Myeloma in the Octogenarians: Disease Characteristics and Clinical Outcomes in the Era of Modern Anti-Myeloma Therapy
Authors: Dimopoulos Meletios A. , Terpos Evangelos , Gavriatopoulou Maria , Kalapanida Despoina , Eleutherakis-Papaiakovou Evangelos , Roussou Maria , Mparmparoussi Despoina , Zomas Athanasios , Gika Dimitra , Kartasis Zafiris , Matsouka Charis , Kostis Evangelos , Kontogiannis Sofoklis , Konstantopoulos Kostas , Kastritis Efstathios 
Published: October 2019

Abstract
Multiple Myeloma (MM) is a disease of the elderly and due to the aging population an increasing number of patients are diagnosed at the age ≥80 year. The management of these octogenarians is challenging due to their frailty as a result of co-morbidities and of age-related deterioration of organ function (lung, renal, cardiac). Indeed, age ≥80 year alone is a sufficient parameter to define frailty, according to IMWG recommendations. Thus, most octogenarians are not eligible and are not recruited in clinical trials. The aim of our study was to analyze the disease characteristics and treatment outcomes of patients ≥80 years of age. All patients with symptomatic MM since 1994, who received at least one dose of any therapy and were followed in our center (University of Athens, Greece) were included in the analysis.
Among 610 consecutive patients, 84 (14%) were ≥80 years of age. During these 20 years, there was a steady increase in the proportion of patients ≥80 years who were treated for MM (10% during the 1994-1999 period, 12% during 2000-2005, 14% during 2006-2010 and 16% after 2011). Compared to patients ≤65 years and those 66-79 years, octogenarians had more often moderate or severe renal impairment (p<0.001), performance status (PS) ≥2 (p<0.001), Hb <10 g/dl (p<0.001) and ISS-3 (p<0.001). In patients with available cytogenetics (N=337), del17p (present in 17%, 10% and 4% in patients ≤65, 66-79 and ≥80 years, respectively; p=0.025) and t(4;14) (17%, 9% and 5%, respectively; p=0.034) were more common in patients ≤65 years. The frequency of add1q21 was similar among the three groups.
Patients ≤65 years received more often bortezomib-based regimens upfront (61% vs 15% vs 11% respectively, p<0.001). In contrast, more patients 66-79 years and ≥80 years received IMiDs-based primary therapy (63% & 71% vs 18%, respectively, p<0.001). Response rates to primary therapy were higher in patients ≤65 years (85% vs 79% and 63% for 66-79 and ≥80 years, respectively; p<0.001). Also the quality of response was better in patients ≤65 years (at least VGPR in 56% vs 42% and 17%, respectively; p<0.001).
The median overall survival (OS) was 66% at 5 years for patients ≤65 years, 46 months for those 66-79 years and only 19.5 months for octogenarians (p<0.001). Median PFS was 31, 18 and 11 months, respectively (p<0.001). Early mortality at 2 months was 3%, 6% and 14% (p=0.001) and at 6 months it was 4%, 8% and 23%, respectively (p<0.001). Among patients of the three respective age groups who relapsed, 94%, 91% and 81% of patients received at least one dose of second line therapy (p=0.077). Post relapse OS for those patients was 41, 26 and 25 months, respectively (p=0.002). In the multivariate analysis, age ≥80 was associated with a 3.3-fold higher risk of death compared to patients ≤65 years (p<0.001) and a 2-fold higher risk than patients 66-79 years (p=0.007). A PS ≥2 (p<0.001) and advanced ISS stage (p<0.001) were associated with shorter OS, while the use of bortezomib-based regimens (p=0.001) was associated with better OS compared to conventional regimens. The use of IMiD-based regimens was also independently associated with better OS (p=0.025 for thalidomide and p=0.05 for lenalidomide-based regimens). In the subset of patients with cytogenetics, age ≥80 was associated with a 2.9-fold higher risk of death compared to patients ≤65 years (p=0.001), not significantly different than in patients 66-79 years (p=0.435), while PS <2 (p<0.001), ISS-3 (p=0.003) and the use of bortezomib-based regimens (p=0.019) (but not of IMiD-based regimens) were independently associated with better OS. High risk cytogenetics were independently associated with shorter OS (HR:2.33, p<0.001). When we compared the OS of the octogenarians across different calendar periods we did not found a significant improvement over the past 20 years, while there is a steady improvement of the OS of patients ≤65 and 66-79 years.
In conclusion, myeloma patients ≥80 years present with poor prognostic features, which are probably related to non-MM related conditions, since high risk MM features (such as adverse cytogenetics) are less common. The management of octogenarians should take into account not only myeloma but also their general condition. A comprehensive geriatric assessment should routinely be performed in these patients, in order to identify those most vulnerable and those most likely to tolerate and benefit from novel therapies.

Disclosures
No relevant conflicts of interest to declare.