Upfront Treatment with Novel Agents Improves the Survival of Symptomatic Patients with Multiple Myeloma Who Are Older Than 65 Years

Abstract 1947

The introduction of novel agents and improvements in supportive care over the last years resulted in a significant improvement of the overall survival (OS) of myeloma patients (Brenner et al Blood 2008, Kumar et al Blood 2008, Kastritis et al Leukemia 2009). However, these retrospective studies indicated that this survival benefit was more pronounced in younger patients while in older patients there was only a marginal improvement in outcome. Randomized studies have shown that upfront use of thalidomide with melphalan and prednisone (MPT) offers superior progression free survival (PFS) than MP alone, and in some of these studies there was also a survival advantage. Bortezomib with MP was also superior to MP in a randomized study, both in terms of PFS and OS. However, these studies included selected patients that may not be representative of the general population of elderly patients with myeloma. Thus, we analyzed our database in order to assess the effect of the upfront use of novel agents (thalidomide, bortezomib, lenalidomide) in consecutive patients older than 65 who were treated 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. We included patients who started treatment from January 1995 to January 2010, i.e patients who received similar supportive care. All patients were included in the analysis, regardless of performance status, infections, comorbidities etc. Patients were divided in two groups: those who were treated upfront with conventional regimens (group A, N=76) and those who were treated upfront with novel agent-based regimens (group B, N=115). Demographics of the two groups of patients, including gender and age were similar. Performance status at presentation was also similar among the two groups: 56% of those treated upfront with conventional agents and 57% of those treated upfront with novel agents had an ECOG performance status of 2 or higher. Thirty per cent of patients in group A and 44% of patients in group B were older than 75 years, respectively (p=0.07). The presence of osteolytic bone disease (p=0.313), anemia (Hb <10 g/dl, p=0.139), low platelets (<130,000/ml, p=0.949), albumin <3.5 g/dl (p=0.661), elevated LDH ≥300 IU/L (p=0.412), levels of Bence Jones proteinuria (p=0123), heavy (p=0.220) and light chain isotype (p=0.837) were similar among the two groups. However, patients treated upfront with novel agents presented more often with renal impairment (creatinine ≥2 mg/dl in 29% vs. 16%, p=0.044) and had more often elevated beta2-microglobulin levels (p=0.046) and ISS-3 disease (49% vs. 32%, p=0.1). Response to first line treatment was similar for the two groups: 73% for patients treated with novel agents vs. 67% for patients treated with conventional regimens (p=0.371). The median survival of the patients who were treated with novel agent-based regimens was 47 months while it was 34 months for those who received conventional regimens, but this was not statistically significant (p=0.271). Early death rates (<3 months from the initiation of treatment) were 8% for those treated upfront with novel agents and 11% for those treated with conventional regimens. After adjustment for adverse prognostic factors, such as elevated beta2-microglobulin, renal impairment and advanced age, upfront use of novel agents was associated with a significant reduction in the risk of death (HR=0.621, p=0.029). Subsequently, we performed a multivariate analysis which included established adverse prognostic factors and the upfront use of novel drugs. In this analysis, upfront treatment with novel agents was independently associated with superior outcome and a reduced risk of death (HR=0.626, p=0.033). Other factors independently associated with adverse outcome were ISS stage (ISS-3: HR=2.64, ISS-2: HR=1.25, p=0.032), elevated LDH ≥300 IU/L (HR=3.5, p=0.002) and low platelet counts <130,000/ml (HR=1.68, p=0.038) and age >75 years (HR=2, p=0.002). We conclude that in the general population of elderly patients with MM the upfront use of novel agents is associated with improved survival.