Causes of early death in multiple myeloma patients treated with high‐dose therapy followed by autologous stem cell transplantation: A study based on the nationwide Danish Multiple Myeloma Registry
2017; Wiley; Volume: 92; Issue: 10 Linguagem: Inglês
10.1002/ajh.24857
ISSN1096-8652
AutoresKristian Andersen, Tobias Wirenfeldt Klausen, Niels Abildgaard, Mette Klarskov Andersen, Niels Frost Andersen, Ulf Christian Frølund, Carsten Helleberg, Eigil Kjeldsen, Per Trøllund Pedersen, Sissel Helm‐Petersen, Asta Svirskaite, Birgitte Preiss, Peter Gimsing, Annette Juul Vangsted,
Tópico(s)Chronic Myeloid Leukemia Treatments
ResumoAmerican Journal of HematologyVolume 92, Issue 10 p. E611-E614 E-ONLY ARTICLESFree Access Causes of early death in multiple myeloma patients treated with high-dose therapy followed by autologous stem cell transplantation: A study based on the nationwide Danish Multiple Myeloma Registry Kristian Thidemann Andersen, Corresponding Author Kristian Thidemann Andersen Kristian.Thidemann.Andersen@rsyd.dk orcid.org/0000-0002-8077-7113 Department of Hematology, Lillebælt Hospital Vejle, Kabbeltoft 25, Vejle, 7100 DenmarkCorrespondence Kristian Thidemann Andersen, MD, Department of Hematology, Lillebælt Hospital Vejle, Kabbeltoft 25, 7100 Vejle, Denmark. Email: Kristian.Thidemann.Andersen@rsyd.dkSearch for more papers by this authorTobias Klausen, Tobias Klausen Department of Hematology, Herlev Hospital, Herlev Ringvej 75, Herlev, 2730 DenmarkSearch for more papers by this authorNiels Abildgaard, Niels Abildgaard Department of Hematology, Odense University Hospital, Søndre Boulevard 29, Odense, 5000 DenmarkSearch for more papers by this authorMette Klarskov Andersen, Mette Klarskov Andersen Department of Clinical Genetics, Rigshospitalet, Blegdamsvej 9, København Ø, 2100 DenmarkSearch for more papers by this authorNiels Frost Andersen, Niels Frost Andersen Department of Hematology, Aarhus University Hospital, Tage-Hansens Gade 2, Århus C, 8000 DenmarkSearch for more papers by this authorUlf Christian Frølund, Ulf Christian Frølund Department of Hematology, Roskilde Hospital, Køgevej 7-13, Roskilde, 4000 DenmarkSearch for more papers by this authorCarsten Helleberg, Carsten Helleberg Department of Hematology, Herlev Hospital, Herlev Ringvej 75, Herlev, 2730 DenmarkSearch for more papers by this authorEigil Kjeldsen, Eigil Kjeldsen HemoDiagnostic Laboratory, Aarhus University Hospital, Tage-Hansens Gade 2, Århus C, 8000 DenmarkSearch for more papers by this authorPer Pedersen, Per Pedersen Department of Hematology, Sydvestjysk Sygehus Esbjerg, Finsensgade 35, Esbjerg, 6700 DenmarkSearch for more papers by this authorSissel Helm-Petersen, Sissel Helm-Petersen Department of Hematology, Rigshospitalet, Blegdamsvej 9, København Ø, 2100 DenmarkSearch for more papers by this authorAsta Svirskaite, Asta Svirskaite Department of Hematology, Aalborg University Hospital, Hobrovej 18, Aalborg, 9000 DenmarkSearch for more papers by this authorBirgitte Preiss, Birgitte Preiss Department of Clinical Pathology, Odense University Hospital, J. B. Winsløws Vej 15, Odense, 5000 DenmarkSearch for more papers by this authorPeter Gimsing, Peter Gimsing orcid.org/0000-0002-9403-3860 Department of Hematology, Rigshospitalet, Blegdamsvej 9, København Ø, 2100 DenmarkSearch for more papers by this authorAnnette Juul Vangsted, Annette Juul Vangsted Department of Hematology, Rigshospitalet, Blegdamsvej 9, København Ø, 2100 DenmarkSearch for more papers by this author Kristian Thidemann Andersen, Corresponding Author Kristian Thidemann Andersen Kristian.Thidemann.Andersen@rsyd.dk orcid.org/0000-0002-8077-7113 Department of Hematology, Lillebælt Hospital Vejle, Kabbeltoft 25, Vejle, 7100 DenmarkCorrespondence Kristian Thidemann Andersen, MD, Department of Hematology, Lillebælt Hospital Vejle, Kabbeltoft 25, 7100 Vejle, Denmark. Email: Kristian.Thidemann.Andersen@rsyd.dkSearch for more papers by this authorTobias Klausen, Tobias Klausen Department of Hematology, Herlev Hospital, Herlev Ringvej 75, Herlev, 2730 DenmarkSearch for more papers by this authorNiels Abildgaard, Niels Abildgaard Department of Hematology, Odense University Hospital, Søndre Boulevard 29, Odense, 5000 DenmarkSearch for more papers by this authorMette Klarskov Andersen, Mette Klarskov Andersen Department of Clinical Genetics, Rigshospitalet, Blegdamsvej 9, København Ø, 2100 DenmarkSearch for more papers by this authorNiels Frost Andersen, Niels Frost Andersen Department of Hematology, Aarhus University Hospital, Tage-Hansens Gade 2, Århus C, 8000 DenmarkSearch for more papers by this authorUlf Christian Frølund, Ulf Christian Frølund Department of Hematology, Roskilde Hospital, Køgevej 7-13, Roskilde, 4000 DenmarkSearch for more papers by this authorCarsten Helleberg, Carsten Helleberg Department of Hematology, Herlev Hospital, Herlev Ringvej 75, Herlev, 2730 DenmarkSearch for more papers by this authorEigil Kjeldsen, Eigil Kjeldsen HemoDiagnostic Laboratory, Aarhus University Hospital, Tage-Hansens Gade 2, Århus C, 8000 DenmarkSearch for more papers by this authorPer Pedersen, Per Pedersen Department of Hematology, Sydvestjysk Sygehus Esbjerg, Finsensgade 35, Esbjerg, 6700 DenmarkSearch for more papers by this authorSissel Helm-Petersen, Sissel Helm-Petersen Department of Hematology, Rigshospitalet, Blegdamsvej 9, København Ø, 2100 DenmarkSearch for more papers by this authorAsta Svirskaite, Asta Svirskaite Department of Hematology, Aalborg University Hospital, Hobrovej 18, Aalborg, 9000 DenmarkSearch for more papers by this authorBirgitte Preiss, Birgitte Preiss Department of Clinical Pathology, Odense University Hospital, J. B. Winsløws Vej 15, Odense, 5000 DenmarkSearch for more papers by this authorPeter Gimsing, Peter Gimsing orcid.org/0000-0002-9403-3860 Department of Hematology, Rigshospitalet, Blegdamsvej 9, København Ø, 2100 DenmarkSearch for more papers by this authorAnnette Juul Vangsted, Annette Juul Vangsted Department of Hematology, Rigshospitalet, Blegdamsvej 9, København Ø, 2100 DenmarkSearch for more papers by this author First published: 13 July 2017 https://doi.org/10.1002/ajh.24857Citations: 10 Early death among Danish MM patients treated with HDT-ASCT from 2005 to 2013 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat To the Editor: We have previously shown that infections were the main cause of early death in transplant-ineligible multiple myeloma (MM) patients.1 Recent publications have reported the incidences and causes of early death among MM patients of all ages and they confirm that infections are the leading cause of death ranging from 38% to 68% depending on the definition of early mortality.2, 3 However, these results are from single-center registries and include patients of all ages irrespectively of treatment. To investigate the causes of early death among MM patients treated with high-dose melphalan followed by autologous stem cell transplantation (HDT-ASCT), we conducted a search in the population-based Danish Multiple Myeloma Registry (DMMR), which is a nationwide registry containing information on all newly diagnosed plasma cell disorders in Denmark since January 1, 2005. The database contains baseline information on clinical and laboratory data, pathology, cytogenetics and imaging findings along with given anti-myeloma treatment.4 We defined early death as death within 2 years from the diagnosis of MM. All patients had their medical records reviewed by local hematologists to determine the cause of death as described by Holmström et al. and listed in Supporting Information Table S1.1 High risk cytogenetic aberrations with a cut-off of 10% by fluorescent in situ hybridization (FISH) were defined as t(4;14), t(14;16), and/or del17p. STATA statistical software version 14.0 was used for all calculations (StataCorp, College Station, Texas, USA). All tests were two-sided and P values < .05 were regarded as statistically significant. Fisher's exact test was used to compare categorical variables. Continuous variables were analyzed using independent samples t-test or Wilcoxon Mann-Whitney U test, when appropriate. Right skewed variables were log-transformed. Between January 1, 2005 and December 31, 2013 a total of 3186 patients with plasma cell disorders were registered in the database. We identified 613 MM patients treated with HDT-ASCT as their first-line treatment. None of the patients were lost to follow-up. Thirteen patients (2.1%) died within 100 days post HDT-ASCT defined as treatment-related-mortality and 59 patients (9.6%) died within 2 years from diagnosis. Patient characteristics are shown in Table 1. In the univariate analysis elevated baseline CRP and IgA isotype were significant risk factors of early death 100 days post ASCT, however, in a multivariate analysis these two parameters did not show significance towards early death. The induction regimens in patients with early death within 2 years consisted of Cyclophosphamide + Dexamethasone (59.3%), Cyclophosphamide + Bortezomib + Dexamethasone (25.4%), Bortezomib + Dexamethasone (6.8%), Cyclophosphamide + Thalidomide + Dexamethasone (5.1%), and other regimens (3.4%). The median time from diagnosis to HDT-ASCT was 4.1 months [range 2.3–8.0]. Table 1. Baseline characteristics and selected data in patients, who died within 2 years from diagnosis Baseline characteristics Deaths 0–100 days from ASCT n = 13 Deaths from day 100 post ASCT until 2 years from diagnosis n = 46 All deaths within 2 years from diagnosis n = 59 Univariate analysis between death within 100 days from ASCT vs. death 100 days post ASCT until 2 years from diagnosis P values Multivariate analysis of selected baseline characteristics P values Median age (years)* 59 years [37–69] 56 years [38–67] 57 years [37–69] 0.80 0.86 Sex, male 9 (69.2%) 21 (45.7%) 30 (50.8%) 0.21 ISS stage IIIa 6 (46.2%) 22/42 (52.4%) 28/55 (50.9%) 0.76 0.15 Hb. mmol/L* 5.9 [4.3–8.5] 6.5 [3.7–9.3] 6.4 [3.7–9.3] 0.55 CRP mg/L* 5.0 [1–21] 14.0 [1–317] 12.0 [0–317] .02 0.46 B2M mg/L*b 5.2 [2.6–19.3] 5.6 [1.5–41.3] 5.5 [1.5–41.3] 0.89 s-albumin g/L*c 36 [22–41] 36 [21–47] 36 [21–47] 0.94 LDH U/L* 238 [121–851] 184 [77–712] 185 [77–851] 0.31 Multiple osteolytic lesions 8 (61.5%) 33 (71.7%) 41 (69.5%) 0.51 Immunoparesisd 11 (84.6%) 40/44 (90.9%) 51/57 (89.5%) 0.61 0.59 IgA isotype 1 (7.7%) 20 (43.5%) 21 (35.6%) .02 .07 eGFR<60mL/min/1.73m2e 10 (76.9%) 24 (52.2%) 34 (57.6%) 0.20 0.11 Adverse cytogeneticsf 2/5 (40.0%) 7/19 (36.8%) 9/24 (37.5%) 1.00 Selected data at time of death Infection at time of death 9 (69.2%) 26 (56.5%) 35 (59.3%) 0.53 Progression at time of death 8 (61.5%) 41 (89.1%) 49 (83.1%) .03 Abbreviations: n, number of patients; [range]; ISS, International Scoring System; Hb, hemoglobin; CRP, C-reactive protein; B2M, Beta-2-microglobulin; LDH, Lactate dehydrogenase; eGFR, estimated glomerular filtration rate; Adverse cytogenetics included t(4;14), t(14;16), and/or del17p. *Median values. a Four missing values. b Three missing values. c Two missing values. d Two missing values, immunoparesis: At least one immunoglobulins below reference values: IgA < 0.70 g/L or IgA < 5.1 µmol/L, IgG < 6.1 g/L or IgG < 41 µmol/L and IgM <0.40 g/L or IgM < 0.41 µmol/L. e eGFR calculated with the MDRD Study Equation (with no correction for race, since most Danes are Caucasians). f FISH data were available in 24 patients at diagnosis. Not included in the multivariate analysis due to a large number of missing data. Forty-nine patients (83.1%) had progressive disease (PD) according to IMWG criteria at the time of death. In both patients with and without PD the leading cause of early death was infections seen in a total of 26 patients (44.1%). When including infections seen in combination with renal failure and stroke a total of 35 patients (59.3%) had an infection at the time of death. The most common type of infection was pneumonia (45.7%). Other important causes of early death were PD as an isolated event (30.5%), renal failure (11.9%) and stroke (5.1%) (Supporting Information Table S1). In the subgroup of patients with PD 18 patients (36.7%) died directly as a result of PD including transformation to secondary plasma cell leukemia. The remaining causes of death among patients with progressive disease were infection (42.9%), renal failure (12.2%), cardiovascular disorders (4.1%), stroke (2.0%), and hemorrhagic diathesis (2.0%). All deaths caused by renal failures coincided with infections resulting in an overall of 27 patients (55.1%) suffering from infections at the time of death in this group. Among the 613 HDT-ASCT treated patients from 2005 to 2013 the incidence of early death combined with progressive disease was 8.0%. No significant differences in given induction regimens were observed between patients with progressive disease or not. Patients with treatment-related-mortality presented with immunoparesis, defined as at least one immunoglobulin below reference value, in 84.6% of the cases. In these patients infections were responsible for 69.2% of the deaths. Within 2 years from diagnosis only 10 patients (16.9%) died without signs of progression. The causes of death were infections in 5 patients (8.5%), stroke in 2 patients (3.4%), renal failure in 1 patient (1.7%), and other causes in 2 patients (3.4%). However, the causes of death in patients with both stroke and renal failure were multifactorial and all these patients also suffered from an infection. Cytogenetic information by FISH at diagnosis was available in 24 of the patients (40.7%) who died within 2 years. Forty percent of patients with PD at time of death had adverse cytogenetics compared to only one in four patients without PD (Supporting Information Table S2). The nationwide survey of causes of early death within 2 years from diagnosis among MM patients treated with HDT-ASCT show that 83.1% of the patients had PD at time of death. Thus, PD was the most common cause of early death in transplant-eligible patients. Forty percent of patients with PD had adverse cytogenetics by FISH at the time of diagnosis. Overall, the combination of PD and infection contributed to more than one third (35.6%) of all deaths. It is a well-established clinical observation that uncontrolled disease increases the risk of life-threatening infections. Patients with PD within 2 years define a subgroup with unmet medical needs. Even though bortezomib was incorporated in the Danish induction regimen in 2009 we know from Barlogie et al. that high-risk patients treated with bortezomib still have a poor outcome.5 Moreau et al. established a scoring system on patients with PD who died within 2 years from start of treatment within the clinical trials IFM 2005–01, GIMEMA 26866138-MMY-3006, PETHEMA-GEMMENOS65, and HOVON-65/GMMG-HD4.6 The incidences of patients with MM progression-related early death were 8.7% and 7.0% in their test cohort and validation cohort, respectively. They demonstrated that patients with adverse cytogenetics [t(4;14) and/or del(17p)] in addition to ISS3 and/or elevated LDH had the highest risk of early MM progression-related death within 2 years of 25%. In our national population-based study we find the same incidence of early deaths for patients with PD and in this subgroup of patients infections contributed to the cause of death in 42.9% of the cases. CONFLICTS OF INTEREST Nothing to report. Supporting Information Additional Supporting Information may be found online in the supporting information tab for this article. Filename Description ajh24857-sup-0001-suppinfoTab1.doc39 KB Supporting Information Table 1 ajh24857-sup-0002-suppinfoTab2.doc33 KB Supporting Information Table 2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1 Holmström MO, Gimsing P, Abildgaard N, et al. Causes of early death in multiple myeloma patients who are ineligible for high-dose therapy with hematopoietic stem cell support: a study based on the nationwide Danish Myeloma Database. Am J Hematol. 2015; 90(4): E73– E74. 2 Hsu P, Lin T-W, Gau J-P, et al. Risk of early mortality in patients with newly diagnosed multiple myeloma. Medicine (Baltimore). 2015; 94(50): e2305. 3 Ríos-Tamayo R, Sáinz J, Martínez-López J, et al. Early mortality in multiple myeloma: the time-dependent impact of comorbidity: a population-based study in 621 real-life patients. Am J Hematol. 2016; 91(7): 700– 704. 4 Gimsing P, Holmström MO, Klausen TW, et al. The Danish national multiple myeloma registry. Clin Epidemiol. 2016; 8: 583– 587. 5 Barlogie B, Mitchell A, Van Rhee F, Epstein J, Morgan GJ, Crowley J. Curing myeloma at last: defining criteria and providing the evidence. Blood. 2014; 124(20): 3043– 3051. doi:10.1182/blood-2014-07-552059. 6 Moreau P, Cavo M, Sonneveld P, et al. Combination of International Scoring System 3, highlactate dehydrogenase, and t(4;14) and/or del(17p) identifies patients with multiple myeloma (MM) treated with front-line autologous stem-cell transplantation at high risk of early MM progression-related. JCO. 2014; 32(20): 2173– 2180. Citing Literature Volume92, Issue10October 2017Pages E611-E614 ReferencesRelatedInformation
Referência(s)