Financial Toxicity and Health-Related Quality of Life Profile of Patients With Hematologic Malignancies Treated in a Universal Health Care System.

PURPOSE: We investigated the association of financial toxicity (FT) with the health-related quality of life (HRQoL) profile of patients with hematologic malignancies treated in a universal health care system. METHODS: We did a secondary analysis of six multicenter studies enrolling patients with hematologic malignancies. FT was evaluated using the financial difficulties item of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Multivariable linear regression models were used to assess the mean differences in HRQoL scores between patients with or without FT, while adjusting for key potential confounding factors. We also examined the prevalence of clinically important problems and symptoms by the experience of FT, using established thresholds for the EORTC QLQ-C30. Multivariable binary logistic regression analysis was performed to explore the risk factors associated with FT. RESULTS: Overall, 1,847 patients were analyzed, of whom 441 (23.9%) reported FT. We observed statistically and clinically relevant worse scores for patients with FT compared with those without FT for all the EORTC QLQ-C30 scales. The three largest clinically relevant mean differences between patients with and without FT were observed in pain (∆ = 19.6 [95% CI, 15.7 to 23.5]; P < .001), social functioning (∆ = -18.9 [95% CI, -22.5 to -15.2]; P < .001), and role functioning (Δ = -17.7 [95% CI, -22.1 to -13.3]; P < .001). Patients with FT tended to report a higher prevalence of clinically important problems and symptoms across all EORTC QLQ-C30 scales. In the univariable and multivariable analyses, the presence of FT was associated with the presence of comorbidities, an Eastern Cooperative Oncology Group performance status ≥1, and not receiving a salary. CONCLUSION: Patients with hematologic malignancies treated in the setting of a universal health care system who experience FT have a worse HRQoL profile compared with those without FT.

Impact of minimal residual disease standardised assessment by FDG-PET/CT in transplant-eligible patients with newly diagnosed multiple myeloma enrolled in the imaging sub-study of the FORTE trial.

Background: 18F-FDG-PET/CT is the current standard technique to define minimal residual disease (MRD) outside the bone marrow (BM) in multiple myeloma (MM), recently standardised applying the Deauville scores (DS) to focal lesions (FS) and bone marrow uptake (BMS) and defining the complete metabolic response (CMR) as uptake below the liver background (DS <4). Methods: In this analysis, we aimed at confirming the role of CMR, and complementarity with BM multiparameter flow cytometry (MFC) at 10-5, in an independent cohort of newly diagnosed transplant-eligible MM patients previously enrolled in the phase II randomised FORTE trial. 109 of the 474 global patients enrolled in the trial between February 23, 2015, and April 5, 2017, who had paired PET/CT (performed at baseline [B] and preceding maintenance therapy [PM]) and MFC evaluation, were included in this analysis. Findings: At B, 93% of patients had focal lesions within the bones (FS ≥4 in 89%) and 99% increased BM uptake (BMS ≥4 in 61%). At PM, CMR was achieved in 63% of patients, which was a strong predictor for prolonged PFS in univariate analysis at landmark time PM (HR 0.40, P = 0.0065) and in Cox multivariate analysis (HR 0.31, P = 0.0023). Regarding OS, a trend in favour of CMR was present in univariate (HR 0.44, P = 0.094), and Cox multivariate model (HR 0.17, P = 0.0037). Patients achieving both PET/CT CMR and MFC negativity at PM showed significantly extended PFS in univariate (HR 0.45, P = 0.020) and multivariate analysis (HR 0.41, P = 0.015). Interpretation: We herein confirm the applicability and validity of DS criteria to define CMR and its prognostic relevance and complementarity with MFC at the BM level. Funding: Amgen, Celgene/Bristol Myers Squibb, Italian Ministry of Health (RC-2022-2773423).

Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights.

The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. Currently, the baseline risk is assessed using simple clinical and hematologic parameters, other than evaluating the presence of additional chromosomal abnormalities (ACAs), especially those at "high-risk". Beyond the onset, a re-evaluation of the risk status is mandatory, monitoring the response to TKI treatment. Moreover, novel critical insights are emerging into the role of genomic factors, present at diagnosis or evolving on therapy. This review presents the current knowledge regarding prognostic factors in CML and their potential role for an improved risk classification and a subsequent enhancement of therapeutic decisions and disease management.

Assessment of liver stiffness measurement and ultrasound findings change during inotuzumab ozogamicin cycles for relapsed or refractory acute lymphoblastic leukemia.

In adult patients, acute lymphoblastic leukemia (ALL) is a rare hematological cancer with a cure rate below 50% and frequent relapses. With traditional therapies, patients with relapsed or refractory (R/R) ALL have a survival that may be measured in months; in these patients, inotuzumab ozogamicin (IO) is an effective therapy. IO was linked to increased risk of veno-occlusive disease/sinusoid obstruction syndrome (VOD/SOS), liver injury, and various grade of liver-related complications during clinical trials and real-life settings; however, hepatologic monitoring protocol is not established in this population. In our institution, 21 patients who received IO (median of 6 doses of IO administered) for R/R ALL were prospectively followed for hepatologic surveillance, including clinical evaluation, ultrasonography, and liver stiffness measurement (LSM) biochemistry. After a median follow-up of 17.2 months, two SOS events were reported (both after allogeneic transplant) as IO potentially related clinically relevant adverse event. Mild alterations were reported in almost the totality of patients and moderate-severe liver biochemical alterations in a quarter of patients. Within biochemicals value, AST and ALP showed an augment related to IO administration. LSM linearly augmented for each IO course administered. Baseline LSM was related to liver-related changes, especially with the severity of portal hypertension (PH)-related complications. Pre-transplant LSM was higher in patients receiving IO when compared with a control cohort. PH-related complications were discovered in nearly 77% of patients, with clinically significant PH occurrence and development of ascites in 38% and 14%, respectively. This prospective experience constitutes the rationale to design a hepatologic monitoring program in patients receiving IO. LSM may be of pivotal importance in this program, constituting a rapid and effective screening that quantitatively correlates with liver alterations.

Minimal residual disease assessment by multiparameter flow cytometry in transplant-eligible myeloma in the EMN02/HOVON 95 MM trial.

Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10-4-10-5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p < 0.001), 5-year overall survival was 86% versus 69%, respectively (HR 0.41; p < 0.001). MRD negativity was associated with reduced risk of progression or death in all subgroups, including ISS-III (HR 0.37) and high-risk fluorescence in situ hybridization (FISH) patients (HR 0.38;). In the 1-year maintenance MRD population, 42% of MRD-positive patients at pre-maintenance became MRD-negative after lenalidomide exposure. In conclusion, MRD by MFC is a strong prognostic factor. Lenalidomide maintenance further improved MRD-negativity rate.

Expert review on soft-tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations.

In this review, two types of soft-tissue involvement in multiple myeloma are defined: (i) extramedullary (EMD) with haematogenous spread involving only soft tissues and (ii) paraskeletal (PS) with tumour masses arising from skeletal lesions. The incidence of EMD and PS plasmacytomas at diagnosis ranges from 1·7% to 4·5% and 7% to 34·4% respectively. EMD disease is often associated with high-risk cytogenetics, resistance to therapy and worse prognosis than in PS involvement. In patients with PS involvement a proteasome inhibitor-based regimen may be the best option followed by autologous stem cell transplantation (ASCT) in transplant eligible patients. In patients with EMD disease who are not eligible for ASCT, a proteasome inhibitor-based regimen such as lenalidomide-bortezomib-dexamethasone (RVD) may be the best option, while for those eligible for high-dose therapy a myeloma/lymphoma-like regimen such as bortezomib, thalidomide and dexamethasone (VTD)-RVD/cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) followed by SCT should be considered. In both EMD and PS disease at relapse many strategies have been tried, but this remains a high-unmet need population.

Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study.

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.

Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.

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.

Survival and years of life lost in different age cohorts of patients with multiple myeloma.

PURPOSE: To assess the impact of age on outcome and to analyze the projected years of life lost in patients with multiple myeloma. PATIENTS AND METHODS: Ten thousand five hundred forty-nine patients were evaluated; 6,996 patients were treated with conventional chemotherapy, and 3,553 patients were treated with high-dose therapy with autologous stem-cell transplantation. RESULTS: Mean observed and relative overall survival times in the entire cohort were 3.7 and 3.9 years, respectively. Observed survival decreased steadily from 6.4 years in patients younger than age 50 years to 2.5 years in patients > or = age 80 years. A similar decrease was noted for relative survival. Higher age correlated significantly with higher International Staging System (ISS) stage. Relative excess risk of death differed significantly between 10-year age cohorts beginning from age 40 years (P < .001 for age 50 to 59 v age 40 to 49, P < .001 for age 60 to 69 v age 50 to 59, P < .001 for age 70 to 79 v age 60 to 69, and P = .009 for age > or = 80 v 70 to 79). The average years of life lost per patient was 16.8 years in the entire patient cohort and decreased steadily from 36.1 years in patients younger than 40 years old to 4.6 years in patients > or = age 80 years. CONCLUSION: Age is associated with higher ISS stage and is an important risk factor for early mortality. Survival declined continuously by each decade from age 50 to age > or = 80 from more than 6 to less than 3 years. The average of years of life lost in patients with myeloma is higher than in many other cancers and amounts to more than 30 years in patients younger than 40 years old but decreases to less than 5 years in patients age 80 years or older.

A prospective comparison of 18F-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma.

BACKGROUND AND OBJECTIVES: Bone lesions in multiple myeloma (MM) have been traditionally detected by whole body X-ray (WBXR) survey although magnetic resonance imaging (MRI) has become the gold standard for detecting MM involvement of the spine and pelvis. The aim of this study was to compare a new technique, positron emission tomography (PET) with 18F fluorodeoxyglucose (FDG) integrated with computed tomography (18F-FDG PET-CT), with MRI and WBXR for baseline assessment of bone disease in MM. DESIGN AND METHODS: We prospectively compared 18F-FDG PET-CT, MRI of the spine-pelvis and WBXR in a series of 46 patients with newly diagnosed MM. In 23 patients who received up front autologous transplantation, we also compared post-treatment PET-CT scans with MR images of the spine and pelvis. RESULTS: Overall, PET-CT was superior to planar radiographs in 46% of patients, including 19% with negative WBXR. In 30% of patients, PET-CT scans of the spine and pelvis failed to show abnormal findings in areas in which MRI revealed an abnormal pattern of bone marrow involvement, more frequently of diffuse type. In contrast, in 35% of patients PET-CT enabled the detection of myelomatous lesions in areas which were out of the field of view of MRI. By combining MRI of the spine- pelvis and 18F-FDG PET-CT, the ability to detect sites of active MM, both medullary and extramedullary, was as high as 92%. Following transplantation, 15 patients had negative PET-CT scans (including 13 with a very good partial response or at least a near complete response), but only 8 had normal MRI. INTERPRETATION AND CONCLUSIONS: MRI of the spine and pelvis still remains the gold standard imaging technique for the detection of bone marrow involvement in MM. 18F-FDG PET-CT provides additional and valuable information for the assessment of myeloma bone disease in areas not covered by MRI.

Role of 18F-FDG PET/CT in the assessment of bone involvement in newly diagnosed multiple myeloma: preliminary results.

PURPOSE: Multiple myeloma (MM) is a malignant B cell and plasma cell disorder which involves the skeleton in more than 80% of patients at diagnosis. The aim of this study was to compare whole-body X-ray (WBXR), MRI and (18)F-FDG PET/CT in patients with MM. METHODS: The study population comprised 28 newly diagnosed MM patients. Findings of (18)F-FDG PET/CT were compared with those of WBXR and MRI with regard to the number and site of lesions detected. RESULTS: Comparing (18)F-FDG PET/CT and WBXR, it was found that in 16/28 pts (57%) (18)F-FDG PET/CT detected more lesions, all of which were located in the skeleton. Nine of these 16 patients had a completely negative WBXR survey. In 12/28 pts (43%) the two methods yielded equivalent findings. Comparing (18)F-FDG PET/CT and MRI, it was found that in 7/28 pts (25%), (18)F-FDG PET/CT detected more lytic bone lesions, all of which were located outside the field of view of MRI (bone lesions in six cases and a soft tissue lesion in one). In 14/28 pts (50%), (18)F-FDG PET/CT and MRI detected the same number of lesions in the spine and pelvis, while in 7/28 pts (25%) MRI detected an infiltrative pattern in the spine whereas (18)F-FDG PET/CT was negative. CONCLUSION: (18)F-FDG PET/CT appears to be more sensitive than WBXR for the detection of small lytic bone lesions, whereas it has the same sensitivity as MRI in detecting bone disease of the spine and pelvis. On the other hand, MRI may be superior to (18)F-FDG PET/CT in diagnosing an infiltrative pattern in the spine. Therefore, careful evaluation of MM bone disease at diagnosis should include both MRI of the spine and (18)F-FDG PET/CT.