Overall Survival Patterns in Patients with Multiple Myeloma in the Era of Novel Agents and the Role of Initial Clinical Presentation and Comorbidities: A Population-Based Study
Authors: Oortgiesen Berdien , Roon Eric N. van , Joosten Peter , Kibbelaar Robby , Storm Huib , Hovenga Sjoerd , Van Rees Bas P , Woolthuis Gerhard , Veeger Nic J.G.M. , Hoogendoorn Mels 
Published: October 2019

Abstract
Introduction
Clinical trials have shown improved response rates, progression-free survival and overall survival (OS) in patients with multiple myeloma (MM) when using the novel agents thalidomide, lenalidomide and bortezomib. However, outcome data provided by population-based registries, reflecting real-life, report predominantly improved OS in younger MM patients and only minimal improvement in OS in unselected MM patients older than 65 years. Population-based studies in unselected MM patients in the era of novel agents are relatively limited. Explanations for the marked variation in prognosis across patients may in part be explained by the heterogeneity in the initial clinical presentation, the pre-existing comorbidities, disease biology and response to the therapy. Specific end-organ damage caused by the disease, such as hypercalcemia, renal failure, anemia and bone lesions known as the CRAB symptoms may be associated with worse prognosis in the elderly MM patients. This descriptive prospective population-based cohort study was designed to determine the OS in patients with MM in Friesland, The Netherlands in the era of novel agents, and to analyze the influence of the CRAB symptoms and comorbidities at initial presentation on survival.
Methods
Since 2005 all patients diagnosed with hematological malignancies in Friesland, a province of the Netherlands, are prospectively registered and followed by their clinicians in a population-based registry, the HemoBase. For this analysis, data on clinical characteristics, comorbidities, treatment and outcome of all patients with newly diagnosed MM in Friesland during the period of January 2005 to January 2013 with a follow-up until January 2014 were retrieved from HemoBase. Supplementary information was obtained from the individual patient hospital records. Both symptomatic and asymptomatic patients were included in the study with subgroup analysis on the symptomatic patients. According to the guidelines from IMWG, each CRAB symptom was divided into two categories (11 mg/dL < serum calcium ≤ 11 mg/dL; 2 mg < creatinine ≤ 2 mg/dL; 10.2 g/d ≤ hemoglobin < 10.2 g/dL and the presence or absence of bone lesions). The patients were divided by age groups (<65, 65 – 75 and ≥75 years old) to illustrate differences in survival in the three age categories.
Results
From 2005 till 2013 a total of 270 patients were diagnosed with MM in Friesland. The median observation period was 29 months (range 0.26 - 104; IQR 33). Median age was 70 years (range 32 - 92; IQR 15) with a male predominance (60% male). 34, 34 and 32% of patients were < 65 years, 65 - 75 years and ≥ 75 years, respectively. The Charlson Comorbidity Index (CCI) was 0,1 or ≥2 in 60, 22, 18% of patients, respectively. Sixteen percent of patients were asymptomatic. Of symptomatic patients 63% and 27% had CRAB scores of 1-2 and 3-4, respectively. Ten percent of patients had a CRAB score of 0, but were regarded symptomatic by their treating hematologist. Among the symptomatic MM patients 80% received novel agents, 15% other chemotherapy 6% only radiotherapy. The median OS of all patients is 49.5 months, with median OS for symptomatic and asymptomatic patients of 40 and >100 months respectively. Divided into age categories < 65, 65 – 75 and ≥75 years old, the 50% OS is respectively 92, 40 and 29 months (figure 1). For all patients, implementing novel therapies improved OS compared to other therapies (43.5 vs. 21.1 months, hazard ratio (HR) = 1.8, P = 0.017. Patients with a CCI score of 0 have a higher median OS than patients with a score ≥ 2 (HR = 0.6, P = 0.036). Patients with two or more CRAB symptoms have a lower median OS than patients without any CRAB symptoms (HRadjusted = 2.2, P = 0.028). In multivariate analysis, differences in median OS were significant better for patients without hypercalcemia compared to patients with hypercalcemia (HRadj. = 0.6, P = 0.011) and for patients with a serum creatinine ≤ 2 mg/dL vs. ≥ 2 mg/dL (HRadj. = 0.4, P < 0.0001).
Conclusion
In this population-based study of a complete Dutch cohort of unselected MM patients over the last decade a median OS of 49.5 months was observed. Despite extensive introduction of novel agents increasing age remains an adverse prognostic factor. High comorbidity scores (CCI ≥ 2) and CRAB symptoms, such as hypercalcemia and impaired renal function at initial presentation were significantly correlated with worse median OS.

Disclosures
Hovenga: Jansen Cilag: Research Funding. Woolthuis:Jansen Cilag: Research Funding. Hoogendoorn:Jansen Cilag: Research Funding.