, Fernandez-Gimenez C, García-Sanz R, Mateos MV, Gutierrez NC, Lecrevisse Q, Blanco JF, Hernández J, de las Heras N, Martinez-Lopez J, Roig M, Costa ES, Ocio EM, Perez-Andres M, Maiolino A, Nucci M, De La Rubia J, Lahuerta JJ, San-Miguel JF, Orfao A; Spanish Myeloma Group (GEM); Grupo Castellano-Leones de Gammapatias Monoclonales, cooperative study groups: Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry. Haematologica 2013; 98: 79–86.
Bryant C, Suen H, Brown R, Yang S, Favaloro J, Aklilu E, Gibson J, Ho PJ, Iland H, Fromm P, Woodland N, Nassif N, Hart D, Joshua DE: Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance. Blood Cancer 2013; 3:e148.
Coussens LM, Werb Z: Inflammation and cancer. Nature 2002; 420: 860–867.
Zahorec R: Ratio of neutrophil to lymphocyte counts – rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy 2001; 102: 5–14.
Absenger G, Szkandera J, Stotz M, Postlmayr U, Pichler M, Ress AL, Schaberl-Moser R, Loibner H, Samonigg H, Gerger A: Preoperative neutrophil-to-lymphocyte ratio predicts clinical outcome in patients with stage II and III colon cancer. Anticancer Res 2013; 33: 4591–4594.
Botta C, Barbieri V, Ciliberto D, Rossi A, Rocco D, Addeo R, Staropoli N, Pastina P, Marvaso G, Martellucci I, Guglielmo A, Pirtoli L, Sperlongano P, Gridelli C, Caraglia M, Tassone P, Tagliaferri P, Correale P: Systemic inflammatory status at baseline predicts bevacizumab benefit in advanced non-small cell lung cancer patients. Cancer Biol Ther 2013; 14: 469–475.
Cho IR, Park JC, Park CH, Jo JH, Lee HJ, Kim S, Shim CN, Lee H, Shin SK, Lee SK, Lee YC: Pre-treatment neutrophil to lymphocyte ratio as a prognostic marker to predict chemotherapeutic response and survival outcomes in metastatic advanced gastric cancer. Gastric Cancer 2014; 17: 703–710.
Feng JF, Huang Y, Liu JS: Combination of neutrophil lymphocyte ratio and platelet lymphocyte ratio is a useful predictor of postoperative survival in patients with esophageal squamous cell carcinoma. Onco Targets Ther 2013; 6: 1605–1612.
Li MX, Liu XM, Zhang XF, Zhang JF, Wang WL, Zhu Y, Dong J, Cheng JW, Liu ZW, Ma L, Lv Y: Prognostic role of neutrophil-to-lymphocyte ratio in colorectal cancer: a systematic review and meta-analysis. Int J Cancer 2014; 134: 2403–2413.
Paramanathan A, Saxena A, Morris DL: A systematic review and meta-analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours. Surg Oncol 2014; 23: 31–39.
Santoni M, De Giorgi U, Iacovelli R, Conti A, Burattini L, Rossi L, Luca Burgio S, Berardi R, Muzzonigro G, Cortesi E, Amadori D, Cascinu S: Pre-treatment neutrophil-to-lymphocyte ratio may be associated with the outcome in patients treated with everolimus for metastatic renal cell carcinoma. Br J Cancer 2013; 109: 1755–1759.
Sugiura T, Uesaka K, Kanemoto H, Mizuno T, Okamura Y: Elevated preoperative neutrophil-to-lymphocyte ratio as a predictor of survival after gastroenterostomy in patients with advanced pancreatic adenocarcinoma. Ann Surg Oncol 2013; 20: 4330–4337.
Williams KA, Labidi-Galy SI, Terry KL, Vitonis AF, Welch WR, Goodman A, Cramer DW: Prognostic significance and predictors of the neutrophil-to-lymphocyte ratio in ovarian cancer. Gynecol Oncol 2014; 132: 542–550.
Porrata LF, Ristow K, Habermann T, Inwards DJ, Micallef IN, Markovic SN: Predicting survival for diffuse large B-cell lymphoma patients using baseline neutrophil/lymphocyte ratio. Am J Hematol 2010; 85: 896–899.
Kelkitli E, Atay H, Cilingir F, Güler N, Terzi Y, Ozatlı D, Turgut M: Predicting survival for multiple myeloma patients using baseline neutrophil/lymphocyte ratio. Ann Hematol 2014; 93: 841–846.
Ferrucci PF, Ascierto PA, Pigozzo J, Del Vecchio M, Maio M, Antonini Cappellini GC, Guidoboni M, Queirolo P, Savoia P, Mandalà M, Simeone E, Valpione S, Altomonte M, Spagnolo F, Cocorocchio E, Gandini S, Giannarelli D, Martinoli C: Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Ann Oncol 2016; 27: 732–738.
Proctor MJ, McMillan DC, Morrison DS, Fletcher CD, Horgan PG, Clarke SJ: A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer. Br J Cancer 2012; 107: 695–699.
Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group: International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473.
Absenger G, Szkandera J, Pichler M, Stotz M, Arminger F, Weissmueller M, Schaberl-Moser R, Samonigg H, Stojakovic T, Gerger A: A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients. Br J Cancer 2013; 109: 395–400.
Bladé J, Rosiñol L, Cibeira MT: Prognostic factors for multiple myeloma in the era of novel agents. Ann Oncol 2008; 19(suppl 7): vii117–vii120.
Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.
Diakos CI, Charles KA, McMillan DC, Clarke SJ: Cancer-related inflammation and treatment effectiveness. Lancet Oncol 2014; 15: e493–e503.
de Visser KE, Eichten A, Coussens LM: Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006; 6: 24–37.
Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL: Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 1996; 56: 4625–4629.
Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, Haudenschild C, Lane TF, Hla T: Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 2001; 276: 18563–18569.
Schoppmann SF, Birner P, Stöckl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D: Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 2002; 161: 947–956.
Dannenberg AJ, Subbaramaiah K: Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell 2003; 4: 431–436.
Ribatti D, Ennas MG, Vacca A, Ferreli F, Nico B, Orru S, Sirigu P: Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur J Clin Invest 2003; 33: 420–425.
Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K: Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 2005; 102: 18538–18543.
Horne ZD, Jack R, Gray ZT, Siegfried JM, Wilson DO, Yousem SA, Nason KS, Landreneau RJ, Luketich JD, Schuchert MJ: Increased levels of tumor-infiltrating lymphocytes are associated with improved recurrence-free survival in stage 1A non-small-cell lung cancer. J Surg Res 2011; 171: 1–5.
Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, Aridome K, Hokita S, Aikou T: Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 2000; 88: 577–583.
Zou W: Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005; 5: 263–274.
de Visser KE, Korets LV, Coussens LM: De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 2005; 7: 411–423.
Proctor MJ, Morrison DS, Talwar D, Balmer SM, O’Reilly DS, Foulis AK, Horgan PG, McMillan DC: An inflammation-based prognostic score (mGPS) predicts cancer survival independent of tumour site: a Glasgow Inflammation Outcome Study. Br J Cancer 2011; 104: 726–734.
Pichler M, Hutterer GC, Stojakovic T, Mannweiler S, Pummer K, Zigeuner R: High plasma fibrinogen level represents an independent negative prognostic factor regarding cancer-specific, metastasis-free, as well as overall survival in a European cohort of non-metastatic renal cell carcinoma patients. Br J Cancer 2013; 109: 1123–1129.
Mohri Y, Tanaka K, Ohi M, Yokoe T, Miki C, Kusunoki M: Prognostic significance of host- and tumor-related factors in patients with gastric cancer. World J Surg 2010; 34: 285–290.
Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ: Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005; 91: 181–184.
Halazun KJ, Hardy MA, Rana AA, Woodland DC 4th, Luyten EJ, Mahadev S, Witkowski P, Siegel AB, Brown RS Jr, Emond JC: Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma. Ann Surg 2009; 250: 141–151.
Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim E: Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg 2009; 137: 425–428.
Schmidt H, Suciu S, Punt CJ, Gore M, Kruit W, Patel P, Lienard D, von der Maase H, Eggermont AM, Keilholz U; American Joint Committee on Cancer Stage IV Melanoma; EORTC 18951: Pretreatment levels of peripheral neutrophils and leukocytes as independent predictors of overall survival in patients with American Joint Committee on Cancer Stage IV Melanoma: results of the EORTC 18951 Biochemotherapy Trial. J Clin Oncol 2007; 25: 1562–1569.
Templeton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Ocaña A, Leibowitz-Amit R, Sonpavde G, Knox JJ, Tran B, Tannock IF, Amir E: Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst 2014; 106:dju124.
Romano A, Conticello C, Cavalli M, Vetro C, La Fauci A, Parrinello NL, Di Raimondo F: Immunological dysregulation in multiple myeloma microenvironment. BioMed Res Int 2014; 2014: 198539.
Ramachandran IR, Martner A, Pisklakova A, Condamine T, Chase T, Vogl T, Roth J, Gabrilovich D, Nefedova Y: Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol 2013; 190: 3815–3823.
Görgun GT, Whitehill G, Anderson JL, Hideshima T, Maguire C, Laubach J, Raje N, Munshi NC, Richardson PG, Anderson KC: Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood 2013; 121: 2975–2987.
Giallongo C, Parrinello N, Tibullo D, La Cava P, Romano A, Chiarenza A, Barbagallo I, Palumbo GA, Stagno F, Vigneri P, Di Raimondo F: Myeloid derived suppressor cells (MDSCs) are increased and exert immunosuppressive activity together with polymorphonuclear leukocytes (PMNs) in chronic myeloid leukemia patients. PLoS One 2014; 9:e101848.
Szkandera J, Pichler M, Gerger A, Leithner A: Reply: comment on ‘Elevated preoperative neutrophil/lymphocyte ratio is associated with poor prognosis in soft-tissue sarcoma patients’. Br J Cancer 2013; 108: 2627.
Troppan K, Deutsch A, Gerger A, Stojakovic T, Beham-Schmid C, Wenzl K, Neumeister P, Pichler M: The derived neutrophil to lymphocyte ratio is an independent prognostic factor in patients with diffuse large B-cell lymphoma. Br J Cancer 2014; 110: 369–374.
Zhou X, Wang J, Xia J, Cheng F, Mao J, Zhu J, Guo H: Evaluation of neutrophil-to-lymphocyte ratio in newly diagnosed patients receiving borte- zomib-based therapy for multiple myeloma. Cancer Biomark 2018; 22: 43–48.
Lopez-Millan B, Diaz de la Guardia R, Roca-Ho H, Garcia-Herrero CM, Lavoie JR, Rosu-Myles M, Gonazlez-Rey E, O’Valle F, Criado G, Delgado M, Menendez P: Therapeutic effect of the immunomodulatory drug lenalidomide, but not pomalidomide, in experimental models of rheumatoid arthritis and inflammatory bowel disease. Exp Mol Medicine 2017; 49:e290.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.