Risk factors associated with early mortality in patients with multiple myeloma who were treated upfront with a novel agents containing regimen

Background Although the introduction of novel agents improved the survival outcomes in patients with multiple myeloma (MM), some patients died within one year (early mortality, EM) following diagnosis. In this study, we evaluated the EM rate, and investigated the risk factors associated with EM in MM patients. Methods Retrospective data from 542 patients who were initially treated with a novel agent-containing regimen were analyzed. Results The median overall survival (OS) for the entire cohort was 56.5 months. The median OS in the 2010–2014 group was longer than in the 2002–2009 group (59.2 months vs. 49.1 months, P = 0.054). The rate of EM was 13.8 %, and the most common causes of EM were infection and comorbidity. In multivariate analysis, the age-adjusted Charlson comorbidity index (ACCI ≥ 4), low body mass index (BMI < 20 kg/m2), thrombocytopenia, and renal failure were significantly associated with EM. The presence of none, 1, or ≥ 2 factors was associated with a 4.1 %, 14.3 %, or 27.4 % risk of EM (P < 0.001), respectively. The median OS times were significantly different depending on the presence of factors associated with EM (P < 0.001). Conclusions In conclusion, the ACCI (≥ 4), low BMI, thrombocytopenia and renal failure were strong predictors for EM in the novel agent era. The results of this study will help to identify patients at high risk for EM, and may be helpful to more accurately predict prognosis of MM patients in the novel-agent era.


Background
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by aberrant expansion of malignant plasma cells in bone marrow [1]. MM accounts for 1 % of all cancers and more the 10 % of all hematologic malignancies in the United States [2]. In Asian countries, the incidence of MM is lower than that of Western countries, but is increasing rapidly [3]. Treatment options for MM have expanded since the introduction of melphalan in the 1960s. The median survival of MM patients was less than a year prior to the introduction of this alkylating agent, and treatment with melphalan improves survival [4]. In the 1980s, the introduction of high-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) improved the response rate and survival [5][6][7][8]. Induction therapy with alkylating agents, anthracyclines and corticosteroid, and HDT/ASCT were the main treatment strategy in MM patients.
These treatment paradigms have markedly changed following the introduction of several new agents such as proteasome inhibitor bortezomib, the immunomodulatory drug thalidomide, and its derivative lenalidomide. Treatments with more effective and less toxic agents improved the response rate in relapsed or refractory disease [9,10]. Additionally, their use during induction resulted in considerable improvement of outcomes and extended the overall survival (OS) times [11,12]. The treatment improvements in MM patients also affected early mortality (EM), defined as death within 1 year of diagnosis. A recent single center report showed improvement in EM over the last decade in a large -volume, tertiary MM center [13]. However, 10 % of patients still died within 1 year of diagnosis, and the cause and risk factors for EM have not been thoroughly explored in the novelagent era.
In this study, we evaluated the EM rate and investigated risk factors associated with EM in MM patients initially treated with novel-agent containing regimen.

Patients
This retrospective study analyzed the records of 542 patients with newly diagnosed MM between September 2002 and February 2014 from three institutions in the Republic of Korea. Patients who were initially treated with novel agents such as immunomodulatory drug or proteasome inhibitors were included. Patients diagnosed with monoclonal gammopathy of undetermined significance, asymptomatic MM, and plasma cell leukemia were excluded. Patients who did not receive the induction treatment were also excluded. This study was approved by the Institutional Review Board of Chonnam National University Hwasun Hospital in accordance with the Declaration of Helsinki.
EM was defined as death within one year of diagnosis. Mortality rate and cause at 3, 6, and 12 months following diagnosis was evaluated. Comorbidity score was scored according to the Charlson Comorbidity Index (CCI), as calculated at the time of diagnosis based on the clinical history as well as laboratory and radiologic tests. Age-adjusted Charlson Comorbidity Index (ACCI) was calculated by adding the comorbidity score to the age score, which adds 1 point per decade to ages > 40 years [14]. Body mass index (BMI) was calculated as weight measured in kilograms divided by the square of the height measured in meters (kg/m 2 ). Height and weight at diagnosis or prior to first-line chemotherapy were used to calculate BMI. Clinical staging was performed using the International Staging System (ISS). The cytogenetic risk was classified as standard or high risk based on conventional cytogenetic studies or fluorescent in situ hybridization. Patients with t(4;14), t(14;16), or, 17p deletion were classified as high risk. Normal cytogenetics and other cytogenetic abnormalities were classified as standard risk. Treatment response was assessed on the first day of each treatment cycle according to the International Myeloma Working Group criteria.

Statistical analysis
Pearson's chi-square test for discrete variables and the Mann-Whitney U test for continuous variables were used to compare patient characteristics. OS was defined as the period from the date of diagnosis to the date of the last follow-up or death from any cause. OS was evaluated using Kaplan-Meier estimates and compared using log-rank test. Univariate analysis of factors associated with EM was performed with the χ 2 test. Among the factors, those with P < 0.05 were selected and included in the multivariate logistic regression analysis. All statistical computations were performed using SPSS ver. 21 (SPSS, Chicago, IL, USA). A P-value < 0.05 was considered significant for all analyses.

Patient population
The median age of the patients was 63 years (range, 38-86 years) and 43.0 % were ≥ 65 years. A total of 304 patients (56.1 %) were male. The MM type of 296 patients (54.6 %) was Immunoglobulin (Ig) G, and 20. The clinical characteristics and treatment for these two periods are summarized in Table 1. A total of 215 patients (39.7 %) had at least one comorbidity at the time of diagnosis, and 45.1 % of elderly patients (≥ 65 years) had a concurrent comorbidity. The median ACCI score was three for the entire group (range, 0-9). The median BMI was 23.3 kg/m 2 (range, 13.1-59.2) at the time of diagnosis. Underweight patients (< 18.5 kg/m 2 ) accounted for 13 (2.3 %), and 16 patients (2.9 %) were obese (≥ 30 kg/m 2 ).
All patients were treated with a regimen containing a novel agent after the initial diagnosis. A total of 358 patients (66.1 %) received a thalidomide-based regimen as the first-line treatment, such as cyclophosphamide, thalidomide, and dexamethasone (CTD), or melphalan, prednisolone, and thalidomide (MPT), or thalidomide alone or other combinations. A total of 173 patients (31.9 %) were treated with a bortezomib-containing regimen such as bortezomib, melphalan, and prednisolone (VMP), or bortezomib, cyclophosphamide, and dexamethasone (VCD), or bortezomib and other combinations. Patients who received HDT/ASCT had significantly longer OS compared with those who did not undergo HDT/ASCT (76.1 months vs. 33.2 months, P < 0.001, Fig. 1d). In young patients (< 65 years), the median OS for patients receiving HDT/ASCT was significantly longer than those who did not undergo HDT/ASCT (76.1 months vs. 23.5 months, P < 0.001).

Discussion
The introduction of novel agents with new therapeutic mechanisms has changed the paradigm of MM therapy, and considerably improved outcomes in patients with this disease. Recent studies have demonstrated that improved survival has been sustained following the introduction of novel agents in elderly patients as well as younger patients [13,15]. These survival data mainly come from studies based in Western countries, while data for Asian patients are rare. In this study, Korean MM patients also exhibited improved survival following the introduction of novel agents, but improved survival There was a 13.8 % rate of EM in patients initially treated with novel-agent containing regimen, and the main causes of EM were infection and comorbidity. Infection was reported as a major cause of morbidity and a leading cause of death in patients with MM [16,17]. MM patients are predisposed to infection because of immune dysfunction, placement of vascular catheters, and impaired mucosal integrity due to the effects of chemotherapy and radiotherapy [18,19]. In a recent large population-based study of over 9000 MM patients in the period 1988-2007, the risk of infections and infectionrelated death is significantly increased in MM patients compared to controls, and the incidence of infection was highest within the first year following diagnosis. Furthermore, the risk of infection has increased in the recent decades [20]. In our study, the rate of death from infection was constant within a 12 month period. These results suggest that infection is still a major problem for MM patients treated with novel-agent containing regimen, and the management of early infection throughout the disease course was important to improve survival.
Another goal of this study was to identify factors associated with EM after induction treatment. Because comorbidities present at diagnosis were identified as a major cause of EM in this study, we evaluated the prognostic value of ACCI. The CCI is a statistically validated tool that assigns different weights to patients' comorbidities to predict mortality, and can be adjusted to the patients age [14]. CCI has been demonstrated to affect survival outcomes for various types of cancer, including hematologic malignancies [21][22][23]. In patients with MM, several reports showed that comorbidity score was associated with diminished survival outcomes [24,25]. Comorbidities such as renal impairment, impaired lung function, and poor PS were prognostic for poor OS in MM patients. In multivariate analysis, high ACCI (≥ 4) was significantly associated with EM. In addition, low BMI (< 20 kg/m 2 ) was significantly associated with EM, and 27.1 % of patients with low BMI died within 12 months of diagnosis. We previously reported that a low BMI (< 20 kg/m 2 ) at the time of diagnosis was associated with poor survival [26]. Low BMI may reflect involuntary weight loss caused principally by cancerassociated cachexia [27]. High ACCI and low BMI may  be associated with reduced physical function, poorer tolerance of treatment, and increased toxicity of chemotherapy. Therefore, ACCI and BMI are considered as an important host factors to stratify the risk of myeloma and decide treatment options. The prognostic role of thrombocytopenia is less understood in patients with MM. Several reports explored the prognostic role of thrombocytopenia in MM patients with renal failure. One study showed that thrombocytopenia (< 130 × 10 9 /L) was related to a poor prognosis (HR 2.150, 95 % CI 1.167-3.962, P = 0.014) [28], whereas another study reported no association (HR 1.52, 95 % CI 0.875-2.65, P = 0.136) [29]. In the current study, thrombocytopenia present at initial diagnosis was a strong predictor for EM. A recent study suggested that thrombocytopenia (< 200 × 10 9 /L) was associated with EM, but this was not confirmed by multivariate analysis [13]. Further study is needed to ascertain whether thrombocytopenia has a prognostic role, as well as to determine the appropriate threshold.
This study has some limitations. Validation is an important step in developing a prognostic model. However, the risk factors used in this study were not validated in a separate analysis. The lack of validation step of risk factors can be a limitation of this analysis. Additionally, number of all patients was numerous but number of patients in each group was not very large.

Conclusion
In conclusion, the rate of MM patients in novel-agent era was 13.8 %. Major causes of EM were infection and comorbidity. The ACCI (≥ 4), BMI (< 20 kg/m 2 ), thrombocytopenia, and renal failure were significantly associated with EM. Median OS times were significantly  Fig. 4 a EM rate and b OS according to number of risk factors different depending on the presence of risk factors associated with EM. The results of this study will help to identify patients at high risk for EM, and may be helpful to more accurately predict prognosis of MM patients in the novel-agent era.