In the Era of Novel Agents, Has Early Mortality in Older Patients Decreased?

While novel agents for the treatment of multiple myeloma (MM) have improved patient outcomes and extended survival, these agents are also associated with toxicities such as cardiac complications, infections, vascular complications.

To assess the rate and the causes of early toxic deaths in the novel treatment era, Alessandra Larocca, MD, from the University of Torino, Italy, and colleagues studied early deaths in a series of patients treated with novel agents from two phase III trials evaluating bortezomib- and lenalidomide-based treatment combinations. “Early mortality [or death within the first 24 months after diagnosis of MM] is due to the effects of active disease, comorbidities, and treatment-related complications,” wrote Dr. Larocca and co-authors. “With conventional chemotherapy, early toxic deaths were 10 percent in the first two months.”

They analyzed data for 1,173 patients with newly diagnosed MM who were enrolled in the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) and European Myeloma Network (EMN) trials from May 2006 to September 2012.

Overall, 511 patients received bortezomib-containing regimens and 662 patients received lenalidomide-containing regimens.

A total of 1,146 patients started therapy and could be evaluated in the current analysis. The authors found that death within 24 months of the start of therapy occurred in 207 patients (18%), among whom 61 (5%) died due to adverse events.

Twelve patients (1%) died due to toxicity within 60 days, and this rate increased over time by one percent every six months.

The most common reasons for early toxic deaths were:

  • Cardiac complications (30%; 18 patients)
  • Infections (28%; 17 patients)
  • Vascular complications (15%; 9 patients)

The researchers found that there was no difference in the incidence of toxic deaths according to treatment regimen, occurring in 31 patients (6%) who were treated with bortezomib-containing regimens and 30 patients (6%) who were treated with lenalidomide-containing regimens (p=0.32). In addition, there was no difference in the proportions of toxic events between the two types of regimens.

Dr. Larocca and colleagues identified two factors that were associated with a higher incidence of early toxic death: age >80 years (hazard ratio [HR] = 1.09 per 1-year increase; p=0.002) and tumor burden defined by the International Staging System (ISS) stage (ISS 2 vs. ISS 1: HR=3.81; p=0.01 and ISS 3 vs. ISS 1: HR=5.69; p=0.002). Poor performance status, however, was not a predictor of early death (HR=1.25; p=0.59).

“Novel agents have substantially reduced the risk of toxic deaths as compared to conventional therapy,” Dr. Larocca and colleagues concluded. “Nevertheless, one-third of early deaths occurred due to cumulative specific drug-related toxicities. The two-fold higher risk of toxic mortality in octogenarians indicates the need for a careful assessment of frailty to identify patients who may benefit from a gentler approach.”


Larocca A, Bringhen S, Petrucci MT, et al. Early mortality in elderly patients with newly diagnosed multiple myeloma treated with novel agents. Abstract OP-004. Presented at the 15th International Myeloma Workshop, September 23, 2015; Rome, Italy.