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British Journal of Haematology May 2024Therapeutic strategies for patients with newly diagnosed multiple myeloma (NDMM) have considerably improved during the last 10 years. The IFM2014-03 trial proposed an...
Twice-weekly induction with ixazomib-lenalidomide-dexamethasone (IRd) combination followed by extended IRd consolidation and lenalidomide maintenance in transplant-eligible patients with newly diagnosed multiple myeloma: Results of the phase 2 study IFM2014-03.
Therapeutic strategies for patients with newly diagnosed multiple myeloma (NDMM) have considerably improved during the last 10 years. The IFM2014-03 trial proposed an all-oral triplet induction/consolidation regimen in transplant-eligible NDMM patients, followed by lenalidomide maintenance. Induction consisted of three 21-day cycles of ixazomib, lenalidomide and dexamethasone (IRd), before high-dose Melphalan with transplant followed by eight 28-day cycles of IRd consolidation before 13 cycles of lenalidomide maintenance. Forty-six patients were enrolled and received at least one dose of therapy, and 39 entered the maintenance phase. The primary end-point was stringent complete response after consolidation, and was achieved in nine patients (20.9%, 90% CI 11.4-33.7; p = 0.998). Ten patients (24.4%) had an undetectable minimal residual disease. The overall response rate was 95.7%. The 3-year progression-free survival was 66.3%. No unexpected toxicities were recorded, and only eight patients suspended from any study drug. Of note, 21 (45.7%) patients reported peripheral neuropathy (PN) (grades 1-2 with no serious adverse events). IRd induction and consolidation with transplant before lenalidomide maintenance shows lower response rates compared to other triplet therapies. It could be an alternative for patients who require an all-oral regimen and/or with pre-existent PN, especially if quadruplet regimens including anti-CD38 antibody are not available.
PubMed: 38811169
DOI: 10.1111/bjh.19570 -
Frontiers in Oncology 2024Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) are a widely used high-dose chemotherapy regimen for autologous stem cell transplantation transplant...
INTRODUCTION
Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) are a widely used high-dose chemotherapy regimen for autologous stem cell transplantation transplant (ASCT) in lymphoid malignancies. During BCNU shortages, some centers switched to fotemustine-substituted BEAM (FEAM). Neutropenic enterocolitis (NEC) is a life-threatening complication occurring after intestinal mucosa damage related to intensive chemotherapy. NEC mortality may be up to 30%-50%. In our study, we compared NEC incidence, symptoms, mortality, and transplant outcome in terms of overall survival (OS) and progression-free survival (PFS) in the BEAM . FEAM groups. Furthermore, we compared the cost of hospitalization of patients who did . patients who did not experience a NEC episode (NECe).
METHODS
A total of 191 patients were enrolled in this study (N = 129 and N = 62 were conditioned with BEAM and FEAM, respectively). All patients received bed-side high-resolution ultrasound (US) for NEC diagnosis.
RESULTS AND DISCUSSION
NEC incidence and NEC-related mortality were similar in the BEAM and FEAM groups (31% and 40.3%, p = 0.653, and 5% and 8%, p = 0.627, respectively). At a median follow-up of 116 months, no difference was noted between BEAM . FEAM groups in terms of OS and PFS (p = 0.181 and p = 0.978, respectively). BEAM appeared equivalent to FEAM in terms of NEC incidence and efficacy. The high incidence of NEC and the low mortality is related to a timely US diagnosis and prompt treatment. US knowledge in NEC diagnosis allows to have comparable days of hospitalization of patients NECpos . patients NECneg. The cost analysis of NECpos . NECneg has been also performed.
PubMed: 38803538
DOI: 10.3389/fonc.2024.1369601 -
British Journal of Haematology May 2024This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan-based reduced intensity conditioning (RIC) haematopoietic stem cell...
Haematopoietic stem cell transplantation after reduced intensity conditioning in children and adolescents with chronic myeloid leukaemia: A prospective multicentre trial of the I-BFM Study Group.
This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty-two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first- or second-generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1-guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second-year post-transplant. All patients engrafted. The 1-year transplant-related mortality was 3% (confidence interval [CI]: 0%-6%). After a median follow-up of 6.3 years, 5-year overall survival and event-free survival are 97% (CI: 93%-100%) and 91% (CI: 79%-100%) respectively. The current 5-year leukaemia-free survival with BCR::ABL1 <0.01% is 97% (CI: 88%-100%) and the current TKI- and DLI-free survival is 95% (CI: 85%-100%). The incidence of chronic graft-versus-host disease (GvHD) was 32%, being severe in four patients (13%). At last follow-up, 31 patients are GvHD-free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP-CML with an excellent disease-free and TKI-free survival.
PubMed: 38803040
DOI: 10.1111/bjh.19535 -
Journal of Personalized Medicine Apr 2024Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective...
BACKGROUND
Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective immunotherapy (IT), such as immune checkpoint inhibitors, has changed the treatment landscape.
METHODS
This study evaluated the role of the association between ILP and IT in the treatment of locally advanced unresectable melanoma, particularly in relation to modern systemic therapies. We analyzed 187 consecutive patients who were treated with ILP (melphalan or melphalan associated with TNF-alpha) for advanced melanoma at the Veneto Institute of Oncology of Padua (Italy) and the Padua University Hospital (Italy) between June 1989 and September 2021. Overall survival (OS), disease-specific survival (DSS), local disease-free survival (local DFS) and distant disease-free survival (distant DFS) were evaluated. Local toxicity was classified according to the Wieberdink scale and surgical complications according to the Clavien-Dindo classification. Response to locoregional therapy was evaluated during follow-up according to the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumor).
RESULTS
A total of 99 patients were treated with ILP and 88 with IT + ILP. The overall response rate was 67% in both groups. At 36 months, OS was 43% in the ILP group and 61% in the ILP + IT group ( = 0.02); DSS was 43% in the ILP group and 64% in the ILP + IT group ( = 0.02); local DFS was the 37% in ILP group and 53% in the ILP + IT group ( = 0.04); and distant DFS was 33% in the ILP group and 35% in the ILP + IT group ( = 0.40). Adjusting for age and lymph node involvement, receiving ILP + IT was associated with improved OS ( = 0.01) and DSS ( = 0.007) but not local DFS ( = 0.13) and distant DFS ( = 0.21).
CONCLUSIONS
Our findings confirm the synergy between ILP and IT. ILP remains a valuable loco-regional treatment option in the era of effective systemic treatments. Further studies are needed to establish the optimal combination of loco-regional and systemic treatments and address the best timing of this combination to obtain the highest local response rate.
PubMed: 38793023
DOI: 10.3390/jpm14050442 -
Cancers May 2024(1) Background: Treosulfan and melphalan (TreoMel)-based high-dose chemotherapy (HDCT) has shown promising safety and efficacy as a conditioning regimen for acute...
(1) Background: Treosulfan and melphalan (TreoMel)-based high-dose chemotherapy (HDCT) has shown promising safety and efficacy as a conditioning regimen for acute myeloid leukemia (AML) patients undergoing autologous stem cell transplantation (ASCT). However, despite intensive first-line induction treatment and upfront consolidation with HDCT and ASCT, AML relapse rates are still high, and further efforts are needed to improve patient outcomes. The aim of this study was to compare two melphalan dose schedules in regard to the safety of TreoMel HDCT and patient outcomes. (2) Methods: We retrospectively analyzed the safety and efficacy of two melphalan dose schedules combined with standard-dose treosulfan in AML patients undergoing HDCT and ASCT at the University Hospital of Bern, Switzerland, between August 2019 and August 2023. Patients received treosulfan 42 g/m combined with either melphalan 140 mg/m (TreoMel 140) or melphalan 200 mg/m (TreoMel 200). Co-primary endpoints were progression-free survival (PFS), overall survival (OS), as well as safety profile. (3) Results: We included a total of 51 AML patients: 31 (60.8%) received TreoMel 140 and 20 (39.2%) TreoMel 200. The patients' basal characteristics were comparable between both cohorts. No significant differences in the duration of hospitalization or the adverse event profile were identified. There were no statistically significant differences in relapse (0.45 vs. 0.30, = 0.381) and mortality rates (0.42 vs. 0.15, = 0.064) between the melphalan 140 mg/m and 200 mg/m cohorts, nor for PFS (HR: 0.81, 95% CI: 0.29-2.28, = 0.70) or OS (HR: 0.70, 95% CI: 0.19-2.57, = 0.59) for the TreoMel 140 vs. TreoMel 200 cohort. (4) Conclusions: A higher dose of melphalan (TreoMel 200) was well tolerated overall. No statistically significant differences for patient outcomes could be observed, possibly due to the relatively small patient cohort and the short follow-up. A longer follow-up and prospective randomized studies would be required to confirm the safety profile and clinical benefit.
PubMed: 38791965
DOI: 10.3390/cancers16101887 -
Annals of Surgical Oncology May 2024
ASO Visual Abstract: Efficacy and Safety of Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter, Phase 3 Study.
PubMed: 38789613
DOI: 10.1245/s10434-024-15421-7 -
Cells May 2024Upfront high-dose therapy with melphalan (HDM) followed by autologous stem cell transplantation (ASCT) has established itself as a core treatment for newly diagnosed... (Review)
Review
Upfront high-dose therapy with melphalan (HDM) followed by autologous stem cell transplantation (ASCT) has established itself as a core treatment for newly diagnosed multiple myeloma (NDMM) patients in the past 30 years. Induction therapy, HDM-ASCT, and subsequent consolidation and maintenance therapy comprise the current fundamental framework for MM treatment. The introduction of anti-CD38 monoclonal antibodies such as daratumumab and isatuximab has changed the treatment paradigm for transplant-eligible NDMM patients in that quadruplets have become the new standard induction therapy. The treatment landscape of MM is undergoing a transformative shift with the introduction of potent new immunotherapies, such as chimeric antigen receptor (CAR)-T cells and bispecific antibodies (BsAbs), which are currently used in the relapsed/refractory setting (RRMM) and are already being tested in the NDMM. This review will focus on the incorporation of immunotherapy in the treatment scenario of NDMM patients eligible for ASCT.
Topics: Humans; Multiple Myeloma; Transplantation, Autologous; Immunotherapy; Hematopoietic Stem Cell Transplantation
PubMed: 38786075
DOI: 10.3390/cells13100853 -
ACS Omega May 2024Melphalan (Mel) is a potent alkylating agent utilized in chemotherapy treatments for a diverse range of malignancies. The need for its accurate and timely detection in...
Electrochemical Detection of Melphalan in Biological Fluids Using a g-CN@ND-COOH@MoSe Modified Electrode Complemented by Molecular Docking Studies with Cellular Tumor Antigen P53.
Melphalan (Mel) is a potent alkylating agent utilized in chemotherapy treatments for a diverse range of malignancies. The need for its accurate and timely detection in pharmaceutical preparations and biological samples is paramount to ensure optimized therapeutic efficacy and to monitor treatment progression. To address this critical need, our study introduced a cutting-edge electrochemical sensor. This device boasts a uniquely modified electrode crafted from graphitic carbon nitride (g-CN), decorated with activated nanodiamonds (ND-COOH) and molybdenum diselenide (MoSe), and specifically designed to detect Mel with unparalleled precision. Our rigorous testing employed advanced techniques such as cyclic voltammetry and differential pulse voltammetry. The outcomes were promising; the sensor consistently exhibited a linear response in the range of 0.5 to 12.5 μM. Even more impressively, the detection threshold was as low as 0.03 μM, highlighting its sensitivity. To further enhance our understanding of Mel's biological interactions, we turned to molecular docking studies. These studies primarily focused on Mel's interaction dynamics with the cellular tumor antigen P53, revealing a binding affinity of -5.0 kcal/mol. A fascinating observation was made when Mel was covalently conjugated with nanodiamond-COOH (ND-COOH). This conjugation resulted in a binding affinity that surged to -10.9 kcal/mol, clearly underscoring our sensor's superior detection capabilities. This observation also reinforced the wisdom behind incorporating ND-COOH in our electrode design. In conclusion, our sensor not only stands out in terms of sensitivity but also excels in selectivity and accuracy. By bridging electrochemical sensing with computational insights, our study illuminates Mel's intricate behavior, driving advancements in sensor technology and potentially revolutionizing cancer therapeutic strategies.
PubMed: 38764632
DOI: 10.1021/acsomega.4c00558 -
Clinical Cancer Research : An Official... May 2024
PubMed: 38745477
DOI: 10.1158/1078-0432.CCR-24-1089 -
International Immunopharmacology Jun 2024Multiple myeloma (MM), a malignancy of plasma cells, is an incurable disease that is characterized by the neoplastic proliferation of plasma cells leading to extensive... (Review)
Review
Multiple myeloma (MM), a malignancy of plasma cells, is an incurable disease that is characterized by the neoplastic proliferation of plasma cells leading to extensive skeletal destruction. This includes osteolytic lesions, osteopenia, and pathologic fractures. MM is clinically manifested through bone pain, renal insufficiency, hypercalcemia, anemia, and recurrent infections. Its prevalence and the need for effective treatment underscore the importance of this research. Recent advancements in MM therapy have been significant, particularly with the integration of daratumumab into first-line treatments. The use of daratumumab in regimens such as DRD (Daratumumab, Revlimid, Dexamethasone) and D-RVd (Daratumumab, Lenalidomide, Bortezomib, Dexamethasone) represents a paradigm shift in the treatment landscape. GRIFFIN and CASSIOPEIA trials have highlighted the efficacy of these regimens, particularly in prolonging progression-free survival and deepening patient responses. The shift from older regimens like MPV (Melphalan, Prednisone, Velcade) to more effective ones like DRD and RVD has been pivotal in treatment strategies. This review also focuses on the potential of Chimeric Antigen Receptor T-cell therapy and bispecific antibodies in MM. CAR-T therapy, which has shown success in other hematological malignancies, is being explored for its ability to specifically target MM cells. The latest clinical trials and research findings are analyzed to evaluate the efficacy and challenges of CAR-T therapy in MM. Additionally, the role of bispecific antibodies, which are designed to bind both cancer cells and T cells, is explored. These antibodies offer a unique mechanism that could complement the effects of CAR-T therapy.
Topics: Humans; Multiple Myeloma; Antibodies, Bispecific; Immunotherapy, Adoptive; Animals; Receptors, Chimeric Antigen
PubMed: 38733817
DOI: 10.1016/j.intimp.2024.112043