EARLY MORTALITY IN ELDERLY NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS TREATED WITH NOVEL AGENTS: A POOLED ANALYSIS OF TWO LARGE RANDOMIZED PHASE III TRIALS

Background
Early mortality in elderly multiple myeloma (MM) patients is usually attributed to combined effects of active disease and co-morbid factors. Before the introduction of novel agents, toxic deaths within 60 days from start of conventional treatment occurred in 10% of patients (Augustson BM. J Clin Oncol 2005, 36:9219), mainly due to infection and renal failure. The use of novel agents has considerably improved MM outcome at the expense of newer toxicity.

Aims
The aim of this analysis is to study early deaths not related to disease progression during treatments with lenalidomide or bortezomib. We analyzed individual patient data from two large multicenter randomized trials to assess the rate and the causes of death, their predictability and whether current management strategies have reduced their frequency.

Methods
A total of 1,173 newly diagnosed MM patients ineligible for autologous transplantation due to age or co-morbidities  enrolled in the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) and European Myeloma Network (EMN) trials from May 2006 to September 2012, were studied. Patients in the GIMEMA MM-03-05 trial (N=511) received bortezomib-containing regimens (Palumbo A. J Clin Oncol 2014, 32:634) and those in the EMN01 trial (N=662) lenalidomide-containing regimens (Magarotto V. Blood 2014, abs ASH).

Results
A total of 1146 patients could be evaluated for this analysis. Within 24 months from start of therapy, 207/1146 patients (18%) died for any causes, 61/1146 (5%) died due to adverse events. Toxic deaths within 60 days occurred in 12 patients (1%) with a linear increase over time of 1% every 6 months (Figure 1). There was no difference in the incidence of toxic deaths between patients receiving bortezomib-containing regimens (31 pts, 6%) and those receiving lenalidomide-containing regimens (30 pts, 5%, p=0.32). The incidence of toxic deaths was significantly higher in patients older than 80 years (11/107 [10%], p=0.005). Twenty-nine percent of deaths were attributable to cardiac complications (18 pts), 18% to infections (17 pts) and 15% to vascular complications (9 pts). By comparing the cause of toxic deaths between the 2 different treatment regimes, there was no significant difference in the proportions of cardiac events, infections, vascular events or other causes. In a multivariate analysis, age (HR 1.09 per 1 year increase, p=0.002) and ISS score (HR 3.81, p=0.01 ISS 2 vs ISS 1; HR 5.69, p=0.002 ISS 3 vs ISS 1) did increase the risk of death but poor performance status did not (HR 1.25, p=0.59). Greater tumor burden and activity (ISS) increased the risk of death because such deaths occurred before the maximal beneficial effect of therapy in reducing tumor load: 92% of patients dying from toxicity within 2 months of start of therapy had achieved a suboptimal response (8 not available, 3 SD, 1 PR, ORR 8%).

Summary
Novel, more effective and more rapid therapies have reduced the risk of toxic deaths as compared to conventional treatments. Nevertheless one-third of early deaths occurred primarily due to cumulative specific drug-related toxicities. Improvement in supportive therapy together with prevention and prompt recognition/treatment of complications are urgently needed to reduce the risk of toxic deaths. The 2-fold higher risk of toxic mortality in octogenarians indicates the need for a careful assessment of frail patients who may benefit from a gentle or even palliative approach.

Keyword(s): Elderly, Imids, Mortality, Proteasome inhibitor

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