Survival until First Progression and Post First Progression Survival Equally Contribute to the Overall Survival of Myeloma Patients: Differences in Patients ≤65 Years of Age Compared to Patients >65 Years
Authors: Kastritis Efstathios , Terpos Evangelos , Roussou Maria , Gavriatopoulou Maria , Gika Dimitra , Gkotzamanidou Maria , Kanellias Nikolaos , Eleutherakis-Papaiakovou Evangelos , Migkou Magdalini , Dimopoulos Meletios A 
Published: October 2019

Abstract
Abstract 4030
Age is a major prognostic factor for the outcome of patients with multiple myeloma (MM), due to more intensive treatment in younger vs. older patients, comorbidities and toxicity, resulting in early discontinuation of treatment in older patients or even differences in disease characteristics. It is believed that the longer survival of patients ≤65 years is, to a large extent, due to the receipt of more lines of therapy and thus they can have an extended survival even after relapse to first line therapy. In order to decipher these differences in the outcome of MM patients of different ages, we analyzed 438 consecutive, unselected patients who were treated in a single center (Department of Clinical Therapeutics, University of Athens School of Medicine) from April 1994 to April 2012, and compared the characteristics and outcome of patients ≤65 years (166 patients), which are usually treated with more intensive therapies (including HDT), to that of patients 66–75 years (154 patients) and >75 years of age (118 patients). Some of these patients were included in clinical trials; however, even patients who were ineligible because of poor performance status, renal impairment or comorbidities were also included, thus, being more representative of the general myeloma population. Differences in the characteristics of patients of different age groups are depicted in the table. Younger patients presented less often with ISS-3, severe anemia, renal impairment or impaired PS than older patients. However, there was no difference in the detection of high risk cytogenetics. Response was higher and deeper in younger patients. Early deaths, within 2 months from initiation of therapy, occurred more often in older patients. Median PFS was longer in younger patients. Similar proportion of patients who relapsed have received 2nd line therapy (p=0.365). Post relapse survival (PRS) was 31 months for patients ≤65 years, 20 months for patients 66–75 years and 15 months for patients >75 years (p<0.001). The difference of PRS between patients 66–75 years and patients >75 years was also significant (p=0.004). Median OS was 71 months for patients <65 years, 46 months for patients 66–75 years and 31.5 months for patients >75 years (p<0.001). Thus, it seems that the OS of patients in each age group is distributed almost equally between the initial phase of the disease and post first relapse/progression (see Table). PFS <12 months was observed in 10% of patients ≤65 years vs. 22.5% and 29% of patients 66–75 and >75 years (p=0.003). PRS for patients with a PFS<12 months was 8 months for those ≤65 years, 10 months and 6 months for patients 66–75 and >75 years. Median OS was significantly better for patients who achieved CR or VGPR (58 months) vs. patients who achieved a PR (39 months) (p<0.001). For patients <65 years who achieved a CR/VGPR median OS has not been reached (4-year OS was 79%), for patients 66–75 years was 52 months and 40 months for those >75 years (p<0.001). Among patients with a minimum follow up ≥10 years (76 patients), 5 (6.5%) remained without progression for ≥10 years (4 of them had received HDT). In order to adjust for imbalances in baseline characteristics and depth of response (CR/VGPR vs. PR), we performed a multivariate analysis in which ISS stage (p<0.001), novel agent-based first line therapy (p=0.01), CR/VGPR (p=0.005) and age ≤65 (p<0.001), but not 66–75 vs. >75 years (p=0.092) were independently associated with improved survival. In conclusion, our data indicate that the survival of MM patients is distributed almost equally between the initial phase i.e. before relapse to first line therapy, and to subsequent phases of their disease i.e. post relapse survival. This is observed across all age groups, but in patients ≤65 years the duration of first response is significantly longer, perhaps due to more intensive therapies and to less frequent early deaths. In this unselected series of patients, the 10-year free of progression rate was 6.5%.
Table ≤65 years 66–75 years >75 years p-value Males 60% 43.5% 51% 0.015 ISS-1 21% 18% 9% 0.02 ISS-2 50% 46% 47% ISS-3 29% 37% 45% Hb <10 g/dl 40% 45% 53% 0.075 eGFR <60 ml/min 29% 45% 55% <0.001 Performance status ≥2 39% 55% 59% 0.001 High risk cytogenetics (n=194) 50% 48% 41% 0.5 Upfront novel agents 73.5% 63% 81% 0.023 CR 34% 27% 17% 0.005 >VGPR 56% 49% 34% 0.001 ≥PR 81% 79% 64% 0.003 Early deaths 2% 6% 12% 0.005 Median PFS (months) 34 19.5 15 0.001 Median PRS (months) 31 20 15 <0.001 Median OS (months) 71 46 31.5 <0.001

Disclosures:
No relevant conflicts of interest to declare.