Michela Ceccolini

Short-Term Thalidomide Incorporated Into Double Autologous Stem-Cell Transplantation Improves Outcomes in Comparison With Double Autotransplantation for Multiple Myeloma

PURPOSE To assess potential benefits with thalidomide incorporated into double autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS One hundred thirty-five patients who received thalidomide from induction until the second ASCT were retrospectively analyzed in comparison with an equal number of pair mates treated with double ASCT not including thalidomide. RESULTS On an intention-to-treat basis, the addition of thalidomide to double ASCT effected a significant improvement in the rate (68% v 49%; P = .001) and duration (62% v 33% at 4 years; P < .001) of at least very good partial response (VGPR), time to progression (TTP; 61% v 41% at 4 years; P < .001) and progression-free survival (PFS; 51% v 31% at 4 years; P = .001). A trend was also noted for extended overall survival (OS) among thalidomide-treated patients (69% at 5 years v 53% for the control group), although the difference between the two groups was not statistically significant (P = .07). Benefits with thalidomide in increasing the rate of VGPR or better response, TTP, and PFS were confirmed in a multivariate analysis. Median OS after relapse was 24 months for patients receiving thalidomide added to double ASCT and 25 months for the control group. Overall, 17% of patients discontinued thalidomide, including 8% because of drug-related adverse events. CONCLUSION In comparison with double ASCT, the addition of first-line thalidomide to double ASCT improved clinical outcomes. Short-term thalidomide was generally well tolerated and had no adverse impact on postrelapse survival.

First-line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma

Abstract:  Background: Bone involvement is frequently observed in multiple myeloma (MM) patients both at diagnosis and during the course of the disease. The evaluation of biochemical markers of bone turnover could allow a dynamic evaluation of the effects of a given therapy on bone metabolism. Methods:  In the present study, markers of bone resorption [urinary free pyridinoline (PYD), deoxypyridinoline (DPYD), N‐terminal telopeptide of collagen I (NTX) and C‐terminal telopeptide (serum crosslaps)] and of bone formation [bone alkaline phosphatase (BAP) and osteocalcin] were evaluated at diagnosis and after induction therapy in 40 patients (23M, 17F, median age = 53.5 yr) enrolled in the ‘Bologna 2002’ clinical trial. By study design, all patients received 4 months of combined thalidomide (100 mg/d for 2 wk then 200 mg/d), dexamethasone (40 mg/d on days 1–4, 9–12, 17–20/28 on odd cycles and on days 1–4 on even cycles) and zoledronic acid (4 mg/28 d). Results: At diagnosis, although bone resorption markers were increased in more than 40% of the patients, only NTX (P = 0.029) and crosslaps (P = 0.000) were significantly related to the extent of skeletal lesions, as assessed by X‐ray. After 4 months of therapy, a significant decrease in mean (±SE) urinary NTX (52.7 ±6.9 nmol/mmol creatinine ±6.9 vs. 14 ± 1.42 nmol/mmol creatinine, P = 0.000) and serum crosslaps (6242.4 ±945 pmol/L vs. 1414.9 ± 173.8 pmol/L, P = 0.000) was observed in patients obtaining ≥partial response, at variance to what has been detected in patients showing

Thalidomide-dexamethasone as induction therapy before autologous stem cell transplantation in patients with newly diagnosed multiple myeloma and renal insufficiency.

The aim of this study was to evaluate the efficacy and the toxicity of thalidomide-dexamethasone (Thal-Dex) as induction therapy before autologous peripheral blood stem cell (PBSC) transplantation in patients with newly diagnosed multiple myeloma (MM) with renal insufficiency. The study included 31 patients with a baseline creatinine clearance value <or=50 mL/min, 7 of whom required chronic hemodialysis. Patients received 4 months of Thal-Dex, followed by PBSC collection and subsequent transplantation. After induction, a partial response (PR) or greater was obtained in 23 patients (74%), including 8 (26%) who achieved a very good PR. Renal function improved more frequently in patients achieving a PR or greater (82%, vs 37% in patients achieving less than a PR; P = .04). Twenty-six patients underwent PBSC mobilization; in 17 of these patients (65%), >4 x 10(6) CD34(+) cells/kg were collected. Double autologous transplantation was performed in 15 patients, and a single autologous transplantation was performed in 7 patients. After a median of 32 months of follow-up, median event-free survival was 30 months, and median survival was not determined. According to our data, Thal-Dex is effective and safe in patients with newly diagnosed MM and renal insufficiency. Given the relationship between recovery of renal function and response to induction treatment, more intensive Thal + bortezomib regimens could be explored to rescue higher numbers of patients.

IL-17/IL-10 double-producing T cells: new link between infections, immunosuppression and acute myeloid leukemia

BackgroundAcute myeloid leukemia (AML) is an incurable disease with fatal infections or relapse being the main causes of death in most cases. In particular, the severe infections occurring in these patients before or during any treatment suggest an intrinsic alteration of the immune system. In this respect, IL-17-producing T helper (Th17) besides playing a key role in regulating inflammatory response, tumor growth and autoimmune diseases, have been shown to protect against bacterial and fungal pathogens. However, the role of Th17 cells in AML has not yet been clarified.MethodsT cell frequencies were assessed by flow cytometry in the peripheral blood of 30 newly diagnosed AML patients and 30 age-matched healthy volunteers. Cytokine production was determined before and after culture of T cells with either Candida Albicans or AML blasts. Statistical analyses were carried out using the paired and unpaired two-tailed Student’s t tests and confirmed with the non parametric Wilcoxon signed-rank test.ResultsA strong increase of Th17 cells producing immunosuppressive IL-10 was observed in AML patients compared with healthy donors. In addition, stimulation of AML-derived T cells with a Candida albicans antigen induced significantly lower IFN-γ production than that observed in healthy donors; intriguingly, depletion of patient Th17 cells restored IFN-γ production after stimulation. To address the role of AML blasts in inducing Th17 alterations, CD4+ cells from healthy donors were co-cultured with CD33+ blasts: data obtained showed that AML blasts induce in healthy donors levels of IL-10-producing Th17 cells similar to those observed in patients.ConclusionsIn AML patients altered Th17 cells actively cause an immunosuppressive state that may promote infections and probably tumor escape. Th17 cells could thus represent a new target to improve AML immunotherapy.

Cost of illness in patients with multiple myeloma in Italy: The CoMiM study

AIMS AND BACKGROUND Multiple myeloma is the second most common hematological cancer. Although it accounts for only a relatively small percentage of all cancer types, the costs associated with managing multiple myeloma are considerable. Available studies are mainly focused on health care costs. The Costo del Mieloma Multiplo (Cost of MM, CoMiM) study investigated the cost of illness of multiple myeloma in Italy during one year of disease management. METHODS CoMiM is a retrospective, prevalence-based, multi-center, cross-sectional study based on a stratified sample of patients seen during normal clinical practice (asymptomatic; symptomatic on drugs; symptomatic receiving autologous stem cell transplantation; plateau/remission). Demographics, clinical history, health care and non-health care resource consumption data were collected. Costs were evaluated from the societal viewpoint and expressed in Euro 2008. RESULTS Data on 236 patients were analyzed (39 asymptomatic, 17%; 29 symptomatic receiving autologous stem-cell transplantation, 12%; 105 symptomatic receiving drugs, 44%; 63 plateau/remission, 27%). The total cost of illness reached € 19,267.1 ± 25,078.6 (asymptomatic, € 959.3 ± 1091.6; symptomatic receiving drugs, € 21,707.8 ± 21,785.3; symptomatic receiving autologous stem-cell transplantation, € 59,243.7 ± 24,214.0; plateau/remission, € 8130.7 ± 15,092.5). The main cost drivers of total cost of illness were drugs and hospital admissions (46.1% and 29.4%, respectively). Antineoplastics and immunomodulators drove the cost of drugs (21.6% and 21.1% of the total cost of illness). Cost of antineoplastics was led by bortezomib (97.4%), whereas the cost driver for immunomodulators was lenalidomide (99.4%). Cost of hospitalization funded by the Italian National Health Service was strongly influenced by transplantation (94.6%), whereas chemotherapy and skeletal fractures did not exceed 1% and 2%, respectively. CONCLUSIONS Despite some limitations, the CoMiM study provides Italian health care decision-makers with an insight into the stratified cost of illness of multiple myeloma patients.

Evaluation of bone disease in multiple myeloma patients carrying the t(4;14) chromosomal translocation

T(4;14) chromosomal abnormality is one of the most adverse prognostic factors predicting for poor outcome in multiple myeloma (MM) patients. It has been recently suggested that bone disease, as evaluated by spinal magnetic resonance imaging (MRI), is relatively infrequent in these patients. In the present study, we aimed at further testing this hypothesis by analyzing the extent of whole bone involvement in patients showing t(4;14) chromosomal translocation as compared with negative patients. For this purpose, 53 consecutive newly diagnosed MM patients (35M, 18F, median age = 55 yr) underwent evaluation of total skeletal X‐ray, whole spine MRI, and at the same time, quantification of markers of bone resorption (urinary N‐terminal telopeptide, pyridinoline, deoxypyridinoline, serum crosslaps), and bone formation (bone alkaline phosphatase and osteocalcin) was performed. The presence of IgH/MMSET fusion gene as a surrogate marker for t(4;14), was detected in 11 patients (20.7%), whose clinical characteristics were similar to those observed in t(4;14) negative patients. The type of marrow involvement at spinal MRI (diffuse vs. focal vs. negative) was the same in both groups of patients, even though overt vertebral fractures were more frequently found in t(4;14) positive cases (82% vs. 43%, P = 0.05); in line with this finding, skeletal lesions were more common in t(4;14) positive patients (mean skeletal score = 8.54 ± 1.36 SE, as compared with 3.42 ± 0.57 SE in t(4;14) negative cases, P = 0.000). These data were confirmed by the evaluation of serum crosslaps, that were significantly increased in patients with t(4;14) abnormality as compared with negative individuals (10 400 pmol/L ± 2160 SE vs. 5640 pmol/L ± 859 SE P = 0.02) Our results indicate that, at variance to what has been previously reported, bone resorption is more prominent in t(4;14) positive patients.

A117 A Phase III Study of VMPT Versus VMP in Newly Diagnosed Elderly Myeloma Patients

8515 Background: In MM patients VMP is superior to MP. In relapsed-refractory patients the 4 drug combination VMPT induced a high proportion of complete responses (CR). METHODS 500 newly diagnosed MM patients ≥ 65 years were randomly assigned to receive VMPT (N=247) or VMP (N=253). Patients were treated with nine 5-week cycles of VMPT (bortezomib 1.3 mg/m2 days 1, 8, 15, 22; melphalan 9 mg/m2 days 1-4; prednisone 60 mg/m2 days 1-4 and thalidomide 50 mg days 1-35) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described). Primary end-point was progression-free survival (PFS). Assuming the hazard ratio (VMP vs VMPT) of 1.35, the total sample size is 500 (250/arm) subjects (power 80%, 2-side alpha 0.05). RESULTS 354 patients (median age 71 years), who received at least 1 cycle were evaluated: 177 VMPT and 177 VMP. Data were analyzed in intention-to-treat. The VGPR rate was 55% in the VMPT group and 45% in the VMP group (p<0.001). After a median follow-up of 14.5 months, the 3-year PFS was 74% in the VMPT group and 70% in the VMP group (HR=0.75, 95% CI 0.45-1.26, p=0.28). The 3-year overall survival (OS) was 88% in the VMPT group and 87% in the VMP group (HR=0.89, 95% CI 0.42-1.87, p=0.75). Subgroup analyses did not show any statistical difference between responses/PFS and either ISS or chromosomal abnormalities (t(4;14) or t(14;16) or del17) in both groups. Age > 75 years was associated with lower VGPR rate (p=0.02) in VMPT but not in VMP. Factors predictive of longer PFS were age ≤ 75 years (p=0.003) and the achievement of VGPR (p=0.0005) in VMPT but not in VMP. The incidence of grade 3-4 adverse events (AEs) was similar in both groups. In the VMPT patients and in the VMP patients, the more frequent AEs were neutropenia (36% vs 31%), thrombocytopenia (20% vs 19%), peripheral neuropathy (18% vs 12%) and infections (14% vs 10%), respectively. CONCLUSIONS VMPT is superior to VMP in terms of response rates. Longer follow-up is needed to assess their effects on PFS and OS. Both regimens appeared to overcome the poor prognosis of ISS and chromosomal abnormalities. An update of these data will be presented. [Table: see text].