Background: MEL-ASCT is standard therapy for multiple myeloma (MM) but is associated with severe infections, at times life-threatening. Objective: To determine the risk factors for severe infection (bacteremia, septic shock, colitis, pneumonia) following MEL - ASCT for MM. Materials and Methods: 382 consecutive MM patients (pts) enrolled in our Total Therapy 2 protocol and who received their first MEL - ASCT between 10/1998 and 12/2002 were included. Variables evaluated included age, sex and MM remission status, severity of mucositis and others. Because of the known association between increased body iron stores and infection, pre-ASCT bone marrow (BM) iron stores were also evaluated. The AUC for severe neutropenia (<100 absolute neutrophils (ANC) / mL) was used as a single variable accounting for both the depth and duration of neutropenia. Results: Median age was 56 years (range: 30–76) and 235 pts (62 %) were males. Severe infections developed in 77 pts (20%) including pneumonia (42 pts). Pre-ASCT risk factors for infection by univariate analysis were increased BM iron stores (OR= 3.601; 95%CI 1.795–7.222; p<0.0007) and low platelets counts (OR for -1000 platelets/μL = 0.997; 95% CI 0.994 – 1; p=0.0381). Increased BM iron stores remained significant by multivariate analysis (OR= 3.601; 95% CI 1.795–7.222; p<0.0007). Post-ASCT risk factors that were significant by both univariate and multivariate analysis were severe mucositis (Grades 3–4 by NCI Common Toxicity Criteria) (OR=1.916; 95% 1.093–3.36; p=0.02) and AUC of severe neutropenia (OR= 1.001/unit; 95% 1–1.002; p=0.03). Neither the duration (days with ANC <1000 / mL) nor the depth of moderate neutropenia (AUC < 1000 neutrophils / mL) predicted infection. Conclusion: MM pts scheduled to undergo MEL - ASCT and who have increased BM iron stores, and those who develop severe mucositis and / or prolonged and profound neutropenia following ASCT should be considered at greater risk for developing severe infection. AUC of severe neutropenia is a useful single marker of both depth and duration of neutropenia and should be included in studies evaluating risk for infection in neutropenic pts.
Background: The importance of MEL dose intensity for patients (pts) with MM is supported by a survival benefit when MEL-ASCT is utilized. This survival advantage is further enhanced when tandem ASCT are applied, suggesting that higher MEL doses would be desirable if gastrointestinal mucositis, the dose limiting toxicity of MEL is not excessive. Objective: To identify the predictors of severe mucositis in MM pts undergoing MEL - ASCT. Patients and methods: 382 consecutive MM pts enrolled in our Total Therapy 2 protocol, who received their first MEL - ASCT between 10/1998 and 12/2002. A MEL dose of 200 mg/m2 BSA was utilized when serum creatinine was < 3 mg/dl (reduced to 140 mg/m2 if > 3 mg/dl). BSA was based on actual weight if < 60 kg or calculated weight if > 60 kg. Mucositis peak was graded 0–4 (NCI Common Toxicity Criteria). Potential covariates included among others age, sex, MM remission status, time period between last chemotherapy and MEL-ASCT, MEL dose in mg/kg, CMV serostatus, DLCO, creatinine clearance (CrCl). Results: BSA dosing of MEL resulted in a wide range of MEL,when calculated based on actual weight (2.5–6.4 mg/kg). Mucositis developed in 83 % of pts and was severe (Grades 3 & 4) in 23 %. By univariate analysis, the following pre-ASCT risk factors for mucositis were identified: lower BSA (OR 0.31/m2; 95% CI 0.111 – 0.881; p=0.027), lower platelet counts (OR 0.998/1000 platelets / mL; 95% CI 0.996 – 1; p=0.025), lower CrCl (OR 0.991/ml/min; 95% CI 0.985 – 0.998; p= 0.011), higher LDH (OR 1.007U/L, 95% CI 1.002 – 1.011; p=0.005), lower DLCO (OR 0.989/unit; 95% CI 0.978 – 1; p= 0.04) and CMV seropositivity (OR 1.51; 95% CI 1.002 – 2.29; p= 0.04). Multivariate analysis identified higher mg/kg MEL dose as the most important risk factor for mucositis (OR=1.58/mg/Kg; 95% CI 1.148 – 2.177; p= 0.005). Additional pre-ASCT risk factors included higher LDH (OR 1.006; 95% CI 1.001 – 1.012; p= 0.007), lower CrCl (OR= 0.991/ml/mn; 95% CI 0.984 – 0.999; p= 0.02), and lower DLCO (OR 0.989; 95% CI 0.978 – 1; p = 0.04). Using the intended mg/kg MEL dose, pre-ASCT CrCl, LDH and DLCO a predictive model for severe mucositis (grade 3 and 4) was developed based on ordinal logistic regression analysis: p= exp(−2.1527−0.00248*PLT−0.00894* CrCl + 0.00646*LDH−0.0114*DLCO + 0.4578* Mel) / [1+exp (−2.1527−0.00248*PLT−0.00894*CrCl + 0.00646*LDH − 0.0114* DLCO + 0.4578* Mel)] This model will be prospectively validated. Conclusions: Dosing MEL on the basis of BSA results in widely variable MEL exposure and risk for severe mucositis following MEL-ASCT. MM pts scheduled to receive MEL-ASCT using a high mg/kg MEL dose and whose pre-ASCT variables include low CrCl, high LDH and /or low DLCO should be considered at greater risk for severe mucositis following ASCT.
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