Clinical Features and Predictive Factors of Early Mortality in Patients with MM Outside of Clinical Trials
Authors: Kobayashi Hiroki , Abe Yoshiaki , Miura Daisuke , Narita Kentaro , Kitadate Akihiro , Takeuchi Masami , Matsue Kosei 
Published: October 2019

Abstract
Background
Novel agents such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have improved the overall survival of patients with newly diagnosed multiple myeloma (NDMM) over the last decade. However, early mortality (EM) remains a serious obstacle for a portion of the patients despite receiving novel agents. The report based on clinical trials showed that age, International Staging System (ISS), lactate dehydrogenase (LDH) levels, and high-risk cytogenetic abnormalities (CA) predict EM due to myeloma progression. The result, however, may differ from real-world settings because the patients of clinical trials are relatively younger and have fewer health problems, and the major cause of EM is not only disease progression, but also infections and comorbidities. In this study, we retrospectively analyzed the clinical variables that affected EM in patients with multiple myeloma (MM) in the real-world setting in the novel agent era.
Patients and Methods
The study population consisted of 238 consecutive patients with NDMM between January 2008 and April 2018 at Kameda Medical Center, Japan. All patients were administered PI- or IMiD-based combined chemotherapy in the frontline setting. Patients diagnosed with smoldering MM and solitary plasmacytoma and who did not receive treatment were excluded in this study. Early mortality was defined as death within two years after diagnosis due to any cause. Comorbidities were evaluated according to the Charlson Comorbidity Index (CCI). Instrumental Activities of Daily Living (IADLs) were retrospectively scored based on medical records. IADLs were assessed by the percentage of the score because the full score of IADLs is different between men and women. High-risk CA was defined by the presence of t(4;14), t(14;16), and del(17p). Statistical analyses were performed with EZR, which is a graphical user interface for R ver. 3.2.2.
Ethical considerations
This study was approved by the institutional review board of Kameda Medical Center and conducted according to the principles of the Declaration of Helsinki.
Results
The median age of the patients was 72.2 years, and the median observation period was 40.8 months. Fifty patients (21.3%) died within two years. The major causes of mortality were myeloma progression (36%), infection (22%), and comorbidities (20%). Baseline involved free light chain (iFLC), LDH > normal range, and high-risk CA were not statistically significant between the patients with or without EM. There were significant differences in age, reduction in iFLC on day 7 from the baseline, ISS stage, Revised-ISS stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≥3, CCI score ≥4, and the percentage of IADL scores between the two groups (Table1). Next, we analyzed IADL scores and the reduction in iFLC on day 7 because these variables were not assessed in previous studies. Receiver-operating characteristic curve analysis showed that the best cutoff values were 50% for IADL scores and 65% for the reduction in iFLC on day 7. Univariate analysis suggested that the factors associated with EM were age >75 years, ISS stage 3, CCI score ≥4, ECOG-PS ≥3, IADL <50%, and iFLC reduction >65% on day 7. The multivariate analysis showed that CCI score ≥4 [odds ratio (OR), 2.43; 95% confidence interval (CI), 1.11-5.32; p=0.027], IADL score <50% (OR, 3.31; 95% CI, 1.42-7.70; p=0.006), and iFLC reduction >65% on day 7 (OR, 3.20; 95% CI, 1.45-7.07, p=0.004) were independent predictive factors for EM (Table2). Thus, the EM predictive score was established according to following variables: CCI score ≥4, IADL score <50%, iFLC reduction >65% on day 7, and ISS stage 3. Sixty patients were categorized with high scores (score ≥3), and half of the patients with high scores died within two years, while only 10% of the patients with low scores (score <3) died within two years (p<0.001).
Conclusion
One-fifth of the patients with NDMM died within two years due to myeloma progression, infection, and comorbidities. Our results suggested that high-risk CA and high levels of LDH did not have predictive value for EM in patients with NDMM outside of clinical trials. The presence of high CCI scores, low IADL scores, and decreases in iFLC (>65%) on day 7 from the baseline were independent prognostic factors, which could reflect both patient and disease factors. The combination of the CCI score, IADL score, ISS stage, and early reduction in iFLC may help in the identification of EM.

Disclosures
No relevant conflicts of interest to declare.