A simple score to predict early severe infections in patients with newly diagnosed multiple myeloma

Cristina Encinas, José-Ángel Hernandez-Rivas, Albert Oriol, Laura Rosiñol, María-Jesús Blanchard, José-María Bellón, Ramón García-Sanz, Javier de la Rubia, Ana López de la Guía, Ana Jímenez-Ubieto, Isidro Jarque, Belén Iñigo, Victoria Dourdil, Felipe de Arriba, Clara Cuéllar Pérez-Ávila, Yolanda Gonzalez, Miguel-Teodoro Hernández, Joan Bargay, Miguel Granell, Paula Rodríguez-Otero, Maialen Silvent, Carmen Cabrera, Rafael Rios, Adrián Alegre, Mercedes Gironella, Marta-Sonia Gonzalez, Anna Sureda, Antonia Sampol, Enrique M Ocio, Isabel Krsnik, Antonio García, Aránzazu García-Mateo, Joan-Alfons Soler, Jesús Martín, José-María Arguiñano, María-Victoria Mateos, Joan Bladé, Jesús F San-Miguel, Juan-José Lahuerta, Joaquín Martínez-López, GEM/PETHEMA (Grupo Español de Mieloma/Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group, Cristina Encinas, José-Ángel Hernandez-Rivas, Albert Oriol, Laura Rosiñol, María-Jesús Blanchard, José-María Bellón, Ramón García-Sanz, Javier de la Rubia, Ana López de la Guía, Ana Jímenez-Ubieto, Isidro Jarque, Belén Iñigo, Victoria Dourdil, Felipe de Arriba, Clara Cuéllar Pérez-Ávila, Yolanda Gonzalez, Miguel-Teodoro Hernández, Joan Bargay, Miguel Granell, Paula Rodríguez-Otero, Maialen Silvent, Carmen Cabrera, Rafael Rios, Adrián Alegre, Mercedes Gironella, Marta-Sonia Gonzalez, Anna Sureda, Antonia Sampol, Enrique M Ocio, Isabel Krsnik, Antonio García, Aránzazu García-Mateo, Joan-Alfons Soler, Jesús Martín, José-María Arguiñano, María-Victoria Mateos, Joan Bladé, Jesús F San-Miguel, Juan-José Lahuerta, Joaquín Martínez-López, GEM/PETHEMA (Grupo Español de Mieloma/Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group

Abstract

Infections remain a common complication in patients with multiple myeloma (MM) and are associated with morbidity and mortality. A risk score to predict the probability of early severe infection could help to identify the patients that would benefit from preventive measures. We undertook a post hoc analysis of infections in four clinical trials from the Spanish Myeloma Group, involving a total of 1347 patients (847 transplant candidates). Regarding the GEM2010 > 65 trial, antibiotic prophylaxis was mandatory, so we excluded it from the final analysis. The incidence of severe infection episodes within the first 6 months was 13.8%, and majority of the patients experiencing the first episode before 4 months (11.1%). 1.2% of patients died because of infections within the first 6 months (1% before 4 months). Variables associated with increased risk of severe infection in the first 4 months included serum albumin ≤30 g/L, ECOG > 1, male sex, and non-IgA type MM. A simple risk score with these variables facilitated the identification of three risk groups with different probabilities of severe infection within the first 4 months: low-risk (score 0-2) 8.2%; intermediate-risk (score 3) 19.2%; and high-risk (score 4) 28.3%. Patients with intermediate/high risk could be candidates for prophylactic antibiotic therapies.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Distribution of the number of infectious events per month from treatment.
Fig. 2
Fig. 2
Cumulative incidence of severe infections comparing non-candidate transplant patients.
Fig. 3. Cumulative incidence.
Fig. 3. Cumulative incidence.
A Cumulative incidence of severe infection and B mortality by infection.
Fig. 4. Impact on overall survival of…
Fig. 4. Impact on overall survival of infection.
A Impact on overall survival of any-grade infection and B severe infection.
Fig. 5. Cumulative incidence of early severe…
Fig. 5. Cumulative incidence of early severe infection according to risk group by Score GEM.
A Three risk groups with different probabilities of early severe infection. B Two risk group when intermediate and high risk were grouped. sHR sub-Hazard ratio, CI 95% confidence interval.

References

    1. Pratt G, Goodyear O, Moss P. Immunodeficiency and immunotherapy in multiple myeloma. Br J Haematol. 2007;138:563–79. doi: 10.1111/j.1365-2141.2007.06705.x.
    1. Blimark C, Holmberg E, Mellqvist U-H, Landgren O, Björkholm M, Hultcrantz M, et al. Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients. Haematologica. 2015;100:107–13. doi: 10.3324/haematol.2014.107714.
    1. Kristinsson SY, Tang M, Pfeiffer RM, Björkholm M, Goldin LR, Blimark C, et al. Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study. Haematologica. 2012;97:854–8. doi: 10.3324/haematol.2011.054015.
    1. Augustson BM, Begum G, Dunn JA, Barth NJ, Davies F, Morgan G, et al. Early mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United Kingdom Medical Research Council trials between 1980 and 2002-Medical Research Council Adult Leukemia Working Party. J Clin Oncol. 2005;23:9219–26. doi: 10.1200/JCO.2005.03.2086.
    1. Huang CT, Liu CJ, Ko PS, Liu HT, Yu YB, Hsiao LT, et al. Risk factors and characteristics of blood stream infections in patients with newly diagnosed multiple myeloma. BMC Infect Dis. 2017;17:33. doi: 10.1186/s12879-016-2155-1.
    1. Bladé J, Rosiñol L. Renal, hematologic and infectious complications in multiple myeloma. Best Pr Res Clin Haematol. 2005;18:635–52. doi: 10.1016/j.beha.2005.01.013.
    1. Rodríguez-Otero P, Mateos MV, Martínez-López J, Martín-Calvo N, Hernández MT, Ocio EM, et al. Early myeloma-related death in elderly patients: development of a clinical prognostic score and evaluation of response sustainability role. Leukemia. 2018;32:2427–34. doi: 10.1038/s41375-018-0072-6.
    1. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122–8. doi: 10.1038/leu.2013.313.
    1. Kristinsson SY, Anderson WF, Landgren O. Improved long-term survival in multiple myeloma up to the age of 80 years. Leukemia. 2014;28:1346–8. doi: 10.1038/leu.2014.23.
    1. Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Björkholm M. Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003. J Clin Oncol. 2007;25:1993–9. doi: 10.1200/JCO.2006.09.0100.
    1. de la Rubia J, Cejalvo MJ, Ribas P. Infectious complications in patients with newly diagnosed multiple myeloma: a complication from the past? Leuk Lymphoma. 2016;57:258–68.. doi: 10.3109/10428194.2015.1088647.
    1. Nucci M, Anaissie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis. 2009;49:1211–25.. doi: 10.1086/605664.
    1. Teh BW, Harrison SJ, Slavin MA, Worth LJ. Epidemiology of bloodstream infections in patients with myeloma receiving current era therapy. Eur J Haematol. 2017;98:149–53.. doi: 10.1111/ejh.12813.
    1. Teh BW, Harrison SJ, Worth LJ, Thursky KA, Slavin MA. Infection risk with immunomodulatory and proteasome inhibitor-based therapies across treatment phases for multiple myeloma: A systematic review and meta-analysis. Eur J Cancer. 2016;67:21–37. doi: 10.1016/j.ejca.2016.07.025.
    1. Teh BW, Worth LJ, Harrison SJ, Thursky KA, Slavin MA. Risks and burden of viral respiratory tract infections in patients with multiple myeloma in the era of immunomodulatory drugs and bortezomib: experience at an Australian Cancer Hospital. Support Care Cancer. 2015;23:1901–6. doi: 10.1007/s00520-014-2550-3.
    1. Basler M, Lauer C, Beck U, Groettrup M. The proteasome inhibitor bortezomib enhances the susceptibility to viral infection. J Immunol. 2009;183:6145–50. doi: 10.4049/jimmunol.0901596.
    1. Wongsaengsak S, Kopel J, Behera TR, Chakraborty R, Ball S. Infection risk with carfilzomib in multiple myeloma: a systematic review and meta-analysis of randomised controlled trials. Br J Haematol. 2020;190:e95–e97. doi: 10.1111/bjh.16735.
    1. Offidani M, Corvatta L, Polloni C, Gentili S, Brioni A, Visani G, et al. Infectious complications in patients with multiple myeloma treated with new drug combinations containing thalidomide. Leuk Lymphoma. 2011;52:776–85. doi: 10.3109/10428194.2011.555027.
    1. Ying L, YinHui T, Yunliang Z, Sun H. Lenalidomide and the risk of serious infection in patients with multiple myeloma: a systematic review and meta-analysis. Oncotarget. 2017;8:46593–600.. doi: 10.18632/oncotarget.16235.
    1. Teh BW, Harrison SJ, Worth LJ, Spelman T, Thursky KA, Slavin MA. Risks, severity and timing of infections in patients with multiple myeloma: a longitudinal cohort study in the era of immunomodulatory drug therapy. Br J Haematol. 2015;171:100–8. doi: 10.1111/bjh.13532.
    1. Chen M, Zhao Y, Xu C, Wang X, Zhang X, Mao B. Immunomodulatory drugs and the risk of serious infection in multiple myeloma: systematic review and meta-analysis of randomized and observational studies. Ann Hematol. 2018;97:925–44.. doi: 10.1007/s00277-018-3284-y.
    1. Mateos M-V, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N. Engl J Med. 2018;378:518–28. doi: 10.1056/NEJMoa1714678.
    1. Drgona L, Gudiol C, Lanini S, Salzberger B, Ippolito G, Mikulska M. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7, and CCR4) Clin Microbiol Infect. 2018;24:S83–94. doi: 10.1016/j.cmi.2018.03.022.
    1. Dumontet C, Hulin C, Dimopoulos MA, Belch A, Dispenzieri A, Ludwig H, et al. A predictive model for risk of early grade ≥ 3 infection in patients with multiple myeloma not eligible for transplant: analysis of the FIRST trial. Leukemia. 2018;32:1404–13.. doi: 10.1038/s41375-018-0133-x.
    1. Robertson JD, Nagesh K, Jowitt SN, Dougal M, Anderson H, Mutton K, et al. Immunogenicity of vaccination against influenza, Streptococcus pneumoniae and Haemophilus influenzae type B in patients with multiple myeloma. Br J Cancer. 2000;82:1261–5. doi: 10.1054/bjoc.1999.1088.
    1. Oken MM, Pomeroy C, Weisdorf D, Bennett JM. Prophylactic antibiotics for the prevention of early infection in multiple myeloma. Am J Med. 1996;100:624–8. doi: 10.1016/S0002-9343(95)00043-7.
    1. Vesole DH, Oken MM, Heckler C, Greipp PR, Katz MS, Jacobus S, et al. Oral antibiotic prophylaxis of early infection in multiple myeloma: a URCC/ECOG randomized phase III study. Leukemia. 2012;26:2517–20. doi: 10.1038/leu.2012.124.
    1. Jung S-H, Kang S-J, Jang H-C, Ahn J-S, Yang D-H, Lee S-S, et al. Effect of levofloxacin prophylaxis for prevention of severe infections in multiple myeloma patients receiving bortezomib-containing regimens. Int J Hematol. 2014;100:473–7. doi: 10.1007/s12185-014-1672-1.
    1. Drayson MT, Bowcock S, Planche T, Iqbal G, Pratt G, Yong K, et al. Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial. Lancet Oncol. 2019;20:1760–72.. doi: 10.1016/S1470-2045(19)30506-6.
    1. Ramasamy K. Reducing infection-related morbidity and mortality in patients with myeloma. Lancet Oncol. 2019;20:1633–5. doi: 10.1016/S1470-2045(19)30649-7.
    1. Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, et al. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018;131:301–10. doi: 10.1182/blood-2017-07-795047.
    1. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55. doi: 10.1097/00000421-198212000-00014.
    1. Mateos M-V, Oriol A, Martínez-López J, Gutiérrez N, Teruel A-I, Paz Rde, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11:934–41. doi: 10.1016/S1470-2045(10)70187-X.
    1. Mateos M-V, Martínez-López J, Hernández M-T, Ocio E-M, Rosiñol L, Martínez R, et al. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016;127:420–5. doi: 10.1182/blood-2015-08-666537.
    1. Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012;120:1589–96. doi: 10.1182/blood-2012-02-408922.
    1. Rosiñol L, Oriol A, Rios R, Sureda A, Blanchard MJ, Hernández MT, et al. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma. Blood. 2019;134:1337–45.. doi: 10.1182/blood.2019000241.
    1. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos M-V, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48. doi: 10.1016/S1470-2045(14)70442-5.
    1. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36:842–54. doi: 10.1002/1097-0142(197509)36:3<842::AID-CNCR2820360303>;2-U.
    1. Greipp PR, San Miguel J, Durie BGM, Crowley JJ, Barlogie B, Bladé J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412–20. doi: 10.1200/JCO.2005.04.242.
    1. Hari PN, Zhang M-J, Roy V, Pérez WS, Bashey A, To LB, et al. Is the International Staging System superior to the Durie–Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant. Leukemia. 2009;23:1528–34. doi: 10.1038/leu.2009.61.
    1. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95:548–67. doi: 10.1002/ajh.25791.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42:377–81. doi: 10.1016/j.jbi.2008.08.010.
    1. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. REDCap consortium. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. doi: 10.1016/j.jbi.2019.103208.
    1. Voorhees PM, Kaufman JL, Laubach J, Sborov DW, Reeves B, Rodriguez C, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136:936–45. doi: 10.1182/blood.2020005288.
    1. Van de Donk NWCJ, Zweegman S, San-Miguel JF, Dimopoulos MA, Cavo M, Suzuki K, et al. Predictive markers of high-grade or serious treatment-emergent infections with Daratumumab-based regimens in Newly Diagnosed Multiple Myeloma (NDMM) Blood. 2020;136:10–11.

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