Predicting Early Mortality in Multiple Myeloma Patients Treated with Novel Agents

BACKGROUND : Despite remarkable therapeutic advances in the last 2 decades and a major improvement in survival, a number of multiple myeloma (MM) patients (pts) present a short-term outcome. AIMS : Our aim was to identify the main factors (baseline characteristics, response to therapy, relapse features) determining early mortality (EM) among a cohort of newly diagnosed symptomatic MM pts treated with novel agents. METHODS : We conducted a national multicenter retrospective study, including a cohort of symptomatic MM pts diagnosed between January/2010 and June/2017, treated with novel agents (bortezomib, thalidomide or lenalidomide) with the maximum age of 75 years-old and living RESULTS : A total of 142 pts were included in the study, 58% male and the median age at diagnosis was 65 y (27-75). IgG was the most frequent subtype (41%), followed by IgA (32%) and light-chain κ (14%) and λ (9%). At diagnosis, renal impairment (RI) was present in 32%, extramedullary disease (EMD) in 18% and bone disease in 69% of the pts; 58.3% were in stage III and 30.6% in stage II (ISS). Fluorescent in situ hybridization analysis was performed in 76 pts, 45% presenting high-risk cytogenetic abnormalities (HRC) [del(17p) and/or t(4;14) and/or t(14;16)]. Hypertension was present at diagnosis in 32% and diabetes in 18% pts. First-line therapy (1 st L) included novel agents in 97% of the pts (64% bortezomib-based (Bor), 23% thalidomide-based (Thal) and 10% bortezomib plus IMID-based (BorIM). Response evaluation showed an overall response rate (ORR) of 73% (12% CR; 25% VGPR; 36% PR); 27% were refractory. Median time to response was 3.2m. Median number of therapy lines was 2 (1-3); 65% of the pts were refractory or progressed after 1 st L therapy, 18% developed extramedullary disease (EMD) and 5 pts progressed to plasma cell leukemia. In pts receiving a 2 nd L therapy, treatment-free interval was 9.2m and the most used regimens were lenalidomide (33%), Thal (25%), Bor (14%) and BorIM (11%) -based. ORR to 2 nd L was 19.5% (3.4% VGPR and 16.1% PR). Six-month, 1-year and 2-years mortality was 7%, 27% and 65%, respectively. Median time until death was 18.2m; 55% of the pts died directly from disease progression (DP) and 45% from other causes [infection in 68% (only 17% of whom in DP), and cardiovascular complications in 13%]. In our study, prior hypertension (HR 1.53; 95% CI 1.01-2.32; p=0.046) and relapse with EMD (HR 2.0; 95% CI 1.23-3.26; p=0.005) were associated with increased risk of death. Pts≥70y also showed an increased risk of death, although not statistically significant (HR 1.42; 95% CI 0.96-2.12; p=0.081). In our cohort, refractoriness to 1 st L treatment was not related to a significant increased risk of death (HR 1.48; 95% CI 0.91-2.40; p=0.11). Moreover, age, HRC, ISS stage, RI, bone disease and lactate dehydrogenase levels didn´t show a mortality predictive value. When comparing pts living nd L treatment (1.2 vs 10.0m; p=0.033) as predictors of death within the first 12m. Finally, in a multivariate analysis only the age at diagnosis >70y (HR 2.11; 95% CI 1.22-3.65; p=0.008) and EMD at relapse/progression (HR 2.55; 95% CI 1.45-4.50; p=0.001) predicted higher risk of mortality. CONCLUSIONS: ORR to 1 st L therapy was similar to the generally expected response rate, showing that IMWG response criteria are not adequate to predict short-term outcome in the era of novel agents. The same was observed with classical baseline risk stratification features, raising the importance of defining a more accurate strategy to predict survival in MM pts. Refractory disease after 2 nd L (higher than generally reported) and infections were the leading contributors to early death in our pts cohort. These data may provide new opportunities to define patient-adapted treatment strategies in order to decrease EM and improve overall survival in MM. Disclosures No relevant conflicts of interest to declare.