Short Progression Free Survival Predicts for Poor Overall Survival In Older Patients with Multiple Myeloma Treated Upfront with Novel Agent-Based Therapy
Authors: Kastritis Efstathios , Roussou Maria , Gavriatopoulou Maria , Migkou Magdalini , Gkotzamanidou Maria , Iakovaki Marina , Efstathiou Eleni , Terpos Evangelos , Dimopoulos Meletios A. 
Published: October 2019

Abstract
Abstract 3035
Data from patients with multiple myeloma (MM) treated with autologous transplantation indicate that a short remission period after high dose therapy, usually less than 12 months, is associated with a poor outcome and limited efficacy of salvage regimens. Also, failure to respond to upfront thalidomide or lenalidomide based-regimens is associated with poor outcome. However, such data are limited for the general, unselected population of elderly or non-transplant treated MM patients, especially after the introduction of novel agents in the upfront treatment of myeloma. Thus, we analyzed the outcome of 115 unselected patients, who were older than 65 years and who were treated upfront with novel agent-based regimens in a single center in Athens, Greece. Many of these patients had been included in clinical trials; however, several patients who were ineligible because of poor performance status, significant renal impairment or comorbidities were also treated with novel agent-based regimens. Thus, these patients are more representative of the general myeloma population. IMWG criteria were used for the assessment of response, progression-free (PFS) and overall survival (OS). Forty three percent of patients were >75 years. Nine percent died within 3 months from initiation of treatment. Among 106 patients who survived for at least 3 months, 77% achieved an objective response: 20% achieved a CR, 26% a VGPR and 33% a PR. On an intention to treat, 58% of patients have progressed so far. Among patients who responded to initial treatment, 19% who had achieved a CR, 27% who had achieved a VGPR and 37% who had achieved a PR, relapsed(p=0.012). At the time of relapse or progression, patients were treated again with novel agents. Median PFS for all patients was 21 months (95% CI: 18–23 months), while median PFS for patients who achieved CR/VGPR or PR as best response was 20 months and 22 months, respectively (p=0.9). Subsequently, we analyzed 94 patients who started treatment at least 12 months before this analysis. Among these patients, 32% had a PFS shorter than 12 months including 26% of patients who initially responded. Depth of response was predictive of probability for early relapse: CR 5%, VGPR 29% and PR 38% (p=0.04). In the univariate analysis, LDH ≥300 IU/L (upper limit of normal 225 IU/L) was the only factor associated with shorter PFS while other factors such as ISS stage, age >75 years, Hb <10 g/dl, platelet counts <130,000/ml) did not affect PFS. The probability for two-year OS for patients who achieved a CR was 93%, for patients with VGPR was 69% and for patients who achieved a PR was 83% (p=0.188). Baseline factors associated with poor OS in the univariate analysis, included age >75 years (median OS of 28 months vs. 62 for patients younger than 75 years, p<0.001), hemoglobin <10 g/dl (p=0.05), platelet counts <130,000/ml (p=0.012), ISS stage (p=0.031) and elevated LDH (p<0.001). Furthermore, patients who relapsed or progressed within the first 12 months had a median survival of 18 months compared to a median survival of 53 months for patients who relapsed after at least 12 months from treatment initiation (p<0.001). In the multivariate analysis, PFS <12 months was the most significant adverse prognostic factor associated with a 12.7 (95% CI 5–33) fold increase in the risk for death. Other factors associated with poor survival were elevated LDH ≥300 IU/L (HR=10.7, p=0.001), age >75 years (HR=5.37, p<0.001), baseline platelet counts <130,000/ml (HR=4.65, p=0.001) and ISS-3 (HR=3, p=0.007). In conclusion, in elderly patients (‘65 years) who are treated upfront with novel agents, short PFS (less than 12 months) is associated with a very poor outcome and a more than 12 –fold increase in the hazard of death. Probably due to the limited number of patients, we did not observe a statistically significant correlation of the depth of response with OS. However, a significantly lower percentage of patients who had achieved a CR experienced an early relapse. Our data indicate that salvage treatments for patients who fail to respond or progress early after frontline therapy with novel agent-based regimens may not be effective and new drugs and treatment strategies are needed. These patients should be encouraged to participate in clinical trials which investigate experimental agents and combinations.

Disclosures:
Dimopoulos: Ortho-Biotech: Honoraria; Celgene: Honoraria; Millennium: Honoraria.