Very Early Death (<2 months) In Myeloma Is Associated With Advanced Age, Poor Performance Status and Reduced Use Of Novel Agents, While Early Death Within 12 Months Is Associated With High Risk Features Of Both The Disease and The Patient
Authors: Kastritis Efstathios , Terpos Evangelos , Roussou Maria , Eleutherakis-Papaiakovou Evangelos , Gavriatopoulou Maria , Kalapanida Despoina , Migkou Magdalini , Kanellias Nikolaos , Christoulas Dimitrios , Gika Dimitra , Mparmparoussi Despoina , Matsouka Charis , Dimopoulos Meletios A. 
Published: October 2019

Abstract
The outcome of patients with multiple myeloma (MM) is heterogeneous and the median survival of patients with symptomatic disease ranges from a few months to several years. Although the survival of MM patients has increased over the past 10 years, there is still a proportion of patients who die within a few months from the initiation of therapy, even when they are treated with the most contemporary drug regimens. Our aim was to identify the factors that are associated with early death among patients with symptomatic myeloma and explore whether incorporation of new therapies has also improved short-term outcome.
We analyzed 509 consecutive patients that have been treated in a single center (Department of Clinical Therapeutics, Athens, Greece) from January 1994 to December 2012. All patients, irrespective of age or performance status (PS) who received at least one dose of therapy were included in the analysis. Median age of the patients was 69 years (range 31-92 years); 62% were older than 65 and 27% older than 75 years. Osteolytic bone disease (in plain X-rays) was present in 74% of the patients; 25% had ISS-1, 35.5% had ISS-2 and 39.5% ISS-3 disease. Elevated LDH >300 IU/L was present in 8%; 21% had severe renal impairment (eGFR<30 ml/min/1.73m2). Primary therapy with conventional chemotherapy (CC) was given in 25.5%, IMiDs-based (mainly thalidomide) in 48% and bortezomib-based regimens in 26.5% of the patients.
Two-month, 6-month and one-year mortality was 6%, 13% and 18%, respectively. Age >75 years was strongly associated with higher rates of early mortality (2-month, 6-month and 1 year mortality was 8%, 11% and 21% vs. 4%, 5% and 10% for patients <75 years, p<0.001). Other factors associated with early mortality included PS ≥2 (2-month, 6-month and 1-year mortality were 9%, 13% and 23% vs. 2%, 3% and 7% for patients with PS≤1, p<0.001), anemia (Hb<10 g/dl), ISS-3 disease (2-month, 6-month and 1-year mortality were 12%, 16% and 28% vs. 3%, 4% and 11% for patients with ISS-2 vs. 1%, 2% and 2% for patients with ISS-1, p<0.001), platelet counts <130x109/L (p<0.001), or eGFR<30 ml/min/1.73m2 (p<0.001). Primary therapy with novel agents (thalidomide, bortezomib or lenalidomide) was associated with reduced early mortality: 2-month, 6-month and 1-year mortality rate was 10%, 14% and 22% for those who received CC vs. 5%, 8% and 16% for patients who received IMiDs-based therapy vs. 3%, 4% and 8% for patients who received bortezomib-based therapy (p<0.001). In multivariate analysis the strongest predictors of death within <2 months were age >75 years (HR: 3, 95% CI 1.25-7.3, p=0.014), PS >1 (HR: 2.88, 95% CI 1.02-8, p=0.045), while ISS-3 had marginal independent significance (HR: 8, 95% CI 0.99-67, p=0.051). Importantly, the upfront use of bortezomib-based regimens (HR: 0.21 95% CI 0.06-0.73, p<0.014) or IMiDs-based regimens (HR: 0.27, 95% CI 0.1-0.68) reduced the risk of early death over CC. However, there was a strong interaction between the type of therapy and age >75 years, as only a minority of patients >75 years received bortezomib-based therapy. When this interaction was accounted for in the model, then it was significant (p=0.041), indicating that age >75 years was associated with early death also due to the reduced use of bortezomib (but not of IMiDs). In multivariate analysis for predictors of death within the first 12 months from initiation of therapy age >75 years (HR: 4.125, 95% CI 2.2-7.7,p<0.001), PS >1 (HR: 2.5, 95% CI 1.33-4.7, p=0.005), ISS-3 (HR: 7.5, 95% CI 2.44-23, p<0.001) and LDH ≥300 IU/L (HR: 3.5, 95% CI 1.5-7.9, p<0.003) were associated with increased risk, while the upfront use of bortezomib-based regimens (HR: 0.26, 95% CI 0.11-0.64, p=0.003) or IMiDs-based regimens (HR: 0.38, 95% CI0.19-0.75, p=0.005) reduced the risk of early death over CC. However, if patients who died within the first two months were excluded, then the type of primary therapy was not significant.
The above results indicate that host characteristics (age, PS) are crucial predictors of very early death (<2 months) but the use of very active therapy is crucial for the rapid disease control and the management of early complications, like renal impairment, in order to reduce very early mortality. However, later in the course of the disease, it is the disease characteristics, which are depicted in ISS stage and LDH levels, along with patient’s characteristics (age, PS) that are the major predictors of early death (within 12 months).

Disclosures:
No relevant conflicts of interest to declare.