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

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]. 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 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. Nothing to report. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Table 1 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.