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 <scp>D</scp>anish <scp>M</scp>yeloma <scp>D</scp>atabase
Authors: Morten O. Holmström, Peter Gimsing, Niels Abildgaard, Niels F. Andersen, Carsten Helleberg, Niels Aage T. Clausen, Tobias W. Klausen, Mikael Frederiksen, Dan L. Kristensen, Herdis Larsen, Per T. Pedersen, Kristian Thidemann Andersen, Robert Schou Pedersen, Bo Amdi Jensen, Henrik Gregersen, Annette J. Vangsted
Journal: American Journal of Hematology (2015)

In a recent publication, Sant et al. presented population-based survival of European hematological malignancies before and after the introduction of new effective treatment strategies 1. Survival for multiple myeloma patients had improved significantly in Europe among younger patients, but not in the elderly patients 1. Studies on causes of death among the elderly patients with multiple myeloma (MM) are difficult to conduct due to low compliance. A study by Augustson et al. found a 2 months overall mortality of 10% for patients included in the United Kingdom Medical Research Council trials and 60% of the these deaths were found in patients older than 65 years 2. Here, the most common causes of death were pneumonia and renal failure 2. Among 155 octogenarians registered in the Greek Myeloma Study Group database 14% died within 2 months 3. Other studies confirm that the most common causes of early death are renal failure and infections and among the latter pneumonia and septicemia prevail 4-6. To establish intervention strategies to improve survival, we studied the causes of early death in elderly or frail MM patients ineligible for high-dose chemotherapy in an unselected nationwide population. All medical records from myeloma patients who died within 30 and 180 days of diagnosis were thoroughly analyzed. Since 2005 all newly diagnosed MM patients have been registered in the Danish nationwide population-based database (DMMD). The DMMD includes clinical data, laboratory data, and symptoms at diagnosis 7. We used the DMMD to identify patients ineligible for high-dose therapy (HDT) who died early. SPSS statistical software was used for all calculations (SPSS for Windows, 19.0.0. 2010, Armonk, NY: IBM Inc). All tests were two-sided and P-values < 0.05 were regarded as statistically significant. Fisher's exact test or Pearson's χ2-test were used to compare categorical variables. Continuous variables were analyzed using independent samples t-test. Multivariable analysis was performed using a binary logistic regression and right skewed variables (beta 2 microglobulin(B2M), CRP, and lactate dehydrogenase(LDH)) were log-transformed. We identified 1,497 patients from 2005 to 2012 who did not undergo HDT. The characteristics of these patients are shown in Supporting Information Table S1. Anti-myeloma treatment is presented in Supporting Information Table S2. In this cohort, 330 patients (22.0%) died within 180 days of diagnosis and 99 patients (6.6%) died within 30 days from diagnosis. Data on death causes were available on 212 patients and 50.9% died of an infection. Microbiological cultures were made in all 108 patients who died of an infection and 69 (63.8%) of the patients were infected with at least one microorganism (Supporting Information Tables S3 and S4). Gram positive cocci and Gram negative rods were found in 73.7% of all isolates but no specific pattern of pathogens was found. Eighteen patients were infected with more than one pathogen. Death caused by renal failure was seen in 9.9% of the patients and 42.9% of patients on dialysis at diagnosis died within 180 days. Causes of death among patients with renal failure are multifactorial and could not be ascribed to failure to dialyze. Other causes of death were cardiovascular failure (10.8%), respiratory failure (6.6%), stroke (3.8%), and other causes (17%) (Supporting Information Table S5). There was no difference in causes of death among patients who died within 30 days as compared to patients who died between 31 and 180 days from diagnosis (P = 0.34 Fisher's exact test). Prognostic markers for death within 30 days and within 180 days were assessed. Multivariable analysis with a backward selection method showed that low serum albumin [odds ratio (OR): 1.08 (confidence interval (CI):1.04–1.13; P < 0.001)] and high LDH [OR: 5.4 (CI: 1.5–19.9; P = 0.01)] were the most significant parameters for death within 30 days. For patients who died within 180 days of diagnosis, the most significant parameters for early death was low WHO performance status [OR: 4.8 (CI: 3.2–7.2; P = 0.001)]; high B2M [OR: 1.5 (CI: 1.2–1.9; P < 0.001)]; low s-albumin [OR: 1.05 (CI: 1.02–1.08); P = 0.003)]; high LDH [OR: 1.7 (CI: 1.3–2.4; P < 0.001)]. When comparing death within 180 days in the periods 2005–2008 and 2009–2012, a trend was seen for improved survival (P = 0.08). Our goal is to improve the nationwide survival of myeloma patients. We have established a national registry of all myeloma patients to identify areas of intervention. A population-based survey showed no difference in causes of death among patients ineligible for HDT, who died within 30 days from diagnosis as compared to patients who died between 31 and 180 days. Patients who died within 30 days had higher LDH levels and lower levels of plasma albumin as compared to those patients who died within 31–180 days, and may reflect patients with high tumor burden and a high degree of stress caused by severe infection, impaired kidney, and liver function. When compared with patients who died later than 180 days of diagnosis, WHO performance status was worse in patients with early death. A clinician will not find these results surprising. However, our data may imply that elderly patients with multiple myeloma are diagnosed with delay and a nationwide focus is now on accelerated diagnosis to clarify whether individuals presenting with an M-protein in blood or urine or with myeloma associated symptoms are suffering from myeloma. Furthermore, our survey showed that among patients with early deaths the most common causes of deaths were infections, cardiovascular failure, and renal failure. Standard induction treatment for patients ineligible for HDT now includes adjustment of chemotherapy dose according to co-morbidity and a proteasome inhibitor. Clinicians use several approaches to avoid life-threatening infections among the elderly such as granulocyte colony-stimulating factor (G-CSF) in patients with neutropenia and supportive treatment with immunoglobulins. To provide the patients with the best antibiotic treatment in future we are now conducting a nationwide prospective study on prophylactic antibiotic treatment. Morten O. Holmström,1 Peter Gimsing,2 Niels Abildgaard,3 Niels F. Andersen,4 Carsten Helleberg,5 Niels Aage T. Clausen,1,5 Tobias W. Klausen,5 Mikael Frederiksen,6 Dan L. Kristensen,7 Herdis Larsen,8 Per T. Pedersen,9 Kristian Thidemann Andersen,10 Robert Schou Pedersen,11 Bo Amdi Jensen,1 Henrik Gregersen,8 and Annette J. Vangsted2* 1Department of Hematology, Roskilde Hospital, Roskilde 4000, Denmark; 2Department of Hematology, Rigshospitalet, Copenhagen 2100, Denmark; 3Department of Hematology, Odense University Hospital, Odense 5000, Denmark; 4Department of Hematology, Aahus University Hospital, Århus 8000, Denmark; 5Department of Hematology, Herlev Hospital, Herlev 2730, Denmark; 6Department of Hematology, Sygehus Sønderjylland, Aabenraa 6200, Denmark; 7Department of Oncology, Næstved Hospital, Næstved 4700, Denmark; 8Department of Hematology, Aalborg University Hospital, 9000 Aalborg, Denmark; 9Department of Hematology, Sydvestjysk Sygehus Esbjerg, Esbjerg 6700, Denmark; 10Department of Medicine, Sygehus Lillebælt Vejle, Vejle 7100, Denmark; 11Department of Hematology and Medicine, Regionshospitalet Holstebro, Holstebro Lægårdvej 7500, Denmark Additional Supporting Information may be found in the online version of this article. 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