Retrospective Analysis of Infections In An Unselected Cohort of Patients with Multiple Myeloma Treated with Lenalidomide Combinations Therapies

Abstract 5135

IMiDs exert various effects on the immune system altering cytokine production, regulating T cell costimulation and enhancing NK cell cytotoxicity. Particularly, lenalidomide is 50000 times more potent than thalidomide in inhibiting tumour necrosis factor a (TNFa), playing an important role in immune response against bacterial and virus infection. Moreover, lenalidomide causes myelosuppression, mainly neutropenia, more often than thalidomide.

We assessed the incidence, type and major factors affecting infections in 127 patients with multiple myeloma (MM) receiving lenalidomide-based regimens. Median age was 67 years (range 40–88) and 53.5% were older than 65 years. Fifty-four patients (42.5%) had newly diagnosed MM whereas the remaining 73 (57.5%) had relapsed/refractory disease. Among this group, 67% of patients had previous received more than one line of therapy and 26% had undergone APSCT. ISS stage 2–3 and renal failure were recognized in 54.5% and 8.5% of patients, respectively, and 15% of them had a ECOG PS >= 2. Eighty patients (63%) received lenalidomide plus dexamethasone and 47 (37%) lenalidomide combined with steroids and chemotherapy. Median courses of lenalidomide administered was 6 (range 1–28). Nearly all patients (95%) received trimethoprim-sulfamethoxazole (TMP-SMZ) as prophylaxis for infections and granulocyte-colony stimulating factor was used according to guidelines.

Twenty-six patients (20.5%) developed infections resulting of grade 1–2 in 8 patients (6%) and 3–5 in the remaining 18 (14%). There were two deaths (1.5%) due to infections. Type of infection were: pneumonia in 15 (58%), upper respiratory tract infections in 3 (11.5%), FUO in 3 (11.5%), septic shock by gram-negative microorganisms in 2 (8%), cholecystitis in 2 (8%) and VZV infection in one (4%). Risk of grade 3–5 infection was 16% at 12 months; 62.5%, 69% and 94% of infections occurred at 3, 4 and 6 months, respectively. Univariate analysis showed that ISS 2–3 (16.5% vs 7%; p=0.017), creatinine > 2 mg/dl (23.5 vs 10.5%; p=0.087) and WBC < 4000/mcl (33% vs 12.7%: p=0.087) prior therapy were associated with development of severe infection, whereas all other variables as sex, age, PS, disease status, monoclonal component level, thrombocytopenia prior therapy, renal failure, type of therapy and number of prior lines of therapy did not affect infections. Multivariate analysis selected only ISS as factor affecting severe infection development. Particularly, the risk of grade 3–5 infections at 6 months was 18% in patients with ISS 2–3 if compared with 6% in those with ISS 1 (p=0.034). As regard outcome parameters, there was a trend for a longer PFS in patients without infection (median PFS = 8 vs 16 months in patients without infections; p=0.064); however, OS of patients developing infection was significantly shorter compared to that of patients who did not develop infections (median OS=26 vs 33 months; p=0.001). Multivariate analysis showed that infections significantly affected OS (HR=3.2; 95%CI=1.5–6.7; p=0.002) adjusted for age, PS, ISS, renal function and therapy with 2 or 3 drugs.

In clinical practice, infections represent a frequent complication in patients with MM receiving lenalidomide-based regimens, as reported in phase II-III trials. Respiratory infections accounted for a large majority (nearly 70%), although severe gram-negative septic shock should be taken into account in neutropenic patients. Nearly all patients who developed infections during the first 6 months of therapy and those with higher tumour burden have been found to be at higher risk.

In conclusion, a broader antibiotic prophylaxis (ie TMP-SFZ plus fluoroquinolones) should be taken into consideration to prevent severe infections and ameliorate final outcome of patients treated with lenalidomide.