Incidence and risk factors for infections in the real-world setting in newly diagnosed myeloma patients treated with modern induction regimens

Abstract Infections are a common cause of morbidity and mortality in patients with multiple myeloma (MM). Novel treatments have substantially improved the outcomes of MM patients; however, the risk of infectious complications continues to be significant. Data from clinical trials indicate some increase in the risk of infections, especially with recent drug combinations; however, patients in everyday clinical practice may be more vulnerable and may have more co-morbidities than those enrolled in clinical trials. Thus, in the real world setting the burden of infectious complications after the introduction of novel treatments has not been thoroughly evaluated. We aimed to describe the incidence and risk factors for infections in a modern cohort of newly diagnosed MM (NDMM) treated with modern regimens. The analysis included 541 consecutive NDMM patients that started treatment after 1/1/2020, in a single center (Department of Clinical Therapeutics, Athens, Greece). Grade (Gr)≥2 infections during the first 12 months of treatment were prospectively recorded in our database. All patients received prophylaxis with valacyclovir and >90% with TMP/SMX, per institutional guidelines. Prophylaxis with levofloxacin was not used routinely. No patient received immunoglobulin supplementation during induction. The level of polyclonal IgG in those with IgG myeloma was derived by extracting the monoclonal protein measured by densitometry from the total IgG. Time-to-infection was calculated from the start of treatment up to 12 months. The median patients' age was 67 (32-91) years; 56% were >65 and 54% were female. IgG MM was reported in 60% of patients, IgA in 22% and light chain only in 17%; 32% had polyclonal IgG level <400 mg/dL; 71% had IgA <70 mg/dL and 82% IgM <40 mg/dL; 89% had immunoparesis in at least one of the polyclonal IgG, IgA or IgM. Induction therapy contained a PI in 77%, lenalidomide in 77%, VRd in 54%, and 41% received anti-CD38 MoAb containing regimen. At least one Gr≥2 infection was recorded in 168 (31%) patients. The cumulative 3-, 6- and 12-month infection rate was 14%, 20% and 29%, respectively, indicating a higher risk early after starting therapy. Most infections were Gr 2; Gr≥3 infections occurred in 56 (10.3%) including Gr 5 in 17 (3.1%) patients. The most common sites were lower (N=57) and upper respiratory tract infections (N=19), urinary tract infections (N=16), COVID-19 (N=45) and bloodstream infections NOS (N=10). We focused on various factors for their association with higher risk of Gr≥3 infections. In univariate analysis, advanced disease stage [ISS-3 (p<0.001), R2-ISS (p=0.021), R-ISS (p=0.001)], severe renal dysfunction [eGFR<30 ml/min/1.73 m2, (p<0.001)], poor performance status (PS>1, p<0.001), serum albumin<3.5 gr/dl (p=0.009) were associated with significantly higher risk of Gr≥3 infection. Patients age (either >65 or >75 years), polyclonal IgG<400 mg/dL or immunoparesis of 1 or 2 uninvolved Igs were not associated with a significantly higher risk of Gr≥3 infection. Notably, induction with VRd (p=0.001) and use of lenalidomide-based regimens (p<0.001) were associated with lower risk, while anti-CD38 MoAbs did not increase the risk of Gr≥3 infection in our cohort (p=0.201). However, in a sensitivity analysis, there was a significant interaction of treatment type with age, severity of renal dysfunction, ISS-3 stage and ECOG-PS (p<0.001). In multivariate analysis, eGFR<30 ml/min/1.73 m2 (HR: 2.55, p=0.011) and PS >1 (HR: 4.3, p<0.001) remained the most important prognostic factors associated with Gr ≥3 infection risk. We formulated a score with these 2 factors so that the 3-month cumulative incidence of Gr≥3 infection was 1% vs 10% vs 25%, when none, one or both risk factors were present, respectively. The corresponding 6- and 12- month risk was 2% vs 14% vs 31% and 4% vs 33% vs 36%. This score also classified patients in three different risk groups across all induction regimens (with or without anti-CD38, VRD, PI or lenalidomide) and among different age groups (p<0.001 in all).In summary, infections remain a significant risk in NDMM treated with modern regimens. Patient-related factors (renal dysfunction and poor PS) identify those at significant risk for serious infections but, importantly, more effective modern induction regimens do not significantly increase this risk in the short term. For high-risk patients, preventive strategies and early infection recognition and management are crucial.