Risk of Early Severe Infections in Newly Diagnosed Multiple Myeloma Patients Treated with Novel Agents: A Pooled Analysis

Background. Infections represent a major cause of toxicity in newly diagnosed multiple myeloma (NDMM) patients, and their incidence is higher during the first 4 months of therapy (Dumontet, Leukemia 2018). The use of prophylactic levofloxacin for the first 3 months of therapy demonstrated to reduce rates of infections (Dryson, Lancet Hematol 2019). However, factors predicting the risk of infections in patients treated with novel agents and the need for antimicrobial prophylaxis for all vs selected patients remain under debate. We investigated the incidence of severe infections and associated baseline risk-factors in NDMM patients.

Methods. Data from Italian patients enrolled in clinical trials and receiving carfilzomib-based (IST-CAR-506, IST-CAR-561), bortezomib-based (EMN02) and lenalidomide-based (EMN01, RV-MM-PI-0752, RV-MM-EMN-441) treatment were pooled together and analyzed. The primary aim of the analysis was to evaluate the incidence of severe infections, defined as any grade (G) 3-5 event or G2 if involving the lung/lower respiratory tract (CTCAE version 4.0). The rate of early severe infections (i.e. infections occurring during the first 4 months of treatment) was also analyzed. Secondary goals were to identify baseline factors associated with an increased risk of early severe infections and to evaluate the impact of early severe infections on treatment outcome.

Results. A total of 1892 patients were included in the analysis. Median age was 65 years, 970 (51%) patients were transplant eligible (TE) and 922 (49%) transplant ineligible (NTE). Overall, 1059 (56%) patients received IMiD-based induction therapy and 833 (44%) a PI-based induction therapy. Median follow-up was 68 months. We recorded 898 infections of any grade, of which 436 (49%) were considered severe. Most frequent severe infections included lung/lower respiratory tract infection (50%), febrile neutropenia (23%) and sepsis/septic shock (10%). Overall, severe infections occurred when myeloma response to treatment was ≤PR in 62% of cases, VGPR in 29% and sCR/CR in 9%. 654 (35%) patients reported at least 1 infection of any grade and 377 (20%) patients at least one severe infection. Early infections (first 4 months) occurred in 243 patients (13%) and early severe infections in 129 patients (6.8%). Overall, 21 patients (1.1%) died due to infection, of whom 6 during the first 4 months. In a multivariate analysis (Table), main factors associated with increased risk of early severe infections were ISS stage 3 (OR 2.14, 95% CI 1.32-3.48), presence of del17p by FISH (OR 1.80, 95% CI 1.1-2.96), intermediate fit status (OR 1.88 95% CI 1.1-3.21) and frail status (OR 2.12, 95% CI 1.08-4.18) according to IMWG frailty score (Palumbo, Blood 2015). No difference in risk of early severe infections was observed according to induction treatment with PI vs IMiD (OR 1.10, 95%CI 0.68-1.78). In a time-dependent Cox regression analysis adjusted for potential confounders (age, RISS stage and performance status), the risk of disease progression/death was significantly higher in patients who had an early severe infection compared to patients without early severe infection (median PFS 21.3 months vs 31.3 months, HR 1.32, 95% CI 1.07-1.63, p<0.01). A significant impact was observed also on survival (median OS 45.8 vs 95.8 months respectively, HR 1.72, 95% CI 1.34-2.21, p<0.01).

Conclusions. We found that 34% of patients experiencing severe infections had the event during the first 4 months of therapy. Patients with aggressive disease and elderly frail patients are at higher risk of early severe infections, hampering treatment adherence and efficacy, and eventually affecting PFS and OS. Identifying patients more susceptible to severe infections through easily available parameters could pave the way for the evaluation of risk-adapted antimicrobial prophylaxis in clinical trials.